Usersclub

Home | Contact Us | Newsletter | Usersclub | Books | Audio Seminars

 

 

 

All seminars come with 10+ best practice documents, such as SOPs, checklists, master plans

 

Learning from Recent Warning Letters Related to GMP Laboratory Controls

For Preparation of FDA and International GMP Laboratory Inspections

Recorded, available at any time 

Recorded

Learning from Recent Warning Letters and 483's Related to Computer Validation and Part 11

With Case Studies to Avoid and Respond to 483's and Warning Letters

Recorded

 

Learning from Recent Warning Letters Related to Good Laboratory Practices

For Preparation of FDA and International GLP Inspections

Recorded, available at any time

 

Electronic Records

 

Periodic Review and Evaluation of Computer Systems

With strategies and tools for FDA and EU compliance

July 28, 2011

 

Understanding and Implementing the New Final EU Annex 11

Learn about specific requirements and get tools for implementation

Recorded

 

Understanding and Preparing for FDA's New Part 11 Inspection Program

With 10+ Best Practice Guides for Easy Implementation

Recorded

 

Electronic Raw Data in Regulated Environments

Definition, generation and archiving for FDA Part 11, HIPAA and SOX compliance

Recorded

 

FDA's 21 CFR Part 11

Introduction and Strategies and Tools for Implementation

Recorded

 

Cost Effective Electronic Data Archiving for FDA Compliance

Understanding and Implementing the New GAMP Guide

Recorded

 

Electronic Audit Trails for FDA Compliance
Requirements - Design - Implementation - Validation - Documentation

Recorded

 

FDA Compliant Electronic Records Management

Recorded

 

Using the SAFE Standard for Digital Signatures

For legally enforceable IP Protection, Electronic Transactions and FDA Submissions

Recorded

 

Auditing Computer Systems for Part 11 and Annex 11 Compliance

Prepare your organization for upcoming FDA and EU inspection

Recorded

Laboratories

 

LABORATORIES

 

Understanding the Updated USP Chapters 232/233 for Metal Impurities

With SOPs and Case Studies for Easy Implementation

Recorded

 

 

FDA Warning Letters, Form 483 Observations, Establishment Inspection Reports

Download more than 500 documents: SOPs, examples, templates, checklists, FDA waning letters, 483 inspectional observations, FDA and other official guidelines, presentations/publications from FDA personnel.

Important: Warning letters should be interpreted in the context of full content. Just looking at extracts may be misleading. And sometimes they include good advice from the FDA not mentioned in the extract.

 

 

W-308

Keywords: Data integrity, audit trail, complete records, acceptance criteria, sterility testing

  • Primary deviations
    No or inadequate audit trail, failure to follow adequate written procedures for the preparation of master production and control records designed to assure uniformity from batch to batch. (21 CFR 211.186(a)) , Failure to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records. (21 CFR 211.68(b))
    Failure to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards. (21 CFR 211.194(a))
     , missing acceptance criteria for sterility testing, or acceptance criteria for sterility testing not met

  • Examples
    - Your stand-alone computer systems lacked controls, such as routine audit trail review and full data retention, to prevent analysts from deleting data. Although you implemented a procedure to begin reviewing audit trails of your high performance liquid chromatography (HPLC) Empower system on January 11, 2016, you had not performed any reviews prior to our inspection. Furthermore, the procedure you implemented on January 11 required (b)(4) random audit trail review (b)(4)
    - We acknowledge your commitment to strengthening your procedures to assure user access restrictions and implement audit trails for computerized systems. However, simply activating audit trail functions and instituting user controls are insufficient to correct the data integrity problems observed at your facility and to prevent their recurrence.
    - In response to this letter, provide details of your retrospective review of the HPLC and other laboratory data, such as Fourier transform infrared spectroscopy, gas chromatography, UV spectrophotometry, and (b)(4) analyzer data. Indicate the period covered in your review and your rationale for selecting that timeframe

    - Our investigators found quality-related documents in a waste bin. Among these documents were an incomplete sterility test data sheet, a form used to track the movement of 
    (b)(4) samples, a media fill incubation card, and others. The incomplete sterility test data sheet had been filled out to track information about a “(b)(4)” sterility check. After an error was observed on the original data sheet, the record was torn and discarded with no written explanation
    -
    Our investigators observed colony counts for environmental and personnel monitoring that did not match your official records. For example, one contact plate from a Grade B area had a reported result of (b)(4) CFU, but our investigator counted (b)(4) CFUs on the plate. Five other plates had reported results of (b)(4) CFU, although our investigator counted (b)(4) CFU on each plate.

W-307

Keywords: cleaning procedures, quality unit, identity test, method validation, historical batches,

  1. Primary deviations
    Failure to have adequate cleaning procedures to prevent contamination or carry-over material that would alter API quality, quality unit does not exercise its responsibility to ensure the API manufactured at the facility are in compliance with CGMP, and meet established specifications for quality and purity.  production deviations not reported and evaluated, critical deviations not investigated and conclusions not recorded, failure to ensure that test procedures are scientifically sound and appropriate to ensure that your API conform to established standards of quality and/or purity.
  • Examples
    - Our investigator observed rust, insects, damaged interiors, and/or drug residues in (b)(4) of (b)(4) pieces of manufacturing equipment.
    - This equipment was identified as “clean” and was either in direct contact with API or could potentially contact API. Your deficient cleaning and maintenance practices present an unacceptable risk of introducing foreign contaminants, or cross-contamination between drugs.
    -Our investigator found that on June 30, 2014, batches (b)(4) and (b)(4) of (b)(4) United States Pharmacopeia (USP) API were released without testing by ultraviolet (UV) spectrometry for identity or (b)(4) content, because the UV was out of order.
    - Your change control form stated, “Batches shall be released on conditional basis and as soon as UV maintenance issue rectified analysis shall be performed for identification and (b)(4) content.”
    - Your June 30, 2014 certificate of analysis states “UV & (b)(4) result shall be updated.” However, our inspection found that identity and (b)(4) testing was never performed. It is unacceptable to distribute batches without conducting the required quality control tests to assure your API meets its quality attributes.
    - In your response, you state that your UV spectrophotometer broke down. Your quality department felt the quality of the released batches was adequate because
    other required release tests were passed, high performance liquid chromatography (HPLC) testing was done, and trend data for (b)(4) was satisfactory. Your response is inadequate.
    -Our investigator’s review of your 2014 and 2015 annual product quality reviews (APQR) revealed that your firm had eight critical process parameter failures related to time limits for (b)(4) or (b)(4) operations under (b)(4) conditions for (b)(4) USP API,
    - For example, batch (b)(4), Deviation Report D/PR/052/14 under Operation (b)(4) specifies that (b)(4) should be attained within (b)(4). However, the actual (b)(4) time was more than (b)(4). Furthermore, you failed to conduct adequate investigations into these significant deviations prior to making batch disposition decisions
    - In your Critical process parameters in manufacturing process of (b)(4) document, signed on February 19, 2016, you stated, “Under (b)(4) condition, (b)(4) degrades to give the (b)(4) material and (b)(4). The (b)(4) material and (b)(4) will react with (b)(4) to generate the (b)(4) impurity.” Failure to meet time limits for (b)(4) or (b)(4) operations could lead to inconsistent strength and purity.
    - Your response is inadequate. Although you attribute these failures to mechanical breakdowns and operator delays, your response lacks a comprehensive assessment of how these critical deviations affected your API quality 
    - During a review of your customer complaints, our investigator found a September 13, 2014, complaint concerning a batch of (b)(4) ((b)(4)) that failed water content. The specification range of (b)(4) water content was (b)(4)% to (b)(4)%. Although your firm measured (b)(4)% water content during the release of the batch, the complainant measured (b)(4)% water content.
    - Your retrospective analysis concluded that your firm’s laboratory reported lower water content results than your customer’s laboratory obtained for all (b)(4) batches of (b)(4) you supplied to the customer. Significantly, our inspection revealed that you had not validated your method for measuring water content
    - According to your response, you have completed method validation for water content. However, your response is inadequate because it does not detail your investigation into the released API batches tested using non-validated method.
    - In response to this letter, provide:
    - Retrospective review or retesting of all batches of (b)(4) that remain within retest period or expiry
    - A review of all test methods to ensure they are validated

W-306

Keywords: complete batch records, laboratory determination, stability, identity test studies

  • Primary deviations
    Inappropriate laboratory determination of satisfactory conformance to final specifications, no or insufficient to support expiration states, no or insufficient determination of the identity of components sourced from various suppliers, including your active ingredients, process parameters for batch records not definesd
  • Examples
    - You failed to sufficiently test batches for conformance to specifications. For example, out of approximately (b)(4) total batches of (b)(4) released in 2015, you tested only three batches for identity and strength, and two batches for microbiological quality
    - many of your drug products have expiration dates of without any supporting stability studies
    - you accepted and used active raw materials in your drug products based only on their appearance and odor
    - For example, your batch record for (b)(4) Gel product lot (b)(4) did not define and document process parameters to assure that the in-process materials and the finished drug product meets predetermined quality requirements.

W-305

Keywords: data integrity, remediation, incomplete records, uncontrolled cGMP forms

  • Primary deviations
    Original data stored in an “unofficial” and uncontrolled electronic spreadsheet on a shared computer network drive, no adequate quality control unit,
  • Examples
    -
    Our investigator observed many copies of uncontrolled blank and partially-completed CGMP forms (e.g., environmental monitoring recordings, OOS forms, water testing sheets, and clean room entry and exit logs) without any accountability or oversight of your quality unit
    - Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products
    - For example, a supervisor said he photocopied a blank OOS form and transcribed the information because he had made mistakes in the original document. Although your procedures required correcting mistakes on the original form, he made a new copy of a blank OOS form and rewrote the data.
    - Our investigator documented that your employees used paper shredders to destroy critical laboratory and production records without the appropriate controls and procedures. Shredded documents included High Performance Liquid Chromatography (HPLC) chromatograms and a partially-completed OOS form
  • Data Integrity Remediation

     Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. We strongly recommend that you retain a qualified consultant to assist in your remediation.

     

    In response to this letter, provide the following. 

    A.    A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include:

    ·         A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.

    ·         Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party.

    ·         An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses.

    ·         A comprehensive retrospective evaluation of the nature of the manufacturing and laboratory data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all data integrity lapses.

     

    B.    A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity, and risks posed by ongoing operations.

     

    C.    A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include:

    ·         A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all of the data you generate, including analytical data, manufacturing records, and all data submitted to FDA.

    ·         A comprehensive description of the root causes of your data integrity lapses, including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm.

    ·         Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.

    ·         Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company’s data

    .·         A-status report for any of the above activities already underway or completed. 

-304

Keywords: data integrity, training certificates, testing , authorized access

  • Primary deviations
    testing into compliance, records not completed contemporaneously , 
    analytical instruments not calibrated, qualified, or maintained appropriately, laboratory samples not adequately controlled, access to computer systems and data not limited to authorized individuals
  • Examples
    - Raw  materials, intermediates and finished analytical results found to be failing specifications or otherwise suspect (e.g., OOT) are retested until acceptable results are obtained. These failing or otherwise suspect results are not reported. Other observations included: 
    - Samples are not analyzed according to established laboratory test method procedures,
    - Selected injections were not reported in the official QC data package,
    - The stand-alone computerized system does not have sufficient controls to prevent unauthorized access to, changes to, or omission of data files and folders.
    - Records are not completed contemporaneously,
    - Laboratory samples are not adequately controlled to prevent mix-ups,
    - pH meter, Karl Fischer and analytical balances were not qualified, calibrated at and were not maintained at regular intervals.  regular interval
    - Laboratory samples were not adequately controlled to prevent mix-ups.
    - during our inspection of the QC analytical laboratory we observed one analysts back-date the working standard issuance

W-303

Keywords: data integrity, training, local language, excel, non-contemporaneous documentation, failure investigation, access to data, global response

  • Primary deviations
    non-contemporaneous documentation of batch production activities, uncontrolled excel spreadsheets used, missing records of equipment maintenance, Falsification and manipulation of employee training records, inadequate response, 
    Examples:inadequate failure investigation,  no access restrictions to laboratory data
  • Examples
    -Two uncontrolled Excel spreadsheets were used to record discrepancies and certain in-process drug quality data. This data was initially missing in the batch manufacturing record. Your firm later entered this data into batch records and backdated them
    - During interviews with our investigators, your contract employee who trains other contract employees on good documentation practices was unable to explain the material he was required to present during training. In addition, while a significant number of your contract employees do not speak English,
    You only provided English training materials to these employees
    - We also found an employee’s failing equipment qualification training assessment form in the trash, yet that employee’s official file showed passing results. According to your company policies, personnel with failing scores must be retrained, but your firm was unable to provide evidence of retraining in the employee’s official record
    -  On August 25, 2014, we found there were no access restrictions to laboratory data generated by the(b)(4) instrument used to test and release raw materials and in-process drug products. Your laboratory computer systems lack necessary controls to prevent data tampering and to detect data that may have been compromised
    - We acknowledge that you are in the process of qualifying a new (b)(4) instrument. However, your response is still inadequate; you failed to evaluate the effects of potentially compromised data on release decisions that rely on data generated by this uncontrolled system

    Recommendations from the FDA
    - These examples are serious CGMP deficiencies and violations. They demonstrate that your quality system does not adequately ensure the accuracy and integrity of data generated and available at your facility. We strongly recommend that you hire a qualified third party auditor/consultant with experience in detecting data integrity problems to help you come into compliance with CGMP regulations and statutory authorities
    In your response to this letter, provide the following
    -
    A comprehensive investigation and evaluation. Describe your methodology. Results should include conclusions about the extent of data integrity deficiencies and their root causes, which may involve record control, contemporaneous recording, deletion of data, and other data integrity deficiencies
    - A risk assessment of how the observed deficiencies may affect the reliability and completeness of quality information available for your drug products. Also determine the consequences of your deficient documentation practices on the quality of drug products released for distribution.
    • A management strategy that includes a detailed global corrective action and preventive action plan
    - Describe the corrective actions you will take, such as contacting your customers, recalling product, conducting additional testing and/or adding lots to your stability programs to assure stability, monitoring complaints, or other steps to assure the quality of your products manufactured under the violative conditions discussed above
    - Describe the preventive actions you will take, such as revising procedures, implementing new controls, training or re-training personnel, or other steps to prevent the recurrence of CGMP violations, including breaches of data integrity.

W-302

Keywords: Integrity, CAPA, Risk assessment, Complete Records, limited autorized access, missing raw data, audit trail, back-dating records, trial injections

  • Primary deviations
    1.Failure to ensure that laboratory records included complete data, missing meta data, 2. Failure to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records
  • Examples
    - During the inspection, your management acknowledged that employees in your QC laboratories conduct trial HPLC injections prior to the injections submitted as the reported test results. These trial injection data files were stored on separate drives from the reported test result data. In some cases original data files were deleted. The results from these trial injections and other original data were not reported. Our investigator found the following examples:
    - a. A QC analyst injected eleven identically or similarly named samples for impurity and assay analysis approximately one to fifteen seconds apart from one another, according to the HPLC audit trail for (b)(4) DMF submission batches (b)(4) and (b)(4). A second analyst injected eight similarly named impurity and assay samples approximately twelve to sixteen seconds apart, according to the HPLC audit trail for the analysis of (b)(4) batches (b)(4) and (b)(4). Neither analyst reported all results obtained during testing. The laboratory incident reports concluded the first analyst deleted 28 original files due to pressure fluctuations and ghost peaks, while the second analyst deleted original trial injections of working standard and sample testing data due to a problem associated with peak shape. However, your laboratory incident reports provide no evidence to support these conclusions. Both analysts also changed the clock prior to reanalyzing the samples.
    - b. A QC analyst injected sample P140818008.lcd for the assay analysis of (b)(4) (batch (b)(4)) prior to the reported sample injections. The “trials” [sic] folder where the original sample injection file was saved had been deleted. Your response acknowledges that an analyst deleted eight injections, including the blank, six standards, and a sample.
    - c. A QC analyst deleted original test method validation data and admitted plans to fabricate sample preparation data. According to the HPLC audit trail, on October 7 and 8, the QC analyst injected two sets of similarly named samples of (b)(4) (#1:P141007001.lcd and #1:P 141007001.lcd) for an impurity analysis method validation study. Your analyst deleted data from the first set of injections and submitted only the second set in the validation documentation. The analyst stated that he planned to back-date the preparation data within the worksheets once all testing was complete. However, aside from balance scale tickets, your firm was unable to provide sample preparation data for either sample. Your response states that you abandoned the method validation study, but you continue to use that method for routine testing. In response to this letter, provide the method validation study that supports your current method for analyzing impurities in (b)(4).
    - d. You did not include metadata with audit trails in your (b)(4) data back-up. In November 2014 the system for HPLC #025 crashed and lost all data collected on the instrument, including audit trail information. We acknowledge that you have implemented (b)(4) and (b)(4) system back-ups. In your response to this letter, provide a copy of the associated procedures and details on how the back-ups are performed.
    - e. Prior to October 2014, your gas chromatography instrument sent injection data to PCs without audit trails. The instrument logbook documented analyses that did not appear in the audit trail after your firm said it turned on the audit trail function. Your response does not explain the missing injection data. In response to this letter, compare the logbook and the audit trail and provide an explanation for the discrepancies identified during the inspection.
    - f. A QC analyst injected sample (b)(4)141119009 for the assay analysis of (b)(4) batch (b)(4), prior to the reported sample injection. The trial injection was stored in the “trails” [sic] folder located on a personal computer. The release chromatogram identified injection (b)(4)141119009 as the sample. The trial and release chromatograms for (b)(4)141119009 do not match, and they identify different peaks. Your response concluded trial injection (b)(4)141119009 was a blank. However, the chromatogram for (b)(4)141119009, collected during the inspection, shows (b)(4) peaks. You do not explain or provide evidence for how you concluded that this injection was a blank. Furthermore, your response includes a chromatogram for trial injection (b)(4)141119009 that differs from the chromatogram our investigator collected. It appears to have been reintegrated; the y-axis scale was changed, and only two of the original (b)(4) peaks can be seen.
    When analysts delete nonconforming test results, the quality unit is presented with incomplete and inaccurate information about the quality of the products. None of your explanations justify your failure to maintain complete records, nor do they support your practice of repeating tests or deleting test results..

    2. During the inspection, our investigator reviewed data from your high performance liquid chromatography (HPLC) analysis for release testing, including assay and impurity testing. Your quality control analysts used administrator privileges to change the controls for the time and date settings and manipulate file names to overwrite injections and delete original HPLC test data. Analysts also routinely turned HPLC audit trails on and off. Your response acknowledges these practices.

    During the inspection the investigator also noted the following examples of uncontrolled access to electronic systems used to generate data:

    a. None of the (b)(4) HPLC instruments in your QC laboratory required user-specific log-in names and passwords. Analysts routinely logged in as “Admin” without a password. Your response failed to provide a detailed description of the user roles and responsibilities associated with each instrument in your QC laboratory. In your response to this letter, provide procedures that address user roles and associated privileges for your laboratory instruments.

    b. Laboratory data generated by the Karl Fischer autotitrator was not restricted. The program used to run your autotitrator, Tiamo™ 2.3 Light, is unable to record audit trails and cannot support accounts with unique user names and passwords for individual users. We acknowledge your commitment to upgrade to a compliant software package. However, your response is inadequate because you failed to provide an interim solution prior to its installation. In your response to this letter, provide a copy of the performance qualification and training activities associated with the newly purchased software.

    c. Your analysts created separate folders on personal computers to store data from trial HPLC injections. For example, during the inspection, our investigator found a data folder labeled “trails” [sic]. In response to this letter, provide an assessment of the content of these folders and an evaluation of results that may not have been investigated.

    We acknowledge your commitment to set up user access restrictions, discontinue the practice of trial injections, and to institute audit trails for computerized systems. Simply activating audit trail functions and instituting user controls are insufficient to correct the broad data manipulation and deletion problems observed at your facility and to prevent their recurrence. Your response is inadequate because the functions and administrative privileges of the IT Head, QC Head, and other personnel remain unclear. In your response, clarify the specific user roles and associated privileges for each laboratory system, and provide an assessment of the effectiveness of these newly implemented system controls. Also provide a comprehensive assessment of other updates made to your computerized systems.

    Recommendations from the FDA

    - In response to this letter, provide the following.

    1. A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include:
    • A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.
    • Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party.
    • An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses.
    • A comprehensive retrospective evaluation of the nature of the testing and manufacturing data integrity deficiencies. We recommend that you engage a qualified third-party consultant with specific expertise in the areas where potential breaches were identified to evaluate all data integrity lapses.

    2. A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity, and risks posed by ongoing operations.

    3. A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include:
    • A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all of the data you generate, including analytical data, manufacturing records, and all data submitted to FDA.
    • A comprehensive description of the root causes of your data integrity lapses, including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm.
    • Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.
    • Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company’s data.
    • A status report for any of the above activities that are already underway or completed.
    The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations.

 

W-301

Keywords: data integrity, complete record, past shipments, facilities, equipment, maintenance

  • Primary deviations
    Failure to maintain complete data of analytical test records, failure to investigate past shipments for incomplete test records, failure to properly maintain facilities and equipment, inadequate response.
  • Examples- 
    -Failure to properly maintain, repair, and keep clean buildings used in the manufacture of APIs in a manner that prevents contamination where open equipment is used. For example, Gaps and holes in outside walls for piping and air ducts which allow contaminants to enter the building
    -
    Failure to properly maintain equipment used in the manufacture of APIs and minimize the risk of contamination, where open equipment is used. For example: Our investigator observed rust, dirt, lubrication leaks, and exposed insulation material on and around open drug manufacturing equipment
    - Failure to maintain complete data derived from all testing and to ensure conformance with established specifications and standards, for example, for analytical test records the name of the analysts performing the tests and the name of the second person reviewing the test results were missing. In addition, no heavy metal analysis was performed
    - Your response failed to specify whether any lots were released that lacked complete analytical testing information, either because the test was not performed or the data was not recorded. You also did not indicate if any lot was released without a secondary review of results to ensure compliance with established standard

 

W-300

Keywords: Raw data, backdating, access to data, deletion of data, data change. audit trail, training, contemporaneous

  • Primary deviations
    Failure to record activities at the time they are performed (not contemporaneous), the batch records do not demonstrate that you completed your required review before releasing your products. destruction of original records, backdating of batch records, failure to prevent unauthorized access or changes to data, no on-the-job training, trainings not recorded, data system lacks electronic audit trail function
  • Examples- 
    - Our investigators found that some of your operators used “rough notes” (unbound, uncontrolled loose paper) to capture critical manufacturing data and then destroyed these original records after transcription into the batch production records
    - One chemist recorded original manufacturing data as rough notes and left these rough notes for the second chemist to transcribe into the batch production records. The next morning, the chemist signed the batch production records and destroyed the original rough notes. We interviewed employees during the inspection who confirmed your firm’s practice of transcribing data to batch records and destroying original records.
    - Our investigators found backdated batch production records dated February 10 to February 25, 2014, signed by your Production Manager and Technical Director in the “Batch Manufacturing Record Reviewed by” section. The Technical Director stated that he was not in the facility on these dates and was “countersigning” for another person who allegedly performed these review activities. However, these records did not contain signatures (contemporaneous or otherwise) of the alternate reviewer who purportedly conducted the review. Furthermore, the Technical Director backdated his own signature to the date the quality unit (QU) reviewed and released your drug product. His backdated signatures are on (b)(4) batch records for lots (b)(4); and (b)(4) batch records for lots (b)(4). You released these batches before the Technical Director returned to the facility and backdated his signatures. The batch records, therefore, do not demonstrate that you completed your required review before releasing your products. You did not distribute these lots to the United States. However, your failure to assure proper review of production and control records before product release raises questions about the authenticity and reliability of your data and the quality of the APIs you produce for the U.S. market.
    - Your laboratory systems lacked access controls to prevent raw data from being deleted or altered. There is no assurance that you maintain complete electronic raw data for your Gas Chromatography (GC) instrument. FDA investigators observed multiple copies of raw data files in the recycle bin connected to the GC instrument QC-04 even in the presence of “Do Not Delete Any Data” notes posted on two laboratory workstation computer monitors.
    - Employees were allowed uncontrolled access to operating systems and data acquisition software tracking residual solvent, and test and moisture content. Our investigators noted that there was no password functionality to log into the operating system or the data acquisition software for the GC, the High Performance Liquid Chromatography (HPLC) instrument QC-17, or the Karl Fischer (KF) Titrator QC-13.
    - In your response, you state that your laboratory GC, HPLC and KF systems are now password-protected and that you have begun drafting analytical software password procedures for the GC, HPLC and KF laboratory instruments. However, your response does not state whether every analyst will have their own user identification and password. You also mention plans to install a validated computer system. However, you did not provide a detailed corrective action and preventive action (CAPA) plan or conduct a review of the reliability of your historical data to ensure the quality of your products distributed to the U.S. market.
    - HPLC SpinChrome and GC Lab Station data acquisition software lacked active audit trail functions to record changes in data, including original results, who made changes, and when
    - In your response, you state that your laboratory GC, HPLC and KF systems are now password-protected and that you have begun drafting analytical software password procedures for the GC, HPLC and KF laboratory instruments. However, your response does not state whether every analyst will have their own user identification and password. You also mention plans to install a validated computer system. However, you did not provide a detailed corrective action and preventive action (CAPA) plan or conduct a review of the reliability of your historical data to ensure the quality of your products distributed to the U.S. market.

    Failure to train employees on their particular operations and related CGMP practices. Multiple employees stated that they had not received on-the-job training for their production operations.

    b) There was no record of training for the GC analyst testing for residual solvent release in final API.

    c) According to your “(b)(4) Training Program” procedure, a report is generated for each training with the names of trainer and trainees, subjects covered, evaluation sheets, etc. However, you were not able to provide any training reports to our investigators.

W-299

Keywords: Data access, audit trail, data integrity, raw data, product testing 

  • Primary deviations
    Unauthorized access to data, unauthorized data manipulation, no active audit trail function, no plan to ensure integrity of raw data, inadequate product testing
  • Examples
    - You lacked controls to prevent the unauthorized manipulation of your laboratory's electronic raw data. Specifically, your infrared (IR) spectrometer did not have access controls to prevent deletion or alteration of raw data. Furthermore, the computer software for this equipment lacked active audit trail functions to record changes to data, including information on original results, the identity of the person making the change, and the date of the change. Audit trails that capture such critical data about the quality of your batch production should be reviewed as part of the batch review and release process.
    - We acknowledge your commitment to upgrade the IR software by adding full audit trail capabilities in compliance with CGMP. In your response, you also commit to obtain information about the (b)(4) archival of all data obtained on laboratory computerized systems, and to evaluate software upgrades to other instrumentation. However, your response is inadequate because you have not specified how you will ensure the integrity of raw analytical data or maintain data before you complete your planned corrective actions and preventive (CAPA) actions.
    - In response to this letter, provide your comprehensive CAPA plan for ensuring that electronic data generated in your manufacturing operations, including laboratory testing, cannot be deleted or altered. It essential that your firm implement controls that prevent the omission of data, and record information about changes to existing data, such as the date of the change, identity of person who made the change, and an explanation or reason for the change. Any such changes should be made in accordance with an established and appropriate procedure. Your response should address your laboratory equipment and any other manufacturing-related equipment that may be affected by the lack of adequate controls to prevent data manipulation.
    - Your quality unit failed to detect that your laboratory altered IR raw data and misrepresented the results for approval and release of APIs
    - Your response is inadequate in that it does not fully address the failure of your quality unit to detect and prevent the manipulation or alteration of laboratory documents. Additionally, your response is incomplete because you have not provided a comprehensive plan to ensure the integrity of all data used to assess the quality and purity of APIs manufactured at your facility..

W-298

Keywords: Data integrity, failure investigation, complaints, peak integration, re-integration.  unauthorized access, batch release, audit trail, electronic, complete records

  • Primary deviations
       Failure to ensure that laboratory records included complete data, multiple incidents of performing "trial" testing of samples, disregarding test results, and reporting only those results from additional tests conducted. failure to create unauthorized folders on laboratory computerized systems, failure to establish and follow appropriate written procedures, failure to prevent objectionable microorganisms in drug products not required to be sterile, inadequate handling of deviations, failing or otherwise atypical results were not investigated and included in the official laboratory control records, corrective actions were not implemented globally, the quality system failed to ensure the adequate investigation and resolution of quality failures..
  • Examples- 
    - 1. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21 CFR 211.194(a)).
    -The inspection of your facility documented multiple incidents of performing "trial" testing of samples, disregarding test results, and reporting only those results from additional tests conducted. For example,
    a. The official release data for (b)(4) and (b)(4) Tablets (b)(4) mg batch (b)(4) for unknown impurities was reported to be within specification (NMT (b)(4)%). However, the chromatographic data showed that the "trial" injection data for this batch failed the unknown impurities specification with a result of (b)(4)%.
    b. The official High Performance Liquid Chromatography (HPLC) impurity data for (b)(4) mg Tablets batch (b)(4) ((b)(4)), 3-month stability time-point @ 25oC/60% RH only included the most favorable result obtained from multiple test results without any justification. The data from this batch was submitted to the U.S. FDA as an exhibit batch.

    In addition to the examples above, our inspection found that 2,803 of 44,643 injection results were not processed or reported in the official data folder for dissolution analysis via HPLC for (b)(4) Tablets. Our inspection identified numerous examples of “trial” injections for various drug products (U.S. and non-U.S. markets), which suggests that this is a common practice.

    Your response to our findings of “trial” injections attempts to explain the rationale for retesting (b)(4) and (b)(4) (1a above). You state that “the unknown were intermittent spikes resulting in aberrant chromatography caused by electronic disturbance or pressure fluctuation.” Your subsequent investigation into the observation concluded that “the unknown impurity peak…is not characteristic of the product and was not observed in the analysis of all commercial and exhibit batches.” The fact that you did not observe the peak in commercial and exhibit batches does not justify disregarding the test run or failing to follow up with appropriate corrective actions and preventive actions.

    According to your response, your laboratory supervisor confirmed that he was aware of the repeated testing of the (b)(4) stability samples (1b above) and that he allowed the analyst to repeat the analysis without conducting further investigation. Your response also states the following: “sample injections were not processed as the analyst failed to record the sample preparations in the analytical laboratory notebook and did not integrate the chromatograms for reporting.” This explanation does not resolve the Agency’s concerns, but instead raises further issues.

    You indicate in your response that you initiated investigations for these incidents, some of which occurred over two (2) years ago; however, you did not provide documentary evidence to support your assertions about the repeat testing and related activities. Your response is inadequate because you did not extend the scope of the investigation to the other electronic systems used in each of your laboratories. As part of your corrective action and preventive action plan, address how your firm intends to ensure the reliability and completeness of all analytical data generated at your facility.

    2. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).

    QC personnel created unauthorized folders on laboratory computerized systems without appropriate oversight. Our review of the HPLC Empower III data collected in 2013-2014 in the commercial QC laboratory found a data folder entitled “WASH.” According to your management, the folder was intended for column wash injections using blank solvent prior to and following sample runs, although you have no standard operating procedure (SOP) detailing this process. One of your laboratory analysts stated that this folder does not contain any standard or sample injection results. However, our investigator found that this folder contained a total of 3,353 injection results, some of which appeared to be samples.

    Your analyst confirmed that the single injection titled “19” in the “WASH” folder represented a trial sample injection performed prior to the official analysis of (b)(4) Tablets on December 19, 2013. From this chromatogram in the “WASH” folder, our investigator documented an unidentified impurity at relative retention time (RRT) (b)(4) calculated at a concentration of (b)(4)%. However, the specification for any unidentified impurity is (b)(4)%. You neither investigated nor reported this out-of-specification (OOS) result.

    Your firm acknowledged that the analysts involved in performing single injections failed to follow good laboratory practices described in the SOP “General Laboratory Working,” and that the analysts conducting the injections in question made decisions to perform unauthorized, unapproved injections. Your response indicates that, during an interview of the laboratory analyst conducted approximately six months after the incident, you determined that he may inadvertently have used an old sample vial from the LC tray for the single injection made for the purpose of a column wash. We question your conclusion about the likely cause without having any supporting documentation or record, and based only on memory of what may have happened six months earlier.

    In correspondence with the Agency, you indicate that no malicious data integrity patterns and practices were found. Also, you state that no intentional activity to disguise, misrepresent or replace failing data with passing data was identified and no evidence of file deletion or manipulation was found. Your response and comments focus primarily on the issue of intent, and do not adequately address the seriousness of the CGMP violations found during the inspection. In addition, FDA’s inspection did not include observations related to deletion of specific files, intentionally or otherwise. Rather, FDA’s concern pertains to the practice of disregarding failing results, conducting trial injections and retesting products without any investigation. We are also concerned that you do not have documentation to support your decision to retest samples of lots that had initially failed to meet specifications, and you allowed manufacturing activities to occur without the oversight of your quality unit.

    As part of your comprehensive evaluation and risk assessment, include a detailed description of all computerized systems in your facility used for testing drugs. This description should include information on each electronic folder that was not created pursuant to a valid SOP and an assessment of every file in each such folder, including information about the sample (product), date of test, lot number and original test result over the last five (5) years, except for data relating to exhibit batches, in which case there is no time limitation. Also provide specific information about all retests during these time frames, where an initial out-of-specification or out-of-trend result was disregarded without an investigation and the date on which you became aware such information had been disregarded. In addition, for each batch, provide the number of injections performed and chromatograms reviewed, and of those, the number that were used to generate a reported result. Furthermore, provide an updated assessment on the possible effects of your firm’s practices on the quality, safety, and efficacy of the drugs you manufacture or plan to manufacture, including drugs covered by approved or pending applications.

    In your corrective action and preventive action plan, describe in detail your revised control process for ensuring that batches with retest results are not released until a thorough investigation is conducted. Also describe how you intend to prevent these failures from recurring in the future, and how you will measure the effectiveness of your corrections. Also describe the procedures established to manage and retain all computerized data.

    3. Your firm failed to establish and follow appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile (21 CFR 211.113(a)).

    On June 23, 2014, during the inspection of the QC Microbiology Laboratory, our investigators observed missing in-progress microbiological test plates for various finished drug products, in-process products, water, and media growth promotion samples. For example:

    a. Finished drug product (b)(4) Tablets (b)(4)mg batches (b)(4) and (b)(4) microbial sample plates/tubes were placed in the incubators on June 19-20, 2014, as documented in your LIMS computer system. The plates should have been incubated for (b)(4) days, per your procedures. On June 23, 2014, no plates/tubes for this batch were observed in any of the incubation chambers.

    b. Finished drug product (b)(4) Tablets (b)(4) mg Exhibit Batch (b)(4) sample for microbial testing was prepared on June 13, 2014. Your firm failed to provide the FDA investigator with the worksheet to document the incubation times and media used for the analysis. Your analyst described that the entire microbial test for this batch had already been completed the previous week but that the analyst had "forgotten" to document the details on the worksheet.

    The FDA investigator noted other instances of missing samples/plates for in-process drug products, potable water, and growth promotion, even though records indicated that they were in the incubator.

    As a result of the above observation, your firm initiated an investigation and reported that 290 (b)(4) plates and 36 media tubes under testing were missing, affecting 45 product sample batches, 12 growth promotion test batches, and 37 negative control plates. Your firm also found discrepancies between the documentation and location of samples/plates and you indicated that the majority of the missing plates were found in the decontamination area for disposal.

    In your response, you refer to an investigation and indicate that “…two analysts momentarily panicked (upon (1) learning that FDA Investigators were approaching the microbiology Lab and (2) seeing used petri plates from the weekend scattered throughout the laboratory)[sic] and directed the lab technician to immediately remove the petri plates from the microbiology lab … in an utterly misguided and ill-conceived attempt to clean up the microbiology lab prior to the start of the FDA inspection.”

    Your response lacks a comprehensive risk assessment of your failure to follow procedures, your inadequate documentation system and your inadequate practices related to microbiological control. Your response failed to evaluate the effect of these violations on product quality, and did not include an assessment as to whether any other batches have been compromised.

    ARPL’s inability to prevent and detect poor recordkeeping practices raises serious concerns regarding the quality system in place at the time of the inspection. Appropriate controls are essential to assure that the information used for making decisions is trustworthy, accurate, and reliable.

    4. Your firm failed to follow written procedures applicable to the quality control unit (21 CFR 211.22(d)) and your quality control unit failed to review and approve all drug product production and control records to determine compliance with all established, approved written procedures before a batch is released or distributed (21 CFR 211.192).

    For example:

    a. Your procedure titled “Quality Unit Responsibility” (#GPOL-004 dated 07/09/2013) states that “any deviation shall be investigated to discover possible causes and prevent possible reoccurrence.” Although your written procedure clearly describes the protocols for handling deviations, your quality unit management indicated to our investigator that there were no deviation reports, no OOS investigations, nor any evaluations to address the possible root cause(s) of the deviations/OOSs. Among other failures, your quality unit did not follow your procedures for conducting investigations into the examples listed in citation #1 of this letter.

    b. Your firm’s implementation of the audit program described in the Global Policy "Audit Program" document #GPOL-015 dated September 7, 2013 is inadequate in that it failed to prevent the recurrence of testing unofficial samples of drug product prior to testing the official sample and generating only those results to be reported.

    c. In addition the inspection revealed that failing or otherwise atypical results were not investigated, nor included in the official laboratory control records as required by 21 CFR 211.192. We reiterate that an investigation is necessary for any out-of-specification (OOS) event. Refer to the FDA's guidance on OOS investigations Guidance for Industry, Investigating Out-of-Specification (OOS), Test Results for Pharmaceutical Production.
    Your quality unit is responsible for assuring that your firm is operating in a sustainable state of control throughout the manufacture and lifecycle of all drugs produced at your facility. Your quality unit has the overall responsibility for oversight and approval of quality related activities. As part of your corrective action and preventive action plan, please describe how your quality unit will provide consistent, adequate review and approval of investigations and production batch records.

    Be aware that Apotex was notified of our concerns with the practice of “trial” injections during FDA’s January 2014 inspection at your Apotex Pharmachem India Pvt. Ltd. located at Plot # 1A Bommasandra Ind. Area, 4th Phase, Jigani Link Road, Bangalore, India. However, our findings during this inspection suggest that corrective actions were not implemented globally. Furthermore, inadequate oversight by your firm’s site-specific quality units is a repeat finding from WL: 320-10-003 dated March 29, 2010. The need for appropriate and global quality oversight was communicated to Apotex senior management during the regulatory meetings held September 11, 2009, March 31, 2010, and April 11, 2014.

    Conclusion

    The foregoing examples are of serious CGMP violations demonstrating that your quality system does not adequately ensure the accuracy and integrity of the data generated at your facility to ensure the safety, effectiveness, and quality of the drug products you manufacture. We found that your quality system failed to ensure the adequate investigation and resolution of quality failures. ARPL failed to investigate OOS results, failed to contemporaneously document failures and report failures, and selected only passing results without the oversight of a quality unit. In your response and in subsequent communications with the agency, you indicated that you interviewed employees and found no evidence of data manipulation or deletion. In focusing on the issues of deletion and alteration of data, you have not sufficiently addressed or resolved other substantial CGMP issues as discussed above. In response to this letter and including the specific requests noted above, provide the following to the Agency:

    1. A comprehensive evaluation of the extent of the inaccuracy of recorded and reported data. As part of your comprehensive evaluation, provide a detailed action plan to investigate the extent of the deficient documentation practices noted above;

    2. A risk assessment of the potential effect of the observed failures on the quality of drug products. As part of your risk assessment, determine the effects of your deficient documentation practices on the quality of the drug product released for distribution; and

    3. A management strategy for your firm that includes the details of your global corrective action and preventive action plan.

    a) As part of your corrective action and preventive action plan, describe the actions you have taken or will take, such as contacting your customers, recalling product, conducting additional testing and/or adding lots to your stability programs to assure stability, monitoring of complaints, or other steps to assure the quality of the product manufactured under the violative conditions discussed above.

    b) In addition, as part of your corrective action and preventive action plan, describe the actions you have taken or will take, such as revising procedures, implementing new controls, training or re-training personnel, or other steps to prevent the recurrence of CGMP violations, including breaches of data integrity.

W-297

Keywords: Laboratory records, complete records, review of records, OOS, failure investigation, trial injections, SOP, audit trail

  • Primary deviations
     Laboratory records incomplete, no review of records, OOS results not investigated, unauthorized trial injections prior to real inspections, OOS “test injections’ not reviewed, ‘trial injections not covered by audit trail, trial sample injections were not reviewed, failure to record and justify any deviations from required laboratory control mechanisms, PCs not configured for audit trail, SOP related to trial injections not followed, global corrections, failure to submit NDA/ANDA Field Alert Reports within three working days of receipt of informatio
  • Examples
    - 1. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21 CFR 211.194(a)).
    - Our inspection identified laboratory test records that you did not review and evaluate in making batch release decisions. These records contained uninvestigated, out of specification (OOS) data. You did not include the data described below when calculating test results that you used to release finished product. You also failed to identify, investigate, and determine the significance of the OOS results discussed below until our investigators identified the excluded records during our inspection.
    - a) During the inspection, your management admitted that employees in both of your Quality Control (QC) laboratories had frequently conducted unauthorized “trial” High Performance Liquid Chromatography (HPLC) injections prior to additional injections that were used in the reported test results. Although your management stated that this practice ended in February 2014, FDA investigators discovered evidence that this practice continues. The inspection found that the names assigned to each sequenced injection were often changed during testing, obscuring the traceability of repeated injections. The data from “trial” injections was not reviewed or considered in determining batch quality. For example,
    - 1) For the related substances analysis of (b)(4) USP (b)(4) mg Tablets batch (b)(4) conducted on February 25, 2013, there were three sample injections of vial 1_8, all named “TEST,” which were run prior to the reported sample injections. The “TEST” injection data was stored in the “Trial” folder located on a personal computer (PC) with no audit trail linked to the HPLC instrument.
    - During the inspection, the calculations that you performed using the target sample weight showed that the “TEST” injections were OOS ((b)(4) as compared to the specification of NMT (b)(4)) for the highest unknown impurity.
    - The “TEST” injections were not reviewed and evaluated when making the batch release decision.
    - 2) For the dissolution analysis of (b)(4) USP (b)(4) mg Capsules batch (b)(4) conducted on July 13, 2013, two sets of six sample preparations each were run on the HPLC system as trial sample injections. The trial injection data was stored in the “Trial” folder located on a PC with no audit trail linked to the HPLC instrument.
    - During the inspection, the calculations that you performed using the target sample weight for three of the injections performed on July 11th, 2013, showed that some of the trial injections produced low dissolution test results (Sample-4 (b)(4)%, Sample-5 (b)(4)%, and Sample-6 (b)(4)%, as compared to the Q-value criteria of NLT (b)(4)% of dissolved active ingredient in 45 minutes)
    - The trial sample injections were not reviewed and evaluated by your firm when making batch release decisions.
    - 3) For the assay analysis of (b)(4) USP (b)(4) mg Capsules ((b)(4) drug product) batch (b)(4) conducted on May 15, 2013, two trial HPLC sample injections were run before the reported sample injections. The trial injection data was stored in the “Trial” folder located on a PC with no audit trail linked to the HPLC instrument.
    - During the inspection, the calculations that you performed showed that one of the extra injections was OOS ((b)(4)%, as compared to the specifications of NLT (b)(4)% and NMT (b)(4)% of label claim)
    - The trial sample injections were not reviewed and evaluated as part of the batch release decision.
    - 4) HPLC sequence GSTA130522-DS showed (b)(4) single injections, in addition to the sequenced injections, during dissolution testing of (b)(4) Tablets ((b)(4) drug product) submission stability batch (b)(4). Two of the extra single injections were from vial 15, labeled as “STD,” indicating that the lab may have injected standard solution and not the test sample solution. Notably, the vial 15 contents were then injected a third time and used as the “Sample 6” test result.
    - The trial sample injections were not reviewed when assessing batch quality and product stability.
    - 5) The audit trail for the dissolution analysis of the 9-month long-term stability sample of (b)(4) USP (b)(4) mg Tablets batch (b)(4) conducted on March 22, 2014, showed a single manual injection that was not included in the official test results package. A manual “trial” sample injection from vial position (b)(4) at 12:29 pm was injected between the Set (b)(4) and Set (b)(4) analytical sequences. No deviation was documented regarding the extra sample injection. In addition, the original injection data obtained for vial position (b)(4) was overwritten and not saved. Because the original data was overwritten, you did not review and evaluate it as part of your batch release decision.
    - Examples (1) through (5) are examples of unreported extra data that FDA investigators observed on the analytical systems in your QC laboratories. The inspection also identified (b)(4) unexplained extra HPLC sample injections for the four stability batches that define the stability characteristics of your (b)(4) formulation.
    - b) The inspection also found similar unreported and unexplained sample data acquired during your gas chromatography (GC), ultra violet (UV) spectroscopy and (b)(4) analyses. The extra GC data was stored in the “Trial” folder located on a PC with no audit trail linked to the GC instrumentation. The extra UV and (b)(4) data was stored on the instrument hard drives. This unreported and unexplained data was not reviewed when assessing batch quality and making product disposition decisions. For example,
    - 1) For the (b)(4) analysis of the 9-month long-term stability sample of (b)(4) USP (b)(4) mg Capsules ((b)(4) drug product) batch (b)(4) conducted on January 10, 2014, three extra analyses that were run prior to the reported sample were found on the instrument hard drive. During the inspection, the calculations that you performed showed that two of the extra analyses were OOS ((b)(4)% & (b)(4)%, as compared to the specification of NMT (b)(4)%).
    - Notably, there were no test sample weight records for the three extra (b)(4) tests. The extra sample data was not reviewed when assessing batch quality and product stability.
    - 2) For the dissolution analysis of (b)(4) USP (b)(4) mg Tablets batch (b)(4) conducted on February 21, 2013, a set of test samples was run 14 minutes prior to the reported test samples. The extra data, named slightly differently than the reported test results, revealed several low dissolution test results ((b)(4)%, and (b)(4)%, as compared to the Q-value criteria of NLT (b)(4)% of dissolved active ingredient in 45 minutes).
    - This trial sample data was not reviewed and evaluated when making the batch disposition decision.
    - Your response states that you have initiated investigations into such extra data, together with data integrity audits. We note that your response does not address the testing you have performed on active pharmaceutical ingredients, in-process goods, and validation samples tested by your QC laboratories. Please address these other drugs in your response to this letter. In addition, your response does not include a complete review of all “trial” data (including samples and standards) generated by your firm to ensure that all of the OOS results have been identified and investigated. As part of your response discussed below under “Summary,” please include the results of such a review, including steps taken to fully understand the scope and significance of this practice.
    - 2. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).
    - FDA investigators discovered a lack of basic laboratory controls to prevent changes to electronically stored data. The following examples show that you lack effective control of the integrity of instrument output data:
    - a) The ten Shimadzu HPLC instruments in the QC “commercial” laboratory were configured to send acquired injection data to PCs without audit trails.
    - b) There was a lack of controls to prevent substitution or overwriting of data. The (b)(4) audit trail dated January 6, 2014, for HPLC MLG/QC/12/026 and the (b)(4) audit trail dated January 15, 2014, for HPLCs MLG/QC/12/031 and MLG/QC/12/027 each showed sample injections marked with the same small graphic symbol. For each of these entries, you replaced the original injection sequence data with data from a single manual injection and failed to save the original sequence data.
    - In your response to this letter, include a chronology of Chromeleon audit trail information that shows all single manual sample injections that replaced data collected during HPLC testing.
    - c) A “File Note” dated February 10, 2014, signed by the QC Head, established that the printed data used for batch disposition decisions from the Metrohm Titrando Instrument MLG/QC/12/048 hard drive was not necessarily the complete data for a batch. Our inspection found that data on the instrument was selected for use and was not protected from change and deletion. Notably, the audit trail capability of this QC “commercial” laboratory instrument was not enabled, even aftercreation of the “File Note.”
    - 3. Your firm failed to record and justify any deviations from required laboratory control mechanisms (21 CFR 211.160(a)).
    - According to your management, a new standard operating procedure (SOP) was approved in February 2014, in order to eliminate your “trial” sample injection practices. However, during our inspection, we observed that your analysts continued these “trial” injection practices after the approval of your new SOP, and that your quality system and your management failed to detect and correct these deviations from the new procedure (see, e.g., Example 1(a)(5) above).

    - Post-Market Reporting Requirements Observation

    - 4. Your firm failed to submit NDA/ANDA Field Alert Reports within three working days of receipt of information concerning any significant chemical, physical, or other change or deterioration in the distributed drug product, or any failure of one or more distributed batches of the drug product to meet the specification established for it in the application (21 CFR 314.81(b)(1)(ii)).
    - You failed to file a Field Alert Report (FAR) within three working days for the failing unknown impurity results observed for (b)(4) Tablets USP batches (b)(4) (12 months @ 25˚C/60% Relative Humidity (RH)) and (b)(4) (6 months @ 25˚C/60% RH and 6 months @ 40˚C/75% RH). We note that in response to our inspection, you ultimately submitted the required FAR on May 12, 2014, which was 26 days late.
    - The NDA/ANDA field alert reporting requirements in 21 CFR 314.81(b)(1)(i) and (ii) require holders of NDAs and ANDAs to submit certain information about distributed drug products to the appropriate FDA district office within three working days of receipt by the applicant. Field Alert Reports help to ensure that significant problems are brought to the Agency’s attention by applicant holders in order to prevent potential safety hazards from drug products already in distribution and also to prevent potential safety hazards with drug products manufactured in the future. When you become aware of a product quality defect that is likely to pose a risk to patients, such as the unknown impurity failure discussed above, you must submit a FAR within the required time period.
    - The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations.

    Summary
    The above examples are of serious CGMP deficiencies and violations demonstrating that your quality system does not adequately ensure the accuracy and integrity of the data generated and available at your facility to support the safety, effectiveness, and quality of the drug products you manufacture.
    - We strongly recommend that you hire a qualified third party auditor/consultant with experience in detecting data integrity problems to assist you with coming into compliance with CGMP regulations and statutory authorities. In your response to this letter, provide the following to the Agency:
    - 1. A comprehensive investigation and evaluation, including a description of the methodology for such investigation and evaluation, of the extent of deficiencies relating to record control, contemporaneous recording, deletion of data, and any other data integrity deficiencies at your firm, such as those identified above;
    - 2. A risk assessment of the potential effect of the observed deficiencies on the quality of your drug products. As part of your risk assessment, determine the effects of your deficient documentation practices on the quality of the drug products released for distribution; and
    - 3. A management strategy for your firm that includes a detailed global corrective action and preventive action plan.
    - a) As part of your corrective action and preventive action plan, describe the corrective actions you will take, such as contacting your customers, recalling product, conducting additional testing and/or adding lots to your stability programs to assure stability, monitoring of complaints, or other steps to assure the quality of the products manufactured under the violative conditions discussed above.
    - b) In addition, as part of your corrective action and preventive action plan, describe the preventive actions you will take, such as revising procedures, implementing new controls, training or re-training personnel, or other steps to prevent the recurrence of CGMP violations, including breaches of data integrity.

W-296

Keywords: Failure investigation, complaints, peak integration, re-integration.  unauthorized access, batch release, audit trail, electronic, complete records,

  • Primary deviations
     Inadequate investigation of customer complaints,  investigation closed before implementation of corrective action,  Data of  peak integration provided in the 483 response different from data presented during the inspection, parameters for multiple chromatographic re-integrations not retained,  no or insufficient control to prevent the use of raw material containing undesirable impurities, batch with unknown impurity released, unauthorized access to data, audit trail feature not used, no control to prevent unauthorized manipulation of electronic raw data, “complete” electronic raw data not maintained,  no back-up, stability samples not tested, ,
  • Examples
    - 1 Failure to adequately investigate complaints and extend the investigations to other batches that may have been affected.
    - Since 2011, your firm has failed to fully investigate and implement corrective actions related to complaints. For example,
    - a. In September 2011, your firm received a customer complaint for an unpleasant odor for batch (b)(4) of (b)(4) API. The investigation into this complaint concluded that the control of (b)(4), a known impurity, may be related to the odor detected, and the investigation was closed in October 2011, before the implementation of the proposed corrective actions. In addition, your investigation did not provide data to support your conclusion. There is no assurance that the changes to the manufacturing process, implemented in response to the odor complaints, were correlated to the odor issue.
    -  In response to this letter, provide a chronology of the changes made to the (b)(4) API manufacturing process to control the process impurities since September 2011. Include documentation of any changes that may have affected the impurity profile of (b)(4) API since September 2011.
    b. In August 2012, your firm received another customer complaint for an unpleasant odor for batches (b)(4) and (b)(4) of (b)(4) API. In addition, the complainant reported the failure of (b)(4) API batch (b)(4) for maximum unknown impurity (at (b)(4)%, exceeding the specification of not more than (b)(4)%).
    - The investigation concluded that the unpleasant odor was related to the presence of (b)(4), a process impurity. The data to support your March 19, 2014 investigation conclusion regarding (b)(4) levels in your (b)(4) API batches was not retained. As part of the investigation, your firm reintegrated multiple chromatograms to determine (b)(4) levels; however, the parameters for the reintegration were not retained.
    - During the inspection we were provided with reintegration results for batch (b)(4) that showed an (b)(4) level of (b)(4) ppm; however, the reintegration results provided in your written response to the Agency related to this same batch indicated that (b)(4) was “not detected.” In response to this letter, explain the discrepancy found between the data provided during the inspection and the data provided in your response.
    - Your firm’s response states that your established specification for (b)(4) is not more than (b)(4) ppm. Provide the details of your scientific justification to support the use of (b)(4) ppm as a specification.
    - Also, describe the controls implemented to prevent recurrence of (b)(4) levels exceeding your in-house specification and explain your assurance that commercial batches of (b)(4) API within expiry meet your in-house specification.
    - Your investigation related to the out-of-specification (OOS) result for the maximum unknown impurity for batch (b)(4), concluded that the impurity had carried over from a raw material used in the API manufacturing process. This investigation did not address the failure of the quality unit to recognize this impurity OOS prior to release.
    - Include in your response information regarding the controls you have in place to prevent the use of raw material containing the undesirable impurity that was responsible for the (b)(4) API batch (b)(4) failure. In addition, provide a chronology for the implementation of your revised raw material controls and a detailed assessment of batches still within expiry that were manufactured prior to the implementation of these controls.
    2. Failure of your quality unit to exercise its responsibility to ensure the APIs manufactured are in compliance with CGMP, and meet established specifications for quality and purity.
    - a. Your firm released (b)(4) API batch (b)(4) with an unknown peak present in the residual solvents chromatogram. Although this unknown peak was not a part of your historical impurity data, neither the analyst nor the supervisor apparently noticed or evaluated this unknown peak during their reviews.
    - Subsequently, a customer complaint was received for this batch, and your investigation identified the unknown peak as (b)(4). Your firm found that this peak was a result of a contamination that occurred during your manufacturing process.
    - Your firm’s response failed to provide adequate assurance that appropriate controls have been implemented to mitigate recurrence of contamination during manufacturing operations. Provide an assessment of the cross-contamination risks due to your current practices for the material flow of solvents, and any corrective actions resulting from this assessment. Also, provide an assessment of the contamination risk for batches within expiry.
    - In response to this letter, provide the corrective actions implemented to ensure that all laboratory data is appropriately analyzed, accurately reported and approved by your quality unit.
    - 3. Failure to prevent unauthorized access or changes to data and to provide adequate controls to prevent omission of data.
    - Your firm did not have proper controls in place to prevent the unauthorized manipulation of your electronic raw data. For example,
    - a. The inspection found that the audit trail feature for your gas chromatography (GC) instruments was not used until October 2013, even though your 2009 GC software validation included a satisfactory evaluation of the audit trail capability.
    - b. There is no assurance that you maintain complete electronic raw data for the (b)(4) GC instruments, the Malvern particle size analyzer, and the ultraviolet (UV) spectrophotometer. Our inspection found that these instruments were connected to stand-alone computers that stored the data and that the data could be deleted.
    - c. Prior to our inspection, your firm failed to have a back-up system for the data generated by one of the (b)(4) Fourier transform infrared spectrometers, the polarimeter, the UV spectrophotometer and the Malvern particle size analyzer.
    - Your response states that data from these, as well as other laboratory instruments is now saved on a central server and that a new LIMS system will be installed in October 2014. Your response provided an interim solution for electronic raw data retention. Provide any additional steps that you are taking to assure integrity of your electronic raw data.
    In response to this letter, provide a copy of your plan(s) to validate the processes of archiving and restoring your electronic data
    - We also note that numerous stability samples have not been tested at the required intervals. Specifically, the inspection found that your 2014 stability program was in backlog and that samples were overdue for testing. In addition, - We are concerned that your quality unit was not aware of this backlog situation
    - In response to this letter, provide information that compares the 2014 delayed results to the expected API impurity profile at the originally planned test intervals. Also, provide the planned schedule for resolution of the backlog.
    - The deviations cited in this letter are not intended to be an all-inclusive list of deviations that exist at your facility. You are responsible for investigating and determining the causes of the deviations identified above and for preventing their recurrence and the occurrence of other deviations.
    - The items listed above, as well as other deficiencies our investigator found, lead us to question the effectiveness of your current quality system to achieve overall compliance with CGMP at your facility. It is apparent that you have not implemented a robust quality system at your firm. Be advised that corporate management is responsible for ensuring the quality, safety, and integrity of products manufactured by Cadila Pharmaceuticals Limited. FDA strongly recommends that your corporate management immediately undertake a comprehensive evaluation of global manufacturing operations to ensure compliance with CGMP expectations

W-295

Keywords: Trial injections, control of HPLC system, raw data files, audit trail, test folders, OOS investigation, microbiological contamination, global corrective actions

  • Primary deviations
     insufficient controls of laboratory HPLC/GC computers to prevent the deletion or alteration of raw data files, electronic raw data can be deleted, audit trail function disabled, global corrective actions, trial injections, no oos investigation, Test folders and samples used to check readiness of the system, Failure to investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, failure to follow appropriate written procedures to prevent microbiological contamination of drug products,
  • Examples
    - Your high performance liquid chromatography (HPLC) and gas chromatography (GC) data acquisition software, TotalChrom®, did not have sufficient controls to prevent the deletion or alteration of raw data files.
    - During the inspection, the investigator observed that the server that maintains electronic raw data for HPLC and GC analyses (the J drive) contains a folder named “Test,” and that chromatographic methods, sequences, and injection data saved into this folder can be deleted by analysts.
    - The investigator also found that data files initially created and stored in the “Test” folder had been deleted, and that back-up files are overwritt
    - In addition, because no audit trail function was enabled for the “Test” folder, your firm was unable to verify what types of injections were made, who made them, or the date or time of deletion. The use of audit trails for computerized analytical instrumentation is essential to ensure the integrity and reliability of the electronic data generated.
    - Your response indicates that you have added computer controls to prevent the deletion of folders and files in the J drive for electronic raw data. However, you provide no evidence demonstrating how your firm will prevent deletion of newly created folders and files in each of your computer systems. We acknowledge your commitment to hire a third party consultant to address the inadequacies of your data systems. However, your response is inadequate as it fails to address how you will enable and review audit trail functions for all of your analytical computer systems
    - In response to this letter, provide specific details about the comprehensive controls in place to ensure the integrity of electronic raw data generated by all computer systems used to support the manufacture and testing of drug products. Your response should demonstrate an understanding of your processes and the appropriate controls needed for each stage of manufacture that generates electronic raw data, as well as for your laboratories.
    - Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21CFR 211.194(a)).
    - a) Our investigators identified your practice of performing trial sample injections for HPLC analyses. For example, trial injections of (b)(4) stability samples (lot (b)(4) and (b)(4)) were acquired in the “Test” folder prior to official testing. Immediately after the trial injections were completed, the official samples were analyzed. The trial injection raw data, captured in the back-up files, were deleted from the test folder.
    - b) You retested analytical samples without reporting original results in laboratory records. Because of this practice, you are unable to assure that all raw data generated is included and evaluated when you review analytical test results to determine whether your products conform with their established specifications and standards.
    - For example, (b)(4) lot #(b)(4) failed the content uniformity test, where sample #8 of (b)(4) resulted with a value (b)(4)%. Your firm proceeded to retest the sample on a different instrument without initiating an out-of-specification (OOS) investigation, as required by your chemistry laboratory investigation standard operating procedure, SOP QAG-097. These injections were not reported as part of the original data or included in your laboratory investigation report. Subsequently, the electronic raw data files were deleted. Moreover, there is no procedure describing the use of re-injections for standards or samples on a different system to verify an original result.
    Your response indicates that the “Test” folders were used to equilibrate the analytical columns and to determine when the system was ready for analysis. It is your responsibility to follow validated methods that include specific procedures to assess the suitability of your instruments. Neither the ICH document Q2R, "Validation of Analytical Procedure: Text and Methodology," nor the United States Pharmacopoeia (USP), General Chapter <1058>, "Analytical Instrument Qualification," provides for use of “trial” injections as part of a validated method. Your rationale that you retested failing samples on different analytical instrumentation to evaluate system suitability is inadequate. See USP General Chapter <621>, “Chromatography,” which discusses system suitability tests and the use of replicate injections of a standard preparation or other standards to determine if the requirements for precision are satisfied.
    - These are serious CGMP violations that demonstrate that your quality system does not adequately ensure the accuracy and integrity of the data you generate to support the safety, effectiveness, and quality of the drug products you manufacture. We acknowledge your commitment to work with a third party consultant to conduct a comprehensive assessment of your firm’s manufacturing, laboratory, and quality operations. However, it is your responsibility to ensure that the third party audit includes a full evaluation of sophisticated electronic systems and the potential for manipulation of such systems. In response to this letter, provide the following to the Agency:
    1. A comprehensive evaluation of the extent of the inaccuracy of the reported data. As part of your comprehensive evaluation, provide a detailed action plan to investigate the extent of the deficient documentation practices noted above;
    2. A risk assessment regarding the potential effect on the quality of drug products. As part of your risk assessment, determine the effects of your deficient documentation practices on the quality of the drug product released for distribution; and
    3. A management strategy for your firm that includes the details of your global corrective action and preventive action plan.
    a) As part of your corrective action and preventive action plan, describe the actions you have taken or will take, such as contacting your customers, recalling product, conducting additional testing and/or adding lots to your stability programs to assure stability, monitoring of complaints, or other steps to assure the quality of the product manufactured under the violative conditions discussed above.
    b) In addition, as part of your corrective action and preventive action plan, describe the actions you have taken or will take, such as revising procedures, implementing new controls, training or re-training personnel, or other steps to prevent the recurrence of CGMP violations, including breaches of data integrity.
    The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other viol

 

W-294

Keywords: Raw data, electronic raw data, method validation, system suitability, complete records, laboratory computer, system, unauthorized access, historical data, audit trail

  • Primary deviations
    Complete raw data from method validation not maintained, electronic raw data supporting HPLC testing not maintained, no controls to prevent the unauthorized manipulation of laboratory’s raw electronic data, selective system suitability test results discarded, unauthorized access to data, failure to review historical data to ensure the quality of your products distributed to the US market, reprocessing procedures for APIs do nor meet intended specifications.
  • Examples

W-293

Keywords: Laboratory system, specifications, raw data, reintegration, audit trail, computer validation, OOS, quality system, 3rd party consultant

  • Primary deviations
    Missing raw data, conformance to established specifications not ensured, reintegration without appropriate documentation
    , reintegration without audit trail, no written procedure manual integration, no unique user ID to access the laboratory system, use of uncontrolled worksheets, no validation plan for computer systems, inadequate handling of OOS situations, lack of contemporaneous documentation of CGMP activities
  • Examples
    -
    your firm made changes to integration parameters for the impurities test without appropriate documentation or justification.
    - your firm implemented reintegration without an audit trail that would have captured the date of the change and who made the change
    - Failure to have a written procedure for manual integration
    - Failure to use separate passwords for each analyst’s access to the laboratory systems. 
    - Use of uncontrolled worksheets for raw analytical data in your laboratory
    - As part of your response, provide a complete validation plan for your laboratory computerized systems.
    -  In addition, include a retrospective review of the analytical data and batch records for all of the APIs distributed that remain within expiration, along with an evaluation of data that may have been generated to support a drug application, including any Drug Master File
    - Your firm did not properly document or investigate out-of-specifications (OOS) and other discrepancies. For example, the inspection documented that OOS Investigation #1203, related to the presence of metal particles in (b)(4), failed to determine the root cause of the contamination or explain why the (b)(4) step was unable to prevent the contamination
    - Your firm did not record all CGMP activities at the time these were performed. The lack of contemporaneous documentation of CGMP activities increases the likelihood of recording erroneous data (21 CFR 211.188).
    - our inspection documented multiple instances where the analysts did not record raw material lot numbers during sample preparation, making it impossible to link the raw materials used to the appropriate test worksheet. This raises concerns about the authenticity of the data that your laboratory testing generate
    - your quality system does not adequately ensure the accuracy and integrity of the data generated and available at your facility to support the safety, effectiveness, and quality of the APIs and drug products you manufacture. 
    - we strongly recommend that you hire a qualified third party auditor/consultant with experience in detecting data integrity problems to assist you with coming into compliance with CGMP regulations and statutory authorities.
    - provide to the agency a management strategy for your firm that includes details of your global corrective action and preventive action plan.

 

W-292

Keywords: Dietary Supplements, Batch Production Records, Production Control, Process Control, Procedures, SOP, Reserve Samples, Complaint Procedures

  • Primary deviations
    Inadequate system for production and process controls, incomplete batch production records, no quality control operations, no reserve samples, no complaint procedure
  • Examples
    -
    You must implement a system of production and process controls to ensure the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in a master manufacturing record (MMR), as required by 21 CFR 111.55. For example
    - During the inspection, you were not able to provide any specifications for the points, steps, or stages in the manufacturing process where controls would be necessary to ensure the quality of the finished product, as required by 21 CFR 111.70
    - Your batch production record must include the identity of the equipment and processing lines used in producing the batch (21 CFR 111.260(b))
    -Your
    batch production reco must include the date and time of the maintenance, cleaning, and sanitizing of the equipment and processing lines used in producing the batch, or a cross-reference to records, such as individual equipment logs, where this information is retained [21 CFR 111.260(c)].
    -
    During the inspection, you were unable to provide any documentation when requested by our investigator that you implemented quality control operations
    - You failed to establish written procedures for manufacturing operations
    - During the inspection, you were unable to provide any documentation when requested by our investigator that you collect and hold reserve samples of each lot of packaged and labeled dietary supplement product that you distributed
    - Your firm failed to establish written procedures to fulfill the requirements related to product complaints

 

W-291

Keywords: Complete records, HPLC raw data, electronic  audit trail, system suitability testing,

  • Primary deviations
    Incomplete records, electronic raw data not saved, wrong definition of raw data, missing electronic audit trail, system suitability test results not reviewed,
  • Examples
    - Failure to maintain complete data derived from all testing and to ensure compliance with established specifications and standards pertaining to data retention and management
    - Your firm did not retain complete raw data from testing performed to ensure the quality of your APIs. Specifically, your firm deleted all electronic raw data supporting your high performance liquid chromatography (HPLC) testing of all API products released to the U.S. market
    - In addition, your firm failed to retain basic chromatographic information such as injection sequence, instrument method or integration method for the tests.
    - Your firm’s lack of data control causes us to question the reliability of your data
    - In addition, your laboratory management was unaware of, and therefore did not follow, the written procedure detailing the review of analytical data.
    - Furthermore, your management confirmed that the review of analytical data did not include evaluating the system suitability parameters to ensure proper column performance.
    - Failure to prevent unauthorized access or changes to data and to provide adequate controls to prevent omission of data
    Failure to ensure that employees receive appropriate and documented training on the particular operations that the employee performs.
    - Your firm did not document any training of production employees on the production operations they perform.
    - Specifically, operators in Synthesis Plant (b)(4) did not have any documented on-the-job training associated with the production operations they perform.
    - In addition, your management was unaware that they should follow the SOP for the issuance of CoAs, which provides for a review of relevant analytical data.
    - Without documented training, there is a lack of assurance that your employees can reliably execute their API manufacturing responsibilities

 

W-290

Keywords: OOS Situations, failure investigations, laboratory records,  complaint handling, quality systems, procedures, data integrity, contemporaneous manner

  • Primary deviations
    Failure to maintain complete data derived from all laboratory tests conducted  failure to investigate and document out-of-specification results, failure to include adequate documentation during complaint investigation, failure to record activities at the time they are performed, record data in the laboratory records in a contemporaneous mannerinadequate quality system, procedures not followed, general lack of reliability and accuracy of data
    generated by your firm's laboratory
  • Examples
    - Your firm lacked accurate raw laboratory data records for API batches shipped by your firm. The inspection revealed that batch samples were retested until acceptable results were obtained. In addition, your quality control (QC) laboratory failed to include complete data on QC testing sheets. Failing or otherwise atypical results were not included in the official laboratory control records, not reported, and not investigated.
    -The inspection documented that your firm discarded sample preparation raw data related to the OOS results. In your response you indicate that the electronic chromatographic data and the weighing log books were available and reviewed during the inspection. However, the raw data and sample preparation information used for the calculation of the test results that were found OOS or disregarded were not in fact available for review
    - According to laboratory analysts interviewed during the inspection, the common practice was to complete the analysis and to record the sample preparation data only if the results were acceptable. If the results obtained were atypical, a fresh sample was to be prepared and analyzed. The original sample testing was not recorded
    - Your plan should also describe your commitment, procedures, actions, and controls to ensure data integrity generally.  This plan should describe the corrective actions implemented to ensure that all managers, supervisors, and quality unit personnel are properly trained in detecting a lack of data integrity and data manipulation.
    - Failure to record activities at the time they are performed.
    - Specifically, your staff used “finished product reports review data” worksheets to document critical laboratory information days after the actual testing was performed. The worksheets reported observations from your firm’s secondary reviewer, and next to each of these listed observations the analyst marked them as corrected. A review of these worksheets revealed that your analysts did not always record data in the laboratory records in a contemporaneous manner as noted in the following examples:
    • (b)(4) USP batch #(b)(4) worksheet dated September 18, 2013, reports “sample wt. taken wrongly." However, the correction to the stability data sheet for this lot gives the appearance that sample weighing was performed on August 10, 2013.

 

W-289

Keywords: API records, API labeling, poor quality system, insufficient 483 response

  • Primary deviations
    Failure to re-label and hold APIs under appropriate CGMP controls. failure to maintain complete records for APIs, failure to transfer all quality or regulatory information received from the API manufacturer to customers, failure to control the API repackaging, relabeling, and holding operations in order to avoid mix-ups and the loss of the API identity, failure to have a Quality Unit responsible for reviewing and approving CGMP documents and procedures, and assuring product quality
  • Examples
    -You did not retain records for the complete traceability for the APIs distributed by your firm. For example, our inspection found that records for 23 lots of APIs did not contain the batch numbers, manufacturing dates, and expiration or retest dates. We also observed inconsistent record retention practices with regard to the original manufacturer including the manufacturer's identity, address, batch number, purchase, receipt, transportation, distribution, and Certificates of Analysis (COAs)
    - Your firm’s COAs lacked the identity of the original manufacturer of the API and the actual testing facility. In addition, it is essential that a COA include batch or lot codes, laboratory testing information, expiry or retest dates, and other relevant information.
    - During the inspection, you stated you did not have a quality unit, provided no written documents describing the roles and responsibilities of a Quality Unit, and had no written procedures for quality activities.
    - Your response indicates that you will make corrective actions but does not provide adequate detail. In response to this letter, provide a written procedure for your quality unit that should include, but not be limited to the following quality oversight activities: approving or rejecting all APIs, packaging and labeling materials; reviewing completed batch and laboratory control records before determining if an API lot can be released; ensuring that discrepancies, complaints, returns, and failures are investigated and resolved; approving all specifications; approving all procedures affecting the quality of APIs: approving raw material vendors, API contract manufacturers, contract laboratories, and other outsourced activities; approving changes that potentially affect API quality for their acceptability; making sure that materials are appropriately tested and the results are reported; making sure that there is stability data to support retest or expiry dates and storage conditions of your APIs.
    - The CGMP deviations listed in this letter as well as other deficiencies our investigators found, lead us to question the effectiveness of your current quality system to achieve overall compliance with CGMP at CBSCHEM Limited, Nan Fung Industrial City, Tuen Mun, New Territories, Hong Kong, and CBSCHEM Limited, Tempe, AZ. It is apparent that you have not implemented a robust quality system at your firm. Be advised that corporate management is responsible for ensuring the quality, safety, and integrity of APIs distributed by CBSCHEM Limited. FDA strongly recommends that your executive management immediately undertake a comprehensive evaluation of your global operations to ensure compliance with CGMP requirements. Due to continuing CGMP issues at your firm, we recommend you engage a third party consultant with appropriate CGMP expertise to assess your firm’s facility, procedures, processes, and systems to ensure that the APIs you distribute have their appropriate identity, strength, quality, and purity

 

W-288

Keywords: Analytical methods, System suitability testing, analytical instrument qualification, inadequate response

  • Primary deviations
    Methods not validated, inadequate system suitability testing, only standard used for system suitability testing, corrective action (method validation) too late, OQ not performed over the operating range
  • Examples
    - The release test methods your firm uses to test aerobic microbial count and endotoxin content of (b)(4) API are not validated
    - Your response indicates that you will validate both the endotoxin content and aerobic microbial count methods. During the inspection, your QC Section Manager indicated to our investigators that these methods, among others, were on a schedule to be validated by the end of September 2010. All test methods should be validated prior to shipping APIs intended for the U.S. market. Include in your response to this letter the analytical method validation summaries for the endotoxin content and aerobic microbial determination for (b)(4
    - In addition, your “Purity of (b)(4) by HPLC” test method does not include a scientifically sound or appropriate system suitability assessment. Currently, you only require (b)(4) injection of a standard to determine if the HPLC system is suitable for use. This (b)(4) injection of a standard is insufficient to determine that the system is suitable for its intended use
    -  Failure of your quality control unit/laboratory to ensure that analytical instrumentation and test equipment used to assure the quality of your APIs has been appropriately qualified and calibrated for their intended use.
    -  your firm has failed to conduct adequate qualifications of your analytical instruments and test equipment. For example, the residual solvent method used to test (b)(4) API has an initial starting gas chromatograph (GC) oven temperature of (b)(4). Your firm’s current qualification of the GC oven temperature does not include temperatures below 100˚C.
    - Additionally, the water bath you use in the assay determination of (b)(4) API is not qualified to maintain a bath temperature of (b)(4), as required in your analytical method.
    - Your response indicates that you will perform instrument calibrations to include the operating ranges used to test (b)(4), and that you will revise your calibration procedures to be able to confirm that the function of the instrument is the same as when the instrument’s Operational Qualification (OQ) was performed.
    - All laboratory instrumentation and equipment that you use to test material manufactured for the U.S. market should have an Operational Qualification (OQ) and should be calibrated to include applicable operating ranges.

 

W-287

Keywords: Excel, time change, reintegration, data integrity, power outages, lab equipment failures, audit trail, password sharing, risk assessment, atypical chromatographic peaks, ICH Q7

  • Excel not controlled, data reintegration not following SOP, incorrect recording of analysis time,  no review of failures through power outages, lab equipment failures not recorded and investigated, HPLC processing methods not recorded, no procedure for  chromatographic integration, re-integration, integration until good. No review of test results, no raw data for sample preparation,  audit trail function disabled, no record of acquisition data, original paper records destroyed, inadequate access controls, password sharing, no record retention policies, unknown chromatographic peaks not investigated, ICH Q7 recommended
  •  Examples:
    - Your analytical methods are not locked to ensure that the same integration parameters are used on each analysis. A QC operator interviewed during the inspection stated that integrations are performed and re-performed until the chromatographic peaks are “good”, but was unable to provide an explanation for the manner in which integration is performed. Moreover, your firm does not have a procedure for the saving of processing methods used for integration.
    - Your response did not include a description of the method by which chromatograph integrations are to be performed (e.g., what constitutes a chromatographic peak, how shoulder peaks are to be handled, etc.). In addition, your response did not include an audit of past chromatographic data to determine whether data used to support release and stability studies originated from appropriately integrated chromatograms. - The investigator observed at least two examples when a manufacturing step was recorded in the batch record before it occurred
    - The production operator had already recorded the start time for step xxx for  as 12:15 PM on October 26, 2012, although it was still 11:00 AM when our investigator noticed this situation.
    - On October 27, 2012, our investigator noticed that a QC analyst was performing a Loss on Drying (LOD) analysis for xxx and had recorded the completion time as xxx and total time as xxx in the usage log book for the LOD oven usage logbook although the step was not yet completed
    - Your response to this observation stated that a new SOP has been created to address this issue and that training on this SOP has occurred. Your response did not address the extent of this practice, the impact on the quality of the product and why your laboratory management failed to detect this practice. Your response also provided no actions to improve oversight by your quality unit (e.g., independence, authority, resources). The above practices observed during the inspection raise concerns regarding the reliability and accuracy of the data generated at your firm, including any other inappropriate data-related practices permitted by your firm when an inspection is not in progress.
    - In response to this letter, provide a summary of your full assessment of all the raw data recorded on each of the batch production and QC laboratory analytical records for the APIs intended for the US market to ensure their reliability.
    - Your firm failed to review and investigate production and QC laboratory deviations, for example
    - The inspection revealed that more than 30 power outages occurred in 2012. The investigator was told that when a power failure occurs, the backup generator does not turn on automatically, but rather needs to be manually started by an employee. In each instance, your firm failed to conduct an investigation into the power outage’s impact on quality of product(s) being manufactured at the time. The inspection documented that, despite the fact that your firm has an uninterrupted power supply used by the QC laboratories, power failures have impacted the QC stability chambers. However, in each case, no investigation was conducted to determine the impact of the power loss on the samples kept within the chambers. ..
    - Deviations pertaining to laboratory equipment failures were not investigated. During the review of the service report log books for HPLC and GC units, the investigator found many instances of servicing due to instrument problems that were not documented as deviations. As such, your firm failed to follow the SOP 1019 entitled “SOP for Deviation Management.” According to this SOP, all service activities for equipment, including laboratory instruments, need to be documented as deviations. Your response stated that the SOP has been changed to require deviations only for instances in which servicing was required to repair a problem with the instrument. Your response failed to address why no deviation was filed and investigated for the instances in which instrument problems were the cause of system maintenance (such as “system problem visit” on May 8, 2012, for Instrument QC/INST/067 or “needle motor stalled” on May 13, 2012, for Instrument QC/INST/022).
    - Please also note, as a general laboratory practice, any equipment malfunction that may have an impact on quality control testing should be appropriately recorded and investigated.
    - Your firm failed to conduct an investigation into unexplained discrepancies (atypical peaks) observed in the related substance assay results for multiple (b)(4) API batches ((b)(4)). During the inspection, the investigator noticed that the related substance chromatograms exhibited several peaks between (b)(4) of retention time. Your firm management did not know the source of these atypical peaks and had not initiated an investigation to document them.
    - Your firm released those lots to the U.S. market despite the detection of atypical peaks during release testing. Your firm’s response stated that you will begin integrating each peak and will conduct an investigation in the case of any peak anomaly. Your response did not address retrospective peak evaluation and risk assessment for these batches and other APIs.
    -  In response to this letter, describe the source of the atypical peaks detected in the related substance assays of the batches described above and in any other API distributed to U.S.
    - The inspection documented that HPLC processing methods (including integration parameters) and re-integrations are executed without a pre-defined, scientifically valid procedure.
    -There is no raw data for the related substance preparation of xxx testing for lots xxx and there is no raw data for the standard and sample preparation for the residual solvent testing of the same lots. Your analysts informed the investigator that no raw data for standard and sample preparations are kept in the records. Your response states that your firm will begin maintaining the raw data used for the assays cited on the Form FDA-483 but makes no commitment to perform a laboratory-wide audit to determine whether other assays conducted in your laboratory also require procedural or administrative changes to maintain all raw data generated during performance.
    - Additionally, as at the 3006418686 site, during the review of the chromatography data at the 3009688205 site, our investigator noticed that the raw data retained does not include the run sequence or the processing method used to perform the peak integrations
    - Your QC personnel perform peak integrations based on analysts’ experience rather than by an approved procedure. Moreover, the chromatography raw data does not include the processing method used to produce the final analytical results; therefore, during the review of the analytical data, it would not be possible to detect any modification to the processing method.
    - Your firm’s response mentions that the QC operations are now under “direct control of administrator”, but it does not define the roles and responsibilities of the administrator to ensure the integrity and reliability of all QC laboratory data
    - The audit trail function for the chromatographic systems was disabled at the time of the inspection; therefore, there is no record for the acquisition of data or modifications to laboratory data. Your response to this deficiency did not discuss how you will ensure that data audit trails will not be disrupted in the future.
    - When weighing samples, reagents, and other laboratory materials, QC analysts write weight values on small pieces of paper, transcribe the values onto the analytical worksheets, and then destroy the original paper on which the weights are written. This was reported to be a normal practice within the laboratory. Our investigator also observed the practice of writing the weight values for samples on a small piece of paper and not on the analytical worksheet. This is an inappropriate documentation practice.
    - Your QC laboratory documentation practices do not support the reliability of the results reported. In response to this letter, provide a retrospective assessment of all the analytical data generated and used for the final API release shipped to U.S. market. Please explain the actions you are taking to prevent these unacceptable record-keeping practices, including but not limited to better defining the oversight role of QC management, as well as senior managers of your company, to ensure that all QC laboratory data is reliable.
    - Your firm failed to have adequate procedures for the use of computerized systems used in the QC laboratory. At the time of the inspections, your QC laboratory personnel shared the same username and password for the operating systems and analytical software on each workstation in the QC laboratory. In addition, no computer lock mechanism had been configured to prevent unauthorized access to the operating system. The investigator noticed that the current QC computer users are able to delete data acquired. In addition, the investigator found that there is no audit trail or trace in the operating system to document deletions.
    - A production employee had recorded the final packed quantity of the batch even though the quantity was not yet known because the operator had not yet weighed the batch
    - Immediately after observing the incident, the investigator requested a copy of page 6 of the batch record containing Step (b)4) and was given a photocopy. A full batch record provided later that day did not include the original page 6. Instead it included a new version of page 6
    - The investigator noticed that the use of the Excel® spreadsheets in analytical calculations are neither controlled nor protected from modifications or deletion. The investigator noticed that the calculation for residual solvent for (b)(4) uses an Excel spreadsheet that has not been qualified. We are concerned about the data generated by your QC laboratory from non-qualified and uncontrolled Excel spreadsheets.
    - In response to this letter, provide a retrospective evaluation of the analytical values reported where such Excel spreadsheets have been used.
    - You are responsible for the accuracy and integrity of the data generated by your firm. A firm must maintain all raw data generated during each test from laboratory instruments. The authenticity of these records is critical, as they are used to demonstrate that each released batch was appropriately tested and met release specifications. 
    - Appropriate record retention policies should also be in place. The observation of premature data entries, when a manufacturing or QC laboratory step(s) has not been completed, into batch records and laboratory worksheets, and the modification and re-creation of batch records calls into question the accuracy and reliability of your firm’s data. We remind you that all production-related and laboratory-related activities are to be recorded at the time at which they are performed.

    - The items listed above, as well as other deficiencies our investigator found, lead us to question the effectiveness of your current quality system to achieve overall compliance with CGMP at your facility. It is apparent that you have not implemented a robust quality system at your firm. Be advised that corporate management is responsible for ensuring the quality, safety, and integrity of drugs manufactured by both Aarti facilities. FDA strongly recommends that your corporate management immediately undertake a comprehensive evaluation of global manufacturing operations to ensure compliance with CGMP regulations.-

 

W-286

Keywords: Procedures, media fill studies, gloves, aseptic processing, environmental monitoring, audit trail, raw data

  • Primary deviations
    - Procedures not followed, inadequate media fill studies, non-sterile gloves used in aseptic processing, poor environmental monitoring system, inadequate failure investigations, inadequate lab controls, only 2 out of 32 stability samples analyzed, clean building, no audit trail on Jasco system, system cannot prevent change or deletion of data
  •  Examples:
    - Non-integral and non-sterile gloves are used for aseptic processing
    - In  intact glove packages examined for the integrity of the gloves inside, our investigators found the gloves to have visible holes, flaking, cracking, and/or discoloration
    - Damaged or incomplete packages were found in many glove packages examined for package integrity
    - Your written response minimizes the importance of ensuring glove integrity and its potential impact on product quality. We disagree with your rationale for the following reasons:
    - Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing (21 CFR 211.42(c)(10)(iv)).
    - Your firm’s (b)(4) “Jasco LC-Net II” HPLC instruments do not have restrictions in place to prevent any change or deletion of analytical raw data
    - Additionally, there is no audit trail in place to determine any previous deletion of raw data.
    - In your response, please submit an assessment of the integrity of the data from the Jasco systems only for lots of finished product still within expiry as of the date of this letter.

 

W-285

Keywords: GMP, stability testing, CAPA, equipment, maintenance, root cause, SOPs, risk assessment, failure investigation, cleaning validation

  • Primary deviations: Inadequate stability testing, not following internal procedures, inadequate failure investigations, no root case analysis, ineffective CAPA, insufficient control of incoming material, SOPs for product testing not followed, inadequate handling of OOS results, no preventive equipment maintenance, inadequate risk assessment,
  • Examples:
    - You failed to follow your written testing program designed to
    assess the stability characteristics of your drug product.
    - Recurring errors and/or deviations during production have not been
    thoroughly investigated or effectively corrected
    - Procedures for laboratory testing are deficient or not followed
    in that operator errors continue to occur while processing/testing
    samples
    - In 2012, the stability time points for several batches were missed
    at the three month time point

 

W-284

Keywords: Data integrity, raw data, HPLC data, security access, training, third party consultants

  • Primary deviations: Laboratory records not complete, HPLC raw data files can be deleted from the hard drive using the common PC login used by all analysts, missing risk assessment on the impact of disabled audit trail, lost equipment activity logs, QC officer had the ability to delete electronic raw data, no or inadequate training, inadequate response to 483, no root case analysis
  • Examples
    - the FDA investigators found unofficial batch records for approximately 75 batches of injectable finished drug products torn in half in a waste area. These records contain data indicating that some batches failed to meet the in-process visual inspection specifications of not more than xxx% defects, while the official batch records for these batches state that these batches had met the specifications
    - The above examples raise serious concerns regarding the integrity, reliability and accuracy of the data generated and available at your facility. In your response to this letter, provide an independent and comprehensive evaluation of the extent of the deletion and destruction of records, a risk assessment regarding the potential impact on the quality of products, and a comprehensive corrective and preventive action plan.  Your submission should include a summary report of your evaluation of the data and records related to the manufacture (including testing, holding, etc.) of all drug products produced at your site
    -  This evaluation should include a detailed investigation of other instances in which your operations and quality units failed to ensure proper testing of materials, review of laboratory results and production data.
    - For all other instances of missing, inaccurate or unreliable tests results are found, describe these findings in your response to this letter.  Your investigation should assess the impact of all these incidents on the quality of the drug products manufactured and released into distribution, and explain the systemic actions that will be instituted to prevent these fundamental breaches of data integrity and management oversight in the future. 
    - Accordingly, you should include a detailed description of your plans to implement a robust quality system in your response to this letter. This remediation plan should describe the broader steps you will be taking to ensure direct corporate oversight over the quality and operations functions of this facility. This system should ensure sustainable compliance with CGMP, including the basic capability to prevent data manipulation and destruction of records.
    - Your firm’s laboratory records failed to include complete records of all stability testing performed.  The FDA investigators identified the practice of performing "trial" sample analysis for High Performance Liquid Chromatography (HPLC) analyses prior to collecting the “official” analytical data for stability testing. These “trials” were performed on multiple products, including (xxx Tablets. These trial runs were not recorded in the equipment use log, and sample preparation data associated with these analyses was destroyed, preventing any calculation or analysis of the resulting data. Your response states that trial runs were conducted using only one of the HPLC instruments located in the stability laboratory, which happened to be the one instrument that the FDA investigators reviewed during the inspection. Your response indicates that you have revised procedures and re-trained your staff. 
    - Your quality control HPLC raw data files can be deleted from the hard drive using the common PC login used by all analysts.
    - Our investigators found that several of the HPLCs had the audit trail functions disabled; therefore, there is no assurance that the data generated using these HPLCs is accurate.
    - However, your firm failed to provide a risk assessment for the products tested using the HPLC instruments that had the audit trail functions disabled. This is especially noteworthy given the fact that prior to the inspection, at least one QC officer had the ability to delete data on the affected system.
    - For example, on March 18, 2013, FDA investigators identified the presence of incomplete training "Questionnaire" records.  Per your training procedures, these questionnaire forms must be completed following each training to assess the individual's competence. The inspection documented over 40 instances of incomplete training records for three of your staff members. In each case, the trainee and trainer names were left blank on the questionnaires, but were pre-filled with the answers.  Incomplete training records were found for critical GMP activities-
    - Your response indicates that these are not GMP documents and that the FDA investigators’ concerns were limited to the department-specific training. Your response did not include a review of all other training documents to determine whether assessments had been appropriately completed and assessed. 
    - In your response to this letter, provide your plan to develop a robust CGMP training program for your personnel, and how you intend to assess the effectiveness of the training
    - As requested above, provide your corrective action plan that describes your commitment, procedures, actions, and controls to ensure data integrity.  This plan should include the corrective actions implemented to ensure that all managers, supervisors, and quality unit personnel are properly trained in detecting data integrity and manipulation.
    - As requested above, provide your corrective action plan that describes your commitment, procedures, actions, and controls to ensure data integrity.  This plan should include the corrective actions implemented to ensure that all managers, supervisors, and quality unit personnel are properly trained in detecting data integrity and manipulation
    - The investigation should provide detailed descriptions of other incidents where your quality unit failed to ensure proper testing of materials and should include a retrospective review of all test results generated by your laboratory personnel. If other instances of non-existent, inaccurate, or unreliable test results are found, your investigation should assess the impact of these discrepancies on the quality of the drug products manufactured at your facility. Provide the documentation of specific training offered to all employees regarding the importance of following CGMP and ensuring that all required tests are performed.
    - In summary, you are responsible for having controls to prevent omissions of data, as well as, recording any changes made to existing data, which should include the date of change, identity of person who made the change, and an explanation or reason for the change. All changes to existing data should be made in accordance with an established procedure
    - We highly recommend that you hire a third party auditor, with experience in detecting data integrity problems, to assist you with this evaluation and to assist with your overall compliance with CGMP. It is your responsibility to ensure that data generated during operations is accurate and that the results reported are a true representation of the quality of your drug products. Provide a list of all the lots of drug products shipped to the U.S. market that relied upon missing, inaccurate, or unreliable test data
    The data integrity consultant should:
    1. Identify any historical period(s) during which inaccurate data occurred at your facilities.
    2. Identify and interview your current employees who were employed prior to, during, or immediately after the relevant period to identify activities, systems, procedures, and management behaviors that may have resulted in or contributed to inaccurate data reporting.
    3. Identify former employees who departed prior to, during, or after the relevant period and make diligent efforts to interview them to determine whether they possess any relevant information regarding any inaccurate data reporting.
    4. Determine whether other evidence supports the information gathered during the interviews, and determine whether additional facilities were involved in or affected by inaccurate data reporting.
    5. Use organizational charts and SOPs to identify the specific managers in place when the inaccurate data reporting was occurring and determine the extent of top and middle management involvement in or awareness of data manipulation.
    6. Determine whether any individual managers identified in item (5) of this subparagraph are still in a position to influence data integrity with respect to CGMP requirements or the submission of applications; and establishing procedures to expand the internal review to any other facilities determine to be involved in or affected by the inaccurate data reporting.

 

 

W-283  483

Keywords: Data integrity, raw data, analytical data, security access, computer validation. impurities, specifications, revalidation

  • Primary deviations: unauthorized access to systems and data, analysts can overwrite existing sample information, no or inadequate electronic audit trail, data system not validated, no periodic audits of computer systems, no specifications for impurities, no periodic revalidation of software, chromatographic integration parameters are not stored, software error checking system not challenged, 
  • Examples:
    -- Operations that could affect the integrity of chromatographic data files
    collected and processed by the data acquisition system are  not controlled by
    electronic audit trails that maintain who, why and what was changed to any
    given sample record. Electronic audit trails are not configured for any of
    the computerized HPLC system, and there are no records of user transactions when data is deleted, copied, renamed or purged.
    - There are insufficient security measures in effect to ensure the
    integrity of chromatographic data housed in the Quality Control Laboratory.
    - There is no post-login security to prevent users from accessing all data
    files. Data is not stored in personal accounts protected by operating
    systems access controls, and all users have read/write access co the data
    scored on each hard drive. Employees without passwords have access to data
    files when analysts leave a terminal without terminating a session.
    - The current data acquisition has not been been validated, challenged
    and evaluated as to its correctness effect on program execution.
    - There are no SOPs or systems in place to initiate revalidation when modifications to the software occur or significant hardware changes are made.
    - There are no provisions for periodic audits of validated computer systems
    - The firm lacks the controls necessary to ensure the integrity of raw data
    generated by the laboratory computer system
    - The firm does not electronically store all integration parameters and chromatograms, nor can the firm determine if reintegration of a sample occurred once or several times
    - Computer software programs which control and document analytical data can
    not ensure data integrity and traceability. Analysts can overwrite the
    existing sample information in the software program's analytical raw data
    files and change results by overwriting the existing sample result data
    files. Once the results are modified, the changes can be saved to the
    current file, or a newly created data file.
    - There are dialog boxes in the program to reject analytical data whenever the user considers the results to be outliers.
    - Operations which delete, corrupt or modify data files before, during or
    after data acquisition are available to analysts.
    - Users without the appropriate security level have access to the DOS platform, and can make inappropriate changes to software programs. Data f1les can be modified, copied, deleted, or renamed.
    - Users can access dialog boxes that add, delete, and rearrange data in a sequence by appending, inserting, copying, deleting, and moving rows
    - Complete data derived from all tests are not maintained by the Q.C. laboratory,
    - The computer laboratory system which calculates the percent purity and potency of products released for distribution and tested for stability by HPLC is
    programmed to overwrite chromatographic data. The firm does not
    electronically store all integration parameters and chromatograms,
    nor can the firm determine if reintegration of a sample occurred once or several times. Each reintegrated chromatogram replaces the previous chromatogram. .
    - There are no SOPs for determining the degree of testing
    necessary to assure the proper function of the system following any
    hardware or software modifications.
    - There are no SOPs in place to periodically revalidate and challenge the software program to assure data acquired on the system is accurate and reliable for determining the purity and potency of products.
    - The software error checking system is not periodically
    challenge and evaluated. Software validation does not include the
    challenge of critical decision paths and error routines within the
    program to determine the effect on program execution.
    - Testing has not been conducted simulating worst case conditions.
    - The firm's procedure for recording analysts original observations (raw data)) on worksheets) is deficient in that there is no worksheet accountability, and the integrity or the recorded data is inconclusive. Worksheets are not identified in a manner that assures the original document was not reproduced.

 

W-282  483

Keywords: Method transfer, method validation, stability indicating methods, software validation, data integrity, audit trail, cleaning validation, equipment maintenance, raw material testing, annual report, training,

  • Primary deviations:  No acceptance criteria for analytical method transfer, method validation inadequate, annual report incomplete, quality of incoming raw material not assured, inadequate training, process to endure data integrity not validated
  • Examples:
    - Accuracy, sensitivity, linearity, LOD, LOQ and/or specificity were not assess in the method validation.
    - The firm failed to determine the acceptability of ten methods prior to using them in the QC laboratory through formal method transfer procedures.
    - The firm uses test methods that are not stability indicating to re-test and release active pharmaceutical ingredients (API). The SOP xxx states in section 2.2.: This procedure applies to the transfer of validated, non-compendial. analytical test methods from the Originating Laboratory (OL) to the Receiving Laboratory (RL) ( including transfers to and from an xxx laboratory)
    - The firm uses USP assay test method for xxx API (a titration method) for raw material retest. Titration is not a stability indicating method and cannot detect unknown degradants. For example ....
    - The software that controls the xxx used for NDA 203312 was not validated. These instruments/equipment were used to analyze the NDA product. The firm did not validate the integrity acquisition system ensure that analysts cannot rewrite or delete analytical data during analysis.
    - Data audit trails were not maintained and instrument audit logs are not saved.
    - The in-process weight checks during the compression and encapsulation process are performed on equipment scales that allow all production personnel to alter data and time when performing these in-process weight checks.
    - The firm does not perform testing of raw material for conformity with all written specifications reported on the vendor's Certificate of Analysis (CoA). They only perform limited testing and have not established the reliability of the supplier's test results. The firm has no documented justification for not performing all tests on the certificate.

 

W-281

Keywords: GMP training, equipment qualification, cleaning validation, product testing, annual product review, testing of incoming materials, just rely on supplier COA, at least one identity test, process validation, product testing

  • Primary deviations:  No GMP training, equipment not qualified, no cleaning validation, no annual  product review, manufacturing process not validated, inadequate procedure for product testing, inadequate qualification of incoming material
  • Examples:
    - Your firm does not provide CGMP training to employees. In response to this letter, provide a copy of your CGMP training program and a timeline for completion of training for all employees.
    - Your firm failed to conduct annual product reviews of all drug products distributed to the U.S. since 2010. In response to this letter, provide written procedures for the review of drug products on an annual basis, including but not limited to, provisions for reviewing complaints, recalls, returned or salvaged drug products, and investigations associated with deviations or batch failures. Also, explain how your firm will ensure that future annual product reviews are conducted. 
    -For example, your manufacturing processes for xxx are not validated.
    - For example, your firm has not established assay method(s) to determine the strength of the active ingredients menthol and/or methyl salicylate for any of your finished drug products containing these ingredients. Your firm only identifies these active ingredients by thin layer chromatography (TLC).
    - your firm does not perform any testing on incoming lots of menthol and methyl salicylate active pharmaceutical ingredients (APIs) prior to use in production.  Rather, you relied solely on certificates of analysis (COA) provided by the suppliers even though you had neither conducted an identity test nor established the reliability of the suppliers’ analyses through appropriate validation of the suppliers’ test results.  
    - In your response to this letter, describe procedures for ......

 

W-280

Keywords: GLP, SOPs, records, QAU, protocols, batch receipt and distribution 

  • Primary deviations: Study not conducted according with the protocol, data entries not signed by the person responsible for recording the data, QAU did not periodically submit the status on each study, the receipt and distribution of each batch not documented, deviations from Standard Operating Procedures not authorized and documented, unforeseen circumstances with impact on quality not noted and no corrective actions were taken, experimental data not accurately documented
  • Examples
    - The protocol indicated that the temperature of the water in the tanks should be maintained at *[(b)(4)]* Review of the Daily Measurements recorded in the Water Quality Record show temperature values outside of this range in several tanks on several days.
    - Quality Assurance Unit (QAU) failed to periodically submit to management and the study director written status reports on each study, noting any problems and the corrective actions taken [21 CFR 58.35(b)(4)]
    - The receipt and distribution of each batch of test and control articles were not documented, including the quantity and date of each batch distributed and returned [21 CFR 58.107(d)]. For example:
    - The amount of test article on hand after the four week treatment period exceeded the amount initially received for two of the three test article usage records audited
    - All deviations from standard operating procedures (SOPs) were not
    authorized by the study director and documented in the raw data [21
    CFR 58.81(a)]..

 

W-279

Keywords: Aseptic processing, microbial contamination, environmental conditions, training, missing root cause

  • Primary deviations:  Staff not adequately trained, procedures not followed, inadequate response because no root cause identified, no procedures or procedures not followed designed to present microbial contamination, no adequate system for monitoring environmental conditions in aseptic processing areas
  • Examples
    - Your firm failed to ensure that each person has the education, training, and experience, or any combination thereof, to enable that person to perform his or her assigned functions
    - Personnel
    were not following the procedures that govern their activities, such as glove change frequency, the handling of dropped objects, personnel monitoring, and sample acquisition.
    - Your response did not provide an explanation for why your (training) system was unable to recognize, identify and mitigate these performance lapses
    - We observed that your smoke study videos were not sufficient to evaluate the quality of your Class
    - Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas

 

W-278

Keywords: Equipment qualification, requalification, laboratory records

  • Primary deviations:  Laboratory records incomplete, no periodic calibration or qualication of equipment, qualification and evaluation of equipment
  • Your firm has failed to calibrate instruments and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met [21 C.F.R. § 211.160(b)(4). For example
    - Your firm does not have an established written program to calibrate/qualify the xxx gas chromatograph (GC) at suitable intervals.
    - Your firm did not calibrate and qualify the xxx high performance liquid chromatography (HPLC) instrumentation adequately, in that there is no periodic qualification or evaluation of the pump, oven, injector, or detector.

 

W-277

Keywords: Quality systems, quality plan, CAPA, change control,, complaint handling, internal audits, management reviews, data trending,  process validation, environmental control, document conrol

  • Primary deviations:  Significant deficiencies relating to management controls, change control, CAPA, complaint handling, audits, purchasing controls.  No management review and and training procedures, no data trending, environmental conditions not controlled, no document control procedure, inadequate complaint procedure, the firm failed to conduct internal and external audits and process validation
  • Examples
    - Quality audits were not conducted to verify that the quality system is effective in fulfilling your quality system objectives
    -
    .No complaint files, revision change records for the labels, procedures and device specifications are maintained
    - No quality plan and policy has been established by the executive management
    - Training procedure has not been established
    - Procedures for identifying training needs have not been established
    - There was no management meetings conducted and no management reviews were performed
    - The firm has no CAPA procedure
    - The quality source data including identifying the causes of non-conformities or other quality problems and the potential causes were not identified and documented
    - There was no trending of quality data sources
    - There complaint procedure did not address the complaint evaluation, investigation, cause determination, corrective action, segregation and disposition or reprocessing of retuned products.
    - Records of all changes to all documents were not maintained
    - No revision history has been maintained for the quality procedures

 

W-276

Keywords: Equipment qualification, stability testing, process validation, laboratory records, method validation

  • Primary deviations:  No adequate stability testing program, no written procedures to validate the performance of manufacturing processes, laboratory records incomplete, incomplete method validation
  • Examples
    - The investigators found deficiencies that lead us to question the effectiveness of your current quality system to achieve overall compliance with CGMP at your facility.  For example, there are several instances of incomplete qualification of equipment and incomplete laboratory data. We recommend that you seek the advice of a third-party consultant for assistance with a complete evaluation to determine the improvements that you will need to make at your firm in order to meet the CGMP requirements for the manufacture of OTC drug products.
    -Your firm does not have laboratory control records which include complete data derived from all tests necessary to ensure compliance with established specifications and standards
    - Your firm failed to include the required raw data, including the sample dilution, mobile phase preparation, equipment used, conditions of the chromatographic system, and the signature and date of the analyst who performed the tests
    .
    - You firm failed to list a mathematical factor used for assay calculation in the test method procedure
    - You failed to maintain important raw data, such as sample and standard preparation for the stability studies performed to justify the (b)(4)-year expiry period, in your analytical records
    - Your firm neither established nor documented the accuracy, sensitivity, specificity, and/or reproducibility of test methods
    - For example, you did not conduct a test for specificity in validation report #CC-VAL-02 for the HPLC method

 

W-275

Keywords: GLP, QAU, master schedule, protocols, internal audits, study reports, SOPs, test and control articles, equipment calibration, archives

  • Primary deviations: No Quality Assurance Unit established, no master schedule maintained, copies of protocols not maintained, studies not inspected, final study reports not reviewed, complete protocols not maintained, inadequate reports of study protocols, missing SOPS, inadequate characterization of test and control articles, inadequate equipment calibration, no archives for storage and retrieval of test data
  • Examples
    - The final study reports for the *[redacted] are deficient in that they failed to include: the name of the study director; the storage location for specimens, raw data, and the final study report; a QAU statement prepared under 21 CFR§ 58.185(a)(14); the signature of the study director; and the date the study director signed the report. [21 CFR §§-58.185(a)(10), (13), (14); 58.185 (b)
    - The form for final study reports, is incomplete because it lacks a description of the transformations, calculations, or operations performed on the data, a summary and analysis of the data, and a statement of the conclusions drawn from the analysis. [21 CFR § 58.185(a)(11)] The investigator found incomplete final study reports for the following studies
    - The inspection found that archives for orderly storage and expedient retrieval of all raw data, documentation, protocols, specimens, and interim and final reports were not maintained. Data was not retrievable showing the cell line and/or lot number of the test article used in studies xxx, and *[redacted]*. In addition, documentation was not retrievable for xxx stability testing

 

W-274

Keywords: Method verification, risk assessment, stability testing, inadequate response

  • Primary deviations:  No or inadequate verification of analytical methods, risk based approach, missing forced degradation, missing forced degradation, no proof of suitability of the method used for stability testing
  • Examples
    - Specifically, your firm failed to conduct and document a verification
    under actual conditions of use of the following laboratory testing
    methods: related substances method (HPLC) and identification (IR) method used for release and stability testing, microbial and endotoxin testing methods used to monitor the quality of the purified water, and assay (titration) method for release and stability testing of xxx API.
    -  In addition, during the inspection your firm could not provide forced degradation data to support suitability of the HPLC test method for stability testing of *(b)(4)* API. Review of the chromatograms from the release testing of
    related substances for xxx API and xxx show peaks that do not separate, suggesting the method is not capable of detecting all related substances present.
    - In your response, you propose to perform a verification of the methods
    according to your firm’s requirements. Your response fails to provide
    the procedures and acceptance criteria for the verification studies and
    failed to determine the impact of the inadequately validated/verified
    methods on previously released materials.
    - In your response to this letter, please address these issues and provide
    a risk assessment for possible impurities present in APIs
    - You are responsible for ensuring that all analytical methods are verified prior to continuing manufacture and release of API lots to US. You are also responsible to ensure that the methods used for releasing product to U.S. comply with CGMP requirements for U.S. (i.e., use of USP methods)

 

W-273

Keywords: Microbiology, inadequate response, equipment cleaning, equipment maintenance, back-up, raw data, security of electronic data, third party auditor, review of electronic audit trail, import alert

  • Primary deviations:  No or inadequate procedures to prevent microbilogical contamination, equipment not cleaned and maintained at appropriate intervals, no risk assessment of the impact of no cleaning validation, no back-up of laboratory raw data, printed copies of e-records do not include all raw data, no security control of electronic data,
  • Examples
    - Your firm has not established or followed appropriate written
    procedures designed to prevent microbiological contamination of drug
    products purporting to be sterile. Such procedures include validation of
    the sterilization process
    - Your response of October 28, 2011, is inadequate because you failed to
    describe the specific steps that you are taking to ensure adequate
    oversight by the quality unit over critical aseptic operations
    - Your firm has not cleaned and maintained equipment at appropriate
    intervals to prevent contamination that would alter the safety,
    identity, strength, or quality of the drug product
    - You do not have data to show that your equipment cleaning procedure is
    adequate to prevent cross-contamination. Specifically, your firm has
    not conducted cleaning validation, cleaning verification, or swab
    recovery studies for non-dedicated equipment used in the production
    - In your response, you commit to conduct cleaning validation studies and
    swab recovery studies. However, your response is inadequate because you failed to provide your risk assessment for all sterile products within expiry that were manufactured in multi-use equipment without validating your cleaning procedure
    - There is no system in place to ensure that all electronic raw data
    from the laboratory is backed up and/or retained.
    - During the inspection, you informed our investigators that electronic
    raw data would not exist for most HPLC assays over two years old because
    data is not backed up and storage space is limited
    - Data is deleted to make space for the most recent test results. You
    also informed our investigators that printed copies of HPLC test results
    are treated as raw data.
    - Printed copies of HPLC test results from your firm’s systems do not
    contain all of the analytical metadata (for example: instrument
    conditions, integration parameters) that is considered part of the raw
    data.
    - We acknowledge that your response indicates that you have created a procedure in order to implement the back-up and retention of HPLC
    data. This electronic HPLC data supports testing, disposition, and other significant quality control decisions, and it is essential that you maintain this information for each batch. In your response, please provide a detailed update on your firm’s implementation of this correction. Also describe your firm’s policy for retaining HPLC raw electronic data associated with pending applications
    - You have not implemented security control of laboratory electronic
    data.
    - All laboratory analysts share the same password for the HPLCs in
    the QC analytical chemistry lab and Omnilog in the microbiology lab.
    -In addition, analysts have access to the HPLCs which allow them to create
    and/or modify validated methods.
    - Your response indicates that SOP EDS-084: Procedure to Assign User
    Access Levels and Privileges for Computerized Analytical System has been
    issued and training has been provided. Please clarify in the response
    to this letter how you define the levels of authorization or the user
    access and privileges for analysts.
    - We also note that your SOP does not have provisions for any audit trail reviews to ensure that deletions and/or modifications do not occur. Please provide an explanation of your firm’s procedures regarding audit trails.
    -We highly recommend that you hire a third party auditor, with experience in detecting data integrity problems, who may assist you in evaluating your overall
    compliance with CGMP
    A review of the batch records that were listed in FDA form 483 is not sufficient. In your response, provide a complete corrective action plan that includes a retrospective review of the analytical data and batch records for all products manufactured at your facility that remain within expiration. In addition, provide the actions taken to prevent recurrence of the problem. Your investigation should be expanded to all other products manufactured at this site and include the establishment of a comprehensive training program for each person engaged in the manufacturing, processing, packaging, or holding of drug products. This plan should include training to all managers, supervisors, and quality unit personnel in detecting data manipulation and questionable practices.
    - In addition, until s your manufacturing practices are verified to comply with CGMPs, your firm will remain under FDA Import Alert, and FDA will continue to refuse admission of all articles manufactured at Gulf Pharmaceutical
    Industries located at Airport Road, Digdaga Area, Ras Al Khaimah, United
    Arab Emirates into the United States

 

W-272

Keywords: Food processing, Part 110, cleaning, sanitation, sampling plan

  • Primary deviations:  inadequate cleaning and sanitation practices, no sampling plan for collection of environmental samples
  • Examples
    - We note that you transfer personnel and equipment between the two facilities seasonally. Taken together, the recovery of /L. monocytogenes /with indistinguishable PFGE patterns from product and environmental samples collected from January 2010 to October 2011 that originated from your El Centro and Salinas facilities indicates that the cleaning and sanitizing practices you employ have not been effective to control /L.  monocytogenes/. In our Draft Guidance for Industry, "Control of Listeria monocytogenes in Refrigerated or Frozen Ready-To-Eat Foods," we recommend a number of practices to control /L. monocytogenes/.
    - Specifically, we recommend that you establish and implement a written plan for the collection of environmental samples from critical surfaces and areas, and for testing those samples for the presence of /Listeria/ species or /L. monocytogenes/. We recommend that you evaluate each plant, product, and process to determine the appropriate monitoring points. You may find our draft guidance for the control of /L. monocytogenes
    - We acknowledge corrections that you made prior to the end of the inspections. We also acknowledge your October 31, 2011 and your February 8, 2012 responses to the FDA 483s for your Salinas and El Centro facilities, respectively, in which you outlined corrections that you had made or would make. However, your responses are inadequate because they did not provide documentation of these corrections.

 

W-271

Keywords:  Complaints, design reviews

  • Primary deviations: Inadequate procedures for complaint handling,
  • Examples
    - Failure to establish and maintain adequate procedures for receiving, reviewing, and evaluating complaints by a formally-designated unit, as required by 21 CFR 820.198(a)
    - For example, your firm’s procedures, *(b)(4)*, do not adequately ensure that oral complaints are documented upon receipt and that complaints are evaluated for Medical Device Report (MDR) reportability
    - We reviewed your firm’s responses and conclude that they are not adequate. Your firm provided updated procedures: *(b)(4)*; however, your firm did not indicate or provide documentation that includes a description and evidence of implementation of any corrections and corrective actions (including consideration of systemic corrective actions) to ensure that complaints are received, reviewed, and evaluated in an effective manner. This includes providing documentation that your firm evaluated the five above-referenced complaints for MDR reportability, documented the required information for the oral complaint, and reviewed all other complaints for MDR reportability and required information.

    - Failure to establish and maintain adequate procedures to ensure that formal, documented reviews of the design results are planned and conducted at appropriate stages of the device’s design development. The procedures shall ensure that participants at each design review include representatives of all functions concerned with the design stage being reviewed and an individual who does not have direct responsibility for the design stage being reviewed, as required by 21 CFR 820.30(e).
    - We reviewed your firm’s responses are not adequate. Your firm provided an updated procedure, *(b)(4)*; however, your firm did not indicate or provide documentation that includes a description and evidence of implementation of any corrections and corrective actions (including consideration of systemic corrective actions) to ensure that the design reviews outlined in the procedure are planned and conducted at appropriate stages.

 

W-270

Keywords: GLP, study data, protocol, approved procedures, status reports, study report

  • Primary deviations: Study data not promptly recorded, study data not signed, revisions to approved protocols not documented, changes not approved, protocol did not contain all required information, QAU failed to inspect each study at regular intervals, internal audit not signed, no procedures for animal care established, study report did not contain all required information, QAU failed to submit status reports on each study
  • Examples:
    - For studies xxxyou failed to record data generated during the conduct of the studies, such as documenting the time and volume of the dose administered. Consequently, the actual dose administered in the studies is unknown.
    - Also, in several instances, the person that weighed the animals in these
    studies prior to dosing did not sign and date the data entries as required.
    - The study director failed to document all changes in or revisions to
    the approved protocol and the reasons for the change or revisions [21
    CFR 58.33(a), 21 CFR 58.120(b)]
    - Protocols xxx failed to specify the body weight range, strain, and age of the test animals
    - The QAU failed to inspect each non clinical study at intervals
    adequate to assure the integrity of the study [21 CFR 58.35(b)(3)]
    - The QAU failed to maintain written and properly signed records of
    each periodic inspection [21 CFR 58.35(b)(3)].
    - The QAU failed to periodically submit written status reports on each
    study to management and the study director [21 CFR 58.35(b)(4)]
    - You failed to establish procedures for animal care [21 CFR 58.90].
    - You failed to include required information in the final study report
    [21 CFR 58.185(a)].*

 

W-269

Keywords:  Device design, acceptance activities

  • Primary deviations: Procedures for validation of device design inadequate, procedures for acceptance activities inadequate,
  • Examples
    - Failure to adequately establish and maintain procedures for validating device design, as required by 21 CFR 820.30(g). For example, your firm's validation protocol procedure entitled WP 4 General Protocol for R&D of ELISA Systems, File Name: WP 4-v2.doc, Version 2.0, Effective January 8, 2010, was not implemented to ensure that a validation protocol for the firm's PRA ELISA test kit design project was documented and approved with defined methods, statistical rationales, and acceptance criteria prior to the start of the testing as part of the validation of the assay system.
    - We reviewed your firm's response and conclude that it is not adequate. Your firm has stated that it realizes that the WP 4 General Protocol for R&D of ELISA Systems was not followed in this instance and that it opened a corrective action (CAR#19-2011) to address this. Additionally, your firm opened a corrective action (CAR#13-2011) to implement changes in the General Protocol for R&D of ELISA Systems to outline procedures for including defined methods and acceptance criteria based upon an established statistical rationale to all development validation protocols. Your firm's response also indicated that all research personnel will be trained to the new procedure and that this process will be audited internally every quarter to ensure compliance as part of PAR #1-2011. These corrective actions were to be completed by 11/15/2011. To date, your firm has not completed the corrective actions and has not provided evidence of implementation of all of the corrective actions indicated in the response.
    - Failure to adequately establish and maintain procedures for acceptance activities including inspections, tests, or other verification activities, as required by 21 CFR 820.80(a)
    - We reviewed your firm's response and conclude that its adequacy cannot be determined at this time. Your firm states that it is initiating a new process to assess each new lot of a kit component in relation to the previous component and established test acceptance standards for each component. These changes will be included in the revision of WP 5 QC Procedures for ELISA & CLIA Kits and Components as part of CARR#16-2011.
    Your firm's response also indicated that personnel will be trained on these new procedures and that management will closely monitor the implementation and continued compliance through regular quarterly internal auditing practices as part of PAR#1 -2011 These corrective actions are scheduled to be completed by 12/15/2011.

 

W-268

Keywords:  Dietary supplement manufacturing, Part 111, equipment cleaning, product specifications, control points, equipment design,

  • Equipment not adequately cleaned, product specifications not verified. specifications for process control points not established, inappropriate design of equipment
  • Examples
    -  You failed to adequately clean equipment and utensils to protect components and dietary supplements from being contaminated by any source, as required by 21 CFR 111.27(a)(3)(v). Specifically, the production procedures your firm uses in manufacturing dietary supplements are not adequate to ensure that preceding products do not contaminate subsequent products
    - You failed to verify that your finished batches of dietary supplements meet product specifications for identity, purity, strength, and composition, and for limits on those types of contamination that may adulterate or that may lead to adulteration of the finished batch,
    - You failed to establish component specifications for each component that you use in the manufacture of a dietary supplement, as required by 21 CFR 111.70(b)
    - You failed to use equipment of appropriate design and construction so
    that use will not result in the contamination of dietary supplements, as
    required by 21 CFR 111.27(a)(2). You also failed to maintain your
    equipment to protect components and dietary supplements against
    contamination from any source, as required by 21 CFR 111.27(a)(3)(v).
    - You also failed to maintain your equipment to protect components and dietary supplements against contamination from any source, as required by 21 CFR 111.27(a)(3)(v). Specifically, your firm is blending all products in *(b)(4)* commercial grade *(b)(4) *and one *(b)(4) *stock pots (i.e. soup pots), and mixing all powder blends with a handheld *(b)(4) *electric**mixer.
    - We have considered your response to these concerns, and determined it to be inadequate. During the inspection, you informed our investigator that you intended to correct these violations by telling your employees "not to hit the bottom of the pot with the mixer." This proposed corrective action will not sufficiently protect against contamination.

 

W-267  

Keywords:  Device, CAPA, complaints, design history files, design changes, design implementation, document control,

  • Primary deviations: CAPA Implementation not adequate, no verification of CAPA effectiveness, inadequate response, procedures for handling complaints inadequate, design history file not adequate, procedures for verification of design changes not adequate, procedures for translation of design into production specification not adequate, procedure to control documents not adequate
  • Examples
    - Failure to establish and maintain adequate procedures for implementing corrective and preventive action that include requirements for verifying or validating the corrective and preventive action (CAPA) to ensure that such action is effective and that it does not adversely affect the finished device as required
    - We reviewed your firm’s response and conclude that it is not adequate. The response included identifying a responsible person for the completion of the retrospective differentiation, identification of real CAPAs, and effectiveness checks of identified CAPAs by March 31, 2012.
    The response is not adequate because your firm has not implemented correction or corrective action. In addition, your firm did not provide documentation that it has investigated its complete CAPA subsystem or that a systemic corrective action was considered.

    - Failure to establish and maintain adequate procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a).
    - Your firm’s response included identifying a responsible person and a target date for several proposed measures. The response is not adequate because your firm has not implemented correction or corrective action. In addition, your firm has not provided documentation that it investigated its entire complaint subsystem or considered a systemic corrective action.
    - Failure to establish and maintain an adequate design history file (DHF) for each type of device that shall contain or reference the records necessary to demonstrate that the design was developed in accordance with an approved design plan and the requirements of Part 820, as required by 21 CFR 820.30(j).
    - The response included identifying a responsible person and a target date for several measures to be completed. The response is not adequate because your firm has not implemented correction or corrective action.
    - Also, your firm did not provide documentation that it has investigated the entire DHF subsystem or that it considered a systemic corrective action. In addition, your firm did not provide documentation that it will train employees on the new design transfer procedure.
    - Failure to establish and maintain adequate procedures for the identification, documentation, validation or, where appropriate, verification, review, and approval of design changes before their implementation, as required by 21 CFR 820.30(i). For example, your firm did not adequately document procedures for design changes to the tubing on the redesigned *(b)(4)*.
    - Your firm’s response included identifying a responsible person and a target date for several measures to be taken. The response is not adequate because your firm has not implemented correction or corrective action. Also, your firm has not provided documentation that it has investigated the entire design change subsystem and that it has considered a systemic corrective action. In addition, your firm did not provide documentation that it will train employees on the new Design Change Procedure
    - Failure to establish and maintain adequate procedures to ensure
    that the device design is correctly translated into production
    specifications, as required by 21 CFR 820.30(h).
    - We reviewed your firm’s response and conclude that it is not adequate because your firm has not implemented correction or corrective action.  Also, your firm has not provided documentation that it has investigated its entire design transfer subsystem to ensure that design transfer deficiencies would not recur and that it has considered a systemic corrective action. In addition, your firm did not provide documentation of employee training on the new design transfer procedures.
    - Failure to establish and maintain adequate procedures to control all documents, as required by 21 CFR 820.40. For example, your firm did not adequately establish document control procedures for documents unrelated to production or engineering changes.
    - We reviewed your firm’s response and conclude that it is not adequate because your firm did not implement correction or corrective action.  Also, your firm has not provided documentation that it conducted an investigation of the entire document control subsystem to ensure that all documents are controlled and that the problem does not recur and that you have considered a systemic corrective action.

 

W-266

Keywords:  Sampling plans, reserve samples, representative sampling, customer complaints, Sampling, sampling plan, microbiological contamination, records of returned drug products, procedures, production records, method transfer, computer validation

  • Primary deviations: Inadequate handling of customer complaints, inadequate procedures to prevent microbiological contamination of drug products, records of returned drug products are not maintained, equipment not suitably located, procedures not followed, deviations from written production procedures not justified, master production and control records incomplete, sampling plans not established or not scientifically sound, samples nor representative, samples not identified, sampling size not scientifically sound, reserve samples not inspected, met, suitability of transferred methods not verified, computer calculations not verified
  • Examples
    - Laboratory controls do not include the establishment of scientifically sound and appropriate sampling plans designed to assure that drug products conform to appropriate standards identity, strength, quality and purity
    - Samples taken of drug products for determination of conformance to written specifications are not representative and properly identified. You can not assure that samples drawn are based on a rational criterion such as random sampling and that the sample tested accurately portrays the material being sampled
    - The size used by the QC Microbiology Laboratory to determine sub-visible particulates in your small volume parenteral products is not scientifically sound.
    - Reserve samples from representative sample lots or batches of drug products selected by acceptable statistical procedures are not examined visually at least once for evidence of deterioration.
    - Your rationale for inspection of reserve samples is not based on acceptable
    statistical sound assessment

 

W-265

Keywords: GLP, Training, SOPs, equipment, facilities, protocols, master schedule. internal audits,

  • Primary deviations: Inadequate training, training records incomplete, testing facility did not fulfill its responsibilities, study director did not fulfill his/her responsibilities, not all required records transferred to the archive, QUA not entirely independent from people engaged in the study, QAU did not fulfill its responsibilities, inadequate calibration, maintenance and cleaning of equipment, SOPs not available or not followed, batches for fully characterized, written protocols not available for each study
  • Examples
    - The study director for the three studies reviewed during the inspection lacks the education, training, and experience, or combination thereof, to perform his functions as GLP study director
    - The testing facility management failed to designate a qualified study director as described in 21 CFR 58.33.
    -  The testing facility management failed to assure that deviations from the regulations were reported by the quality assurance unit and communicated to the study director, and that corrective actions were taken and documented.
    - The study director failed to assure that the protocols for each study were followed or that changes to the protocol were documented and approved
    - The QAU was not entirely separate from and independent of the personnel engaged in the direction and conduct of that study. The QAU manager for study TOX xxx reported directly to the study director
    - The QAU failed to maintain a complete copy of the master schedule sheet of all nonclinical laboratory studies conducted at the testing facility. Specifically, the master schedule failed to identify the test article, test system, the dates studies were initiated, the sponsor, and the name of the study director
    - There is no written documentation of the inspection, cleaning, maintenance, testing, calibration, or standardization of the xxx in which the test article for study TOX  was stored,
    - Failure to establish and follow standard operating procedures (SOPs) setting forth nonclinical laboratory study methods that management is satisfied are adequate to insure the quality and integrity of the data generated in the course of a study. [21 CFR § 58.81 (a) and (b)(6), (b)(7), and (b)(11)].
    - Significant deviations from the SOPs were neither authorized by the study director nor documented in the raw data of the applicable studies.
    -  The study director failed to assure that unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study were noted when they occurred, and that corrective action was taken and/or documented. Specifically, the TOX*[(b)(4)]* protocol contained specific requirements about conducting necropsies but these requirements were not followed. The study director failed to note this deviation from protocol and to take corrective actions

 

W-264 

Keywords: Part 11,security access, data integrity, audit trail, data back-up, corrective action

  • Primary deviations: Single user name for the entire lab, inadequate corrective action, missing audit trail, no data back-up, insufficient details for corrective actions, no time frame for corrective actions
  • Examples 
    - Your firm did not put in place requirements for appropriate usernames and passwords to allow appropriate control over data collected by your firm's computerized systems including UV, IR, HPLC, and GC instruments.
    - All employees in your firm used the same user name and passwords
    - In addition, you did not document the changes made to the software or data stored by the instrument systems.
    - Without proper documentation, you have no assurance of the integrity of the data or the functionality of the software used to determine test results.
    - Your firm had no system in place to ensure appropriate backup of electronic raw data and no standard procedure for naming and saving data for retrieval at a later date.
    - In your response, you state that you will maintain backup of electronic raw data and all technicians will have their own user identification (ID) and password.
    - Your response, however, is inadequate because you do not describe how your firm intends to save and back-up the electronic raw data, nor whether your firm will implement audit trails on your computerized systems.
    - Further, you do not provide a timeframe for accomplishing the intended corrective actions or describe the changes you have made to relevant SOP(s)

 

W-263  483

Keywords: Procedures, quality control unit, failure investigations, batch records, procedures, SOPs, complaint handling, people qualification,

  • Primary deviations: Responsibilities and procedures applicable to quality control unit not followed, missing written records of failure investigations, inadequate failure investigations, investigations not extended to other batches, batch record did not include all required information, deviations from written procedures not recorded and justified, inadequate procedures for complaint handling, inadequate number of qualified personnel, insufficient frequency of GMP training
  • Examples 
    - Your Quality unit failed in the responsibility and authority to monitor Quality Systems to assure the quality of drug products manufactured at your firm
    - Missing written records of failure investigations
    - You have failed to adequately investigate 166 complaint instances  of foreign tables in your drug products since 2009
    - You have failed to extend investigations to all batches of products potentially affected by a problem
    - The batch records do not record the distinctive identification number, code and name of the equipment to identify major equipment to show the specific equipment used in the manufacture of a batch of a drug product
    - in 2011 223 critical complaints have not been properly reviewed

 

W-262

Keywords: Procedures, aseptic processes, media fill studies, failure investigation, repeat observation, response to 483, cleaning validation, process validation, field alert report, repeat violations

  • Primary deviations: Missing procedures for media fill studies, missing failure investigation, failed to find the root cause of the problem, inadequate response to 483, investigation not extended to other batches, missing cleaning and maintenance at appropriate intervals, inadequate process validation, Field Alert Report (FAR) not submitted,
  • Examples 
    - We note that CGMP violations listed in this letter include multiple repeated violations from those cited in the August 2008 Warning Letter issued to Sandoz Inc.’s Wilson, North Carolina facility and repeated observations from previous inspections at your Sandoz Canada Inc. facility in Boucherville, Quebec, Canada.
    - It is apparent that Novartis International AG (Novartis) is not implementing global and sustainable corrective actions. We remind you that you are responsible for ensuring that your firm’s drug manufacturing operations comply with applicable requirements, including the CGMP regulations. FDA expects Novartis to undertake a comprehensive and global assessment of your manufacturing operations to ensure that drug products conform to FDA requirements. Finally, the Agency is concerned about the response of Novartis to this matter.
    - Corporate management has the responsibility to ensure the quality, safety, and integrity of its products. Neither upper management at Novartis nor at Sandoz Inc., nor at Sandoz Canada Inc., ensured global, adequate, or timely resolution of the issues at these sites.
    - Fourteen out of 79 (18%) laboratory investigations lacked documentation of either an investigation into other associated batches or products, or a corrective action

 

W-261

Keywords: Method Transfer, failure investigations, quality control unit, method validation, procedures

  • Primary deviations: Inadequate laboratory failure investigation, responsibility of Quality Control Unit not followed, procedures not followed, no formal transfer of analytical method,
  • Examples 
    - Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that drug products conform to appropriate standards identity, strength, quality and purity
  • The current corporate SOP xxx, "Test Method Transfer Procedure" effective on 06/05/09 states that formal method transfer studies are not required in the following instances:
    - When test procedures employing the techniques are already in use by the receiving laboratory and therefore, the method is not new.
    - When the receiving lab analysts are trained by the R&D or originating lab scientist.
    - When based on professional judgment a formal transfer study is not required but the rationale must be documented.
    - When the test procedure has built in control to verify the performance at each run
    - Corporate xxxx, "Chemical Test Methods Validation Procedure" does not require that method verifications are done at the laboratory site where the method will be utilized. The firm has failed to conduct method verifications at this site for the following samples: xxx, xxx:.

 

W-260

Keywords: Quality Assurance Unit, GLP, final report, equipment, test and control articles

  • Primary deviations: Not all experimental data accurately recorded, QAU did not fulfill its responsibilities, inadequate equipment calibration and maintenance, test and control articles not identified in the final report, studies not conducted in accordance with the protocol, final reports not available for each study
  • Examples
    - Failure of the study director to assure that all experimental data were accurately recorded and verified [21 CFR 58.33(b)] and document the reason for any change in the entries [21 CFR 58.130(e)].
    -. Failure of Quality Assurance Unit (QAU) to fulfill its responsibilities [21CFR 58.35(b)].
    - Failure to identify the test and control articles-with appropriate characteristics in the final report [21 CFR 58.185(a)(4)]
    - Failure to adequately test, calibrate, and/or standardize all equipment used for the generation, measurement, or assessment of data [21 CFR 58.63(a)].
    - Failure to prepare a final report for each nonclinical laboratory study [21 CFR 58.185(a)].
    - The quality assurance unit (QAU) failed to inspect each nonclinical laboratory study at intervals adequate to assure integrity of the study [21 CFR 58.35(b)(3)].*
    - Nonclinical laboratory studies were not conducted in accordance with the protocol [21CFR 58.130(a)].*

 

W-259

Keywords: Quality Control Unit,  failure investigations, method validation, robustness

  • Primary deviations: Responsibility of Quality Control Unit not established, inadequate response to failure investigations, failure to validate analytical test methods used for API for potency testing, no robustness testing,
  • Examples 
    - Failure to validate analytical test methods used for API for potency testing.
    - For example, your firm failed to validate the ONTAK *xxx to quantify Peak A for potency and robustness
    - Your firm has been unable to determine why the chromatographic columns of the same make and model had variability and could not provide adequate separation
    -- Your response, however, fails to provide an adequate scientific rationale to describe the reason why the co-eluting peak is significantly larger in this lot (as compared to the reference chromatogram), address the impact of the overlap of larger peaks, and evaluate how the method can be refined to prevent overlapping peaks

 

W-258

Keywords: Laboratory testing, microorganisms, system suitability, preventive action, failure investigations, OOS, SOP, response to FDA, signatures, test report, method validation, system suitability testing

  • Primary deviations: Inadequate laboratory testing, inadequate system suitability testing, corrective actions not extended to other test methods. no or inadequate method validation studies, corrective actions method validation and system suitability testing too late, failure investigations insufficient  or too late, ,out-of-specification results not reported to clients, SOPs not followed, response for corrective actions not detailed, missing signatures or initials of analyst and reviewer on test reports
  • Examples
    - Your firm has not conducted validation studies for analytical methods routinely used for assay determination of the drug products
    - Your firm has failed to establish and document the accuracy,  sensitivity, specificity, and reproducibility of test methods [21 C.F.R.§ 211.165(e)]. For example:
    - Your firm has not conducted validation studies for analytical methods routinely used for assay determination of the drug products.
    - - In your response, your firm states that the expected completion date for
    the validation of all analytical methods is June 2012. Your response, however, is not adequate since you have not provided interim actions to ensure the reliability of data until the analytical methods are validated

 

W-257

Keywords: Supplier control, quality agreement, 

  • Primary deviations: no purchasing control procedures, no quality agreements, no incoming specifications, no notification of specification changes, design changes not validated
  • Examples
    - Failure to establish and maintain purchasing control procedures
    - There are no incoming component specifications for acceptance and no supplier quality agreements .
    - No notification of specification changes was received by your firm.
    - Design changes are implemented routinely to accommodate each client, but these changes are not validated.

 

W-256

Keywords: Server, Back-up, HPLC Raw Data

  • Primary deviations: No back-up of raw data
  • Examples
    - your firm has failed to periodically conduct back-up procedures for the xxx server since August 2010. This server was used to store, back-up, and/or archive raw test data from computer systems software controlling and monitoring High-performance liquid chromatography (HPLC) systems  During the inspection, the xxx server was observed as being tagged out-of-service since February 2009.
    - In your response, your firm states that you have revised your procedure
    to include the implementation and installation of qualified
    backup software on xxx server to allow for remote backup. Your
    response, however, is inadequate because
    you fail to ......

    -  Your firm does not have adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and/or purity they purport or are represented to possess [2C.F.R. § 211.100(a)]. For example:
    - The process validation conducted for Fentanyl Transdermal System is inadequate in that your final process validation report failed to include and evaluate the impact of all the combined deviations that occurred during process validation. The report failed to include such deviations as (1) the discovery of brown particles in a laboratory sample of Fentanyl Adhesive Mas Solution (FAMS), (2) aborting the cutting/packaging operations during the first process validation lot due to a broken cutting and packing machine, and (3) setting of the IR gauge value below specification during the coating process for the first
    validation lot
    - .In your response, your firm states that the deviations were not considered to have an impact on validation at the time the validation report was prepared.
    - Your response, however, is inadequate because you fail to provide any supporting evidence to substantiate this claim. Your firm’s “Technical Review of Process Validation for Fentanyl Transdermal System” is inadequate because the contents are broad, lacks any supporting raw data, and is unclear as to what specific elements, lot numbers, and records were reviewed.

    - Your firm failed to ensure that the automatic, mechanical, or electronic equipment, or other types of equipment including computers or related systems, will perform a function satisfactorily [21 C.F.R. § 211.68(a)]. For example:
    - The initial qualification for the (b)(4) Cutting and Packing Machine, Model (b)(4) was completed on June 7, 2007. Approximately 25 major and minor changes were implemented between June 14, 2007, and July 15, 2010, before your approval of the re-qualification report for equipment (b)(4).
    - In your response, your firm states that (b)(4) Cutting and Packing Machine is a custom-made unit. The unit consists of subunits that perform functions independently of one another and that modification to one subunit does not necessarily adversely impact other subunits or the equipment as a whole. You added that the requalification requirement was documented in each approved Change Control.
    - Your response, however, is inadequate because you have neither provided documentation to demonstrate your claims of independently functioning subunits, nor have you provided your rationale why each equipment
    change did not necessitate a re-qualification and/or a re-validation of the (b)(4) Cutting and Packing machine.

    - Your firm has not thoroughly investigated any unexplained discrepancy or the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192]. For example:
    - Your firm has failed to conduct thorough investigations into the defects found in pouches for Fentanyl Transdermal System batches during the cutting and packaging operations with the (b)(4) Cutting and Packing Machine,
    - Your firm failed to determine the root cause(s) even though you installed a Primary Packaged Product Inspection Camera and implemented a 100% batch visual inspection.
    - In your response, your firm states that you will improve the investigation process by assessing all closed investigations within the last six months as well as enhancing site procedures. Your response, however, is inadequate because you fail to provide any details of your proposed enhancements. Additionally, your firm has not provided any steps and/or corrective actions to
    resolve the deviation described above.

    - Your firm has failed to conduct thorough investigations of customer complaints resulting from the missing patches from pouches of the Fentanyl Transdermal System. Your firm failed to determine the root cause(s) and/or initiate corrective and preventive actions as required by your Standard Operating Procedure, , titled, "," Revision (b)(4).
    - In your response, your firm states that the various complaints (i.e., (b)(4)) are pending and still under investigation.
    - Your response is inadequate because you received some of the complaints as early as September, 21, 2010, and there is no evidence to demonstrate that your firm has attempted to conduct a root cause analysis or tried to obtain the investigational report from your distribution partner. Additionally, you stated that your SOP, (b)(4), will be enhanced, but you have not provided a revised SOP for our evaluation

    - Your firm has failed to determine actual yield and percentages of theoretical yield at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the drug product [21 C.F.R § 211.103].
    - For example, your firm has failed to determine theoretical yields at appropriate phases of manufacturing based on statistical rationale and/or historical data. For Fentanyl Transdermal System (25/50/75/100 mcg/hr dosage strengths) Change Control #(b)(4), your firm changed the theoretical yield from (b)(4) to (b)(4) for the cutting and packaging operation using only
    developmental process validation and engineering lots instead of historical data of batches manufactured during the 2009 – 2010 period.
    - In your response, your firm states that you will establish a plan to revisit the current yield specifications while continuing to collect data over the next six months to ensure adequate data for establishing statistically relevant yield specifications throughout the appropriate phases of manufacturing.
    - Your response is inadequate because you have not provided sufficient
    details of your plan including the specified types of data to be collected, dosage type, and “appropriate phases” of manufacturing. In addition, your firm has not provided a rationale for collecting only six additional months of data and how that will be statistically relevant to your product/process.

 

W-254

Keywords: Excel spreadsheets, data integrity, validation, data security, raw data

  • Primary deviations: Excel spreadsheets not validated, Excel spreadsheets not protected against unauthorized changes, correct formulas not checked by QAU, correct transcription not verified, chromatographic reintegration not approved, chromatographic data not included in raw data, audit trail not reviewed
  • Examples:
    - There is no assurance of the accuracy and reliability of assay and impurity test results for release and stability testing through expiry in that assay and impurity calculations are made via unvalidated and unprotected Excel spreadsheet programs which are not managed and controlled to insure unauthorized changes to equations and/or calculations do not occur. Your firm does not have written or other hardcopies of assay and impurity calculations in laboratory notebooks. There is no documentation of what the Quality Unit reviewed to assure the correct equation was used and that the correct values were transcribed onto Finished Product Specification Sheets
    - Your firm's procedure allows your laboratory analyst to re-integrate chromatographic data without supervisory or Quality Unit review and approval.
    - Procedures do not require original chromatographic data to be included in your raw data packages and the data approved by the Quality Unit is not compared to the original acquired data.

 

W-253

Keywords: security, integrity, electronic records, preventive action, microbial contamination,  laboratory testing, sample storage

  • Primary deviations: Insufficient control over computer systems and records, inadequate  corrective and preventive actions, insufficient laboratory testing of products, no written procedures to prevent microbial contamination, sample integrity not demonstrated over required sample storage period
  • Examples
    - Your firm has failed to exercise appropriate controls over computer
    or related systems to assure that changes in master production and
    control records, or other records, are instituted only by authorized
    personnel [21 C.F.R § 211.68(b)]
    - For example, your firm lacks control of the *(b)(4)* computer system
    which monitors equipment, room differential pressure, room humidity, and
    stability chambers
    - Although the system is password protected for temperature and humidity set points, all employees have access to the room where the *(b)(4)* computer system is located and the external hard drive is not password protected. During the inspection we observed that an employee was able to alter or delete data without a password and save the changed file
    - In your response, your firm states that additional controls were implemented including validating the remote access to the (b)(4) computer, password protecting the room where the computer is stored, and limiting the (b)(4) control room to authorized personnel only. Although your corrective actions may adequately address the protection of the (b)(4) computer from non-traceable changes, your firm has not taken a global approach to this deficiency. It is our expectation that your other manufacturing and laboratory computerized systems will be reviewed to ensure similar deficiencies do not exist.

 

W-252

Keywords: process validation, failure investigations, OOS, root cause product review, product testing

  • Primary deviations: No validation of manufacturing processes, no thorough investigation of batch failures, no extension of failure investigation to other batches. inadequate product testing
  • Examples:
    -
    Your firm has not established written procedures to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and drug product
    - Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications, whether or not the batch has already been distributed, or extended investigations to other batches of drug product that may have been associated with the specific failure or discrepancy
    - The corrective actions implemented after the April 2010 inspection, as result of the metal contamination, are ineffective as evidenced by the continuing issues observed during the most recent inspection.
    - The analysis during your review of “second pass rejects” only confirms metal contamination and leads to rejection of the product if metal is visible on the exterior of the tablet. Surface inspection by itself is not a satisfactory method to
    confirm or dismiss metal contamination because it limits your ability to
    determine a root cause

 

W-251

Keywords: Product testing, organic volatiles, USP 267, responsibility of quality control unit, incoming material, record retention and destruction, consultant,3rd party auditor, registration in the US, data accuracy, data integrity

  • Primary deviations: Failure of your quality unit to ensure that materials are appropriately tested and the results are reported, failure of your QCU to exercise its responsibility to ensure the APIs manufactured at your facility are in compliance with CGMP, and meet established specifications for quality and purity. failure to perform at least one identity test of each batch of incoming material, company not registered in the US
  • Examples
    - For example, your Quality Control Unit (QCU) approved the release of four *(b)(4) *USP batches (#*(b)(4)*) without data to support that the test for organic volatile impurities (OVI) met release specifications. .While your Certificates of Analysis state that OVI levels conformed to specifications, the inspection found that no testing was done
    - Should product quality or safety concerns arise in the future, the original records pertaining to batches listed in an application may be integral in providing reasonable assurances to the Agency regarding a product and integrity of data submitted to support it.
    - You are responsible for the accuracy and integrity of the data generated by your firm. A firm must maintain all raw data generated during each test, including graphs, charts, and spectra from laboratory instrumentation.
    -These records should be properly identified to demonstrate that each released batch was tested and met release specifications.
    - Appropriate record retention policies should also be in place.
    - Our inspection reported that your firm has destroyed some old, but foundational records for your products.
    - We recommend that your firm reconsider your record retention policy for application-related records. Should product quality or safety concerns arise in the future, the original records pertaining to batches listed in an application may be integral in providing reasonable assurances to the Agency regarding a product and integrity of data submitted to support it.
    - When destruction of documents is appropriate, you should follow a document destruction procedure that ensures documents are destroyed in a controlled manner. This would include, at a minimum, identification of the appropriate documents and retention timelines, documentation of what was destroyed, and the names and signatures of those who witnessed the destruction.
    - Please provide a comprehensive corrective action plan that describes your commitment, procedures, actions, and controls to ensure data integrity. This plan should include training to all managers, supervisors, and quality unit
    - We highly recommend that you hire a third party auditor, with experience in detecting data integrity problems, who may assist you in evaluating your overall compliance with CGMP

 

W-250

Keywords: Facility management, study director, quality assurance unit, study protocols, equipment maintenance and calibration, training, records, archiving

  • Primary deviations: no adequate testing facility management, study director not designated, study protocols not approved, no designation of a QAU, inadequate archiving of records, no final report for the studies, inadequate equipment calibration and maintenance
  • Examples
    - Facility Management: Failure to provide adequate testing facility management (21 CFR 58.31 (a), (c), (f)]
    - management failed to recognize that there were studies
    conducted at their institution subject to the GLP regulations
    including studies conducted
     and submitted by the University as
    the sponsor
    - there was no centralized testing facility management
    responsible for overseeing GLP studies
    - Study director not designated: Management failed to designate study directors with appropriate education, training, and experience to oversee GLP studies and carry out the required responsibilities of a study director
    described in 21 C.F.R. section 58.33.
    - Furthermore, management didn't know who actually conducted the studies
    - Failure to provide adequate study direction (21 CFR 58.33).
    - All nonclinical laboratory studies must have a scientist or other
    professional with appropriate education, training, and experience
    as a study director. As indicated above, the records failed to
    clearly identify the study director, and those individuals
    actually conducting the studies did not fulfill all study director
    requirements including having overall responsibility for
    conducting the study and interpreting/reporting results. There was
    no single point of study control.
    - Study Protocols; Management failed to assure that studies had approved, written protocols that indicated the objectives, methods, records to be
    maintained, and all other requirements for protocols under Part
    120 of the regulations
    - There were unreported deviations to the protocol
    - No Designation of a QAU: Management also failed to carry out additional responsibilities required under GLP regulations including: designating a quality
    assurance unit (QAU), and we note that the previous 1994 GLP
    inspection also listed the lack of a QAU as a deficiency
    - Lacking a QAU, the QAU duties that were not performed included the
    following: maintaining a master schedule and copies of approved
    protocols; periodic inspections of ongoing studies to identify
    problems/deviations, submitting written reports to management of
    findings, and maintaining records of those audits; maintaining
    SOPS describing QAU procedures; reviewing and signing final study
    reports.
     Training:  Management did not assure that all key personnel involved in GLP studies, including management, received GLP training (other than providing copies of the regulations, no internal or external training was available);
    and assuring that all personnel clearly understood their roles and
    responsibilities in GLP studies.
    - Equipment calibration and records: Failure to maintain records for the maintenance and calibration of equipment [21 CFR 58.63 (a)]
    - There were no maintenance logs or daily quality control records
    for the [xxx]  system used for the xxx studies.
    - The maintenance logs maintained by the CWRU hospital Biomedical
    Engineering Department revealed that they only performed safety
    checks on the instrument and no calibrations
    - Archiving of Records: Failure to maintain study documentation and to store materials in an orderly manner for expedient retrieval [21 CFR 58.190]
    - There was no SOP, centralized storage area allowing for the orderly storage and expedient retrieval of records, data, and specimens, or individual responsible for archiving all required records, raw data, and specimens.
    - Researchers were responsible for archiving their own materials and
    maintained materials in their offices, in offsite storage
    facilities, and elsewhere.
    - CWRU staff failed to retrieve records requested by the FDA
    investigators
    - Final Report: There was no final report for the studies.
    - You failed to assure that protocol deviations and QAU inspection reports for study #323 were evaluated by a replacement study director.

 

 

W-249

Keywords: OOS, test records, product quality reviews, test procedures, review of quality documents, method validation

  • Primary deviations: Failure to investigate and document out-of-specification results, failure to ensure that approved test procedures for (b)(4) and (b)(4) HPLC are followed, , failure to have complete and reliable laboratory control records, failure to have adequate product quality reviews, failure of your quality unit to review and approve all appropriate quality related documents
  • Examples
    - For example, the inspection revealed that your firm lacks raw data of the sample and standard weights used for the HPLC assay of (b)(4) and (b)(4). The only record available was an Excel spreadsheet with values entered to calculate the final assay results. In addition, some of the HPLC chromatographs of the lots tested were not included in the batch record. In your response you acknowledged missing raw data, and stated that all raw data is now required to be maintained and included as part of the batch record. However, you made no commitment to evaluate the extent of the problem and review all previous batches where critical data may be missing
    - The batch records also lack the dates, amounts, and identity of the person weighing the material. We are concerned that your quality unit is not exercising its responsibility during the review of the production batch records to ensure the required information is available, prior to releasing your API products.
    - In response to this letter, please detail what global improvements your firm is making to your production and quality systems to address these issues. Include a copy of the master batch records for (b)(4) and (b)(4) products.

 

W-248

Keywords: Training, trainers , adequate number of people, method validation, method transfer

  • Primary deviations: Trainers with limited background, people lack education to perform assigned tasks, insufficient GMP training for temporary employees, method validation not completed, method transfer not completed
  • Examples:
    - Individuals responsible for supervising the processing and holding of a drug product lack the education to perform their assigned functions in such a manner as to assure the drug product has the safety, identity, strength, quality and purity that it purports or is represented to possess.
    - Specifically, ...'
    - Employees engaged in the processing and holding of a drug product lack the education required to perform their assigned functions.
    - Employees are not given training in the particular operations they perform as part of their function, current good manufacturing practices, and written procedures required by current good manufacturing practice regulations.
    - The number of qualified personnel is inadequate to perform and supervise the manufacture, processing, packing, and holding of each drug product
    -
    According to the Laboratory Manager, they do not have the staff to adequately investigate OOS test results, refer to observation #27 for a list of OOS investigations that were not timely.
    -
    In addition, the Quality Control Manager stated they need people to conduct all of the testing (including transferred products).
    - the method validation titled ''Validation of Microbiological Testing" xxx for the microbiological testing of all products and Deionized Water, used in production and cleaning, was not completed adequately in that the following were not determined: Precision, Specificity, and Linearity/Accuracy. In addition, the failure of the system suitability was not investigated and only a few of the many products tested were used in the method validation.
    - method transfers were not completed on the following test methods prior to using them to release ora'! adult and children's drug products. In addition, there is no documentation to support that these methods, which are used for stability testing, are stability indicating.

 

W-247

Keywords: Sample integrity, product test specifications, data traceability, raw data, testing, OOS, complaints

  • Primary deviations: no scientifically sound and appropriate product test specifications, no appropriate sampling plans, GC results not traceable to raw data, original chromatograms lost, in-house laboratory procedures non-existent or inadequate,  no SOP to ensure integrity of samples, test methods no adequately documented,
  • Examples:
    - Your firm has not established scientifically sound and appropriate
    specifications, standards, sampling plans, and test procedures designed
    to assure that tested products conform to appropriate standards of
    identity, strength, quality, and purity [21 C.F.R. § 211.160(b)].
    - The gas chromatographic analysis performed and the data provided to
    the application sponsor is not traceable to raw data. The original
    chromatograms could not be located during the inspection.
    - In-house laboratory procedures for various laboratory tests were
    either non-existent or inadequate. For example, the entire GC and HPLC
    test procedures address only a few precautions to be taken in running
    the instruments. Routine practice consisted of performing test
    procedures provided by customers, and then destroying these procedures
    as soon as the analyses were completed.
    - Your firm's standard operating procedure #CLL-PKL-SOP-10,
    “Maintenance of Integrity of Sample,” is inadequate in that it does not
    assure complete integrity of documentation related to sample analysis.
    It specifies the assignment of a “booking number” to each sample, but no further procedures regarding subsequent documentation are included. Certain elements of sample integrity are addressed in other SOPs, but none of the procedures explicitly call for maintaining sample integrity throughout the testing of the sample.
    - Performance of test methods such as loss on drying, residue on
    ignition, and sulfated ash is not adequately documented. Certain steps
    such as time in and time out of the oven are not recorded, and the
    laboratory record does not provide a format for recording such data.
    - Method verifications for compendial tests are not performed. Any
    method, including compendial methods, must be verified as suitable under
    actual conditions of use. This has not been done for any method provided
    by your clients..

 

W-246

Keywords: Complaint handling. batch reprocessing, laboratory equipment , performance qualification, system suitability testing, raw data, calibration records, equipment re-qualification

  • Primary deviations: Failure to adequately reprocess API batches, to thoroughly investigate complaints for API, for not using USP acceptance criteria. and for not maintaining equipment re-qualification raw-data, suitability of testing method for your residual solvent determination not demonstrated and verified
  • Examples
    - Failure to have an adequate performance qualification (calibration)
    program for the QC laboratory instruments.- Your HPLC calibration lacks a carry over test (sample injection residual
    test), sample energy (intensity of light source), and lamp use hours determination. You fail to challenge the analytical balances for minimum weight, measurement for uncertainty, and drift value. In addition, you do not calibrate the Karl Fisher syringe used during xxx API water
    content analysis.

 

W-245

Keywords: Specifications, Sampling, Supplier assessment, procedures, stability testing, training, laboratory records

  • Primary deviations:  sampling not representative, inadequate supplier assessment, procedures not followed, inadequate training, inadequate control of stability samples, laboratory instrument and method parameters not documented, notebooks not controlled documents, operator cannot read language of SOP
  • Examples
    - Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity [21 C.F.R. § 211.160(b)]. For example
    .
    - Your firm fails to thoroughly investigate unexplained discrepancies or the failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed [21 C.F.R. § 211.192
    - Representative samples are not taken of each shipment of each lot of components for testing or examination
    - There is no assurance that your firm establishes the reliability of the supplier's analyses through appropriate validation of the supplier’s test results at appropriate intervals
    - Your firm does not follow written production and process control procedures in the execution of various production and process control functions, or record and justify deviations from the written procedures
    - Your employees engaged in the manufacture, processing, packing, holding of a drug product lack the training required to perform their assigned functions [21 C.F.R. § 211.25(a)]. For example
    - Your laboratory records are deficient in that they do not include complete data derived from all tests necessary to assure compliance with established specifications and standards, including examinations and assays
    - Stability samples are not properly controlled, stored, and maintained

 

W-244  

Keywords: GLP, reports, stability testing, SOP, bioanalytical methods, master schedule, sampling

  • Primary deviations: Personal not trained, missing SOPs, reports not signed by individuals, articles not tested for stability, study director failed to follow applicable GLP regulations, inadequate validation of bioanalytical methods, QA failed to maintain a master schedule, SOPs not followed without justification, equipment not adequately cleaned, inspected and maintained, inadequate corrections of final reports, sampling not representative, OOS results accepted
  • Examples
    - Testing Facility Management failed to ensure that personnel clearly understand the functions they are to perform [21 CFR 58.31(f)].
    Specifically
    - Testing Facility Management failed to ensure that test article mixtures were appropriately tested for stability
    - Testing Facility Management failed to implement standard operating procedures (SOPs) in writing setting forth nonclinical laboratory study methods that are adequate to ensure the quality and integrity of the data generated in the course of a study. In the 2009 inspection .....
    - Study Directors repeatedly prepared draft final reports without the necessary raw data from contributing scientists.
    - FDA found that Study Directors failed to ensure that bioanalytical methods used in nonclinical laboratory studies were accurate
    - FDA found that SNBL failed to reject bioanalytical runs that exceeded the a priori acceptance limit
    - FDA found that numerous pieces of equipment were not calibrated according to the schedule defined by SNBL procedures. For example:
    a. The temperature verification for a chromatography column heater had expired in August 2008, yet the apparatus was used through September 2009
    - Study Directors failed to sign and date final reports [21 CFR 58.185(b)].
    For example,

 

W-243   

Keywords: Stability Testing, stability indicating methods, forced degradation, OOS, Method Validation, Method Change

  • Primary deviations: Stability testing done with non-stability indicating test methods, used test method inadequate, forced degradation on individual APIs instead all APIs present.
  • Examples
    - Failure of your quality control unit/laboratory to ensure your analytical methods used to evaluate the stability of your APIs are validated to be stability indicating
    .
    - For example, you have not validated the method you currently use to test the stability of xxx to ensure it is stability indicating. You use xxx in the finished drug product.
    - You provided no supporting documentation to demonstrate that the current  method can detect the presence of xxx or unknown impurities/related substances.
    - Also, you performed forced degradation studies on all xxx individually, not on the xxx. We consider these forced degradation studies incomplete. They should include the forced degradation of the to ensure selectivity of the method in the presence of all xxx, and their related impurities/related substances and degradation products
    -
    Your response indicates that you will review the forced degradation studies of each individual xxx making up xxx and that you will establish another assay method for this product if any xxx or impurity is found to increase.
    - Again, this action lacks the evaluation of all being present during forced degradation. As a result, there can be no evaluation of how this xxx could degrade, or the effect of the (b)(4) degradation on the method’s selectivity.
    - There may be a difference in how individual xxx degrade within a of other xxx. Include in your response to this letter an evaluation of the forced degradation of the xxx, and your justification for continuing to use the current method for stability of xxx

 

W-242   

Keywords: Part 11, limited access, computer security, administrative privileges, stability chamber qualification, stability testing, people qualification, sample handling, laboratory raw data, backup data

  • Primary deviations: Inadequate controls over computer systems, no security protocols, users of computer systems have administrative privileges, stability  protocol inadequate, stability chamber not calibrated, inadequate number of people, no control system to prevent sample mix-up, laboratory raw data not reliable, no HPLC backup data
  • Your firm has not exercised appropriate controls over computer or related systems to assure that changes in control records or other records are instituted only by authorized personnel [21 CFR § 211.68(b)J.
    - For example, one user account is established for two analysts to access the laboratory instrument's software on the computer system attached to HPLC systems (b)(4) and . The user account provides full system administrative rights, including editing of the methods and projects
    - In addition, data security protocols are not established that describe the user's roles and responsibilities in terms of privileges to access, change, modify, create, and delete projects and dat

 

W-241    483 with 24 Observations

Keywords: Annual Product Report, NDA-Field Alert Report, stability testing, laboratory refrigerators, lab notebooks, OOT, failure investigation, autoclave recalibration, training, HPLC method validation, method transfer, complaint records. sampling, HPLC qualification, qualification of stability chambers, analytical data review

  • Primary deviations: Inadequate method transfer, inadequate method validation, deficient complaint records, sampling plans incomplete, suitability of testing methods not verified under actual conditions of use, Missing information in the annual product report, NDA-Field Alert Report concerning a failure of distributed batches not submitted within three working days, inadequate storing of stability samples, nor written procedures for specific use of refrigerators, unauthorized use of spiral lab notebooks, no SOP for handling Out-of-Trend investigations, Inadequate documentation of production and process control procedures, batch failure investigation not extended to other batches, no yearly recalibration of an autoclave, inadequate number of people to perform assigned tasks, operators not adequately trained,
  • -There is no standard operating procedure in place that describes the steps to be followed during an Out-of-Trend (OOT) Investigation, besides, the "OOT Investigation" performed was inadequate.
    -The analytical method have not been transferred between the issued laboratory and the two chemists currently working in the QC laboratory. The methods have been transferred before the two chemists were hired. There are no records which document training in the two procedures.
    - There are no records which document validation for one or more of the following areas of analysis: assay by HPLC, assay by titrimetry, water determination by IR spectrophotometer, melting point apparatus and total aerobic microbial count.
    -The HPLC configuration tubing at the time of method validation may not be similar to actual ones used possibly affecting the resolution.- The analytical method have not been transferred between the issued laboratory and the two chemists currently working in the QC laboratory. The methods have been transferred before the two chemists were hired. There are no records which document training in the two procedures.
    - There are no records which document validation for one or more of the following areas of analysis: assay by HPLC, assay by titrimetry, water determination by IR spectrophotometer, melting point apparatus and total aerobic microbial count.
    - The suitability of all testing methods is not verified under actual conditions of use.- The HPLC configuration tubing at the time of method validation may not be similar to actual ones used possibly affecting the resolutio
    n
    - -During the laboratory walkthrough, several solutions were observed inside the refrigerator, with precipitation, that apparently are uses for system suitability testing with no indication of preparation date, lot number, and expiry dates

 

W-240 (2-page 483 with 3 observations)

Keywords: Equipment, Gas Chromatograph, OOS, Calibration, Training

  • Primary deviations: No investigation of failed GC calibration, no employee training for GC calibration.
  • Examples
    - Your Quality control unit failed to implement an effective system to ensure all deviations and non-conformances are adequately investigated and documented and corrective action is implemented in a timely manner.
    - There was no documentation that an investigation was conducted to determine the root cause of the failed calibrations of the Gas Chromatograph (GC) on 9/18/08 and 10/20/08 that were identified and cited during the May 2008 FDA inspection. In addition, your firm failed to implement adequate corrective action to prevent recurrence
    - Your quality control unit failed to adequately train personnel to perform their duties as follows: Operations and QC personnel was not trained properly on SOP  for Operation of the xxx Gas Chromatograph, and failed to follow these procedures in the conduct of the last three GC Calibrations performed on 9/19/09, 12/17/09 and 3/16/10

 

 

W-239 (12-page 483 with 12 deviations)

Keywords: Record availability, record accuracy, org charts, CAPA, cleaning validation, system suitability testing, SST, training, storage of reference samples

  • Primary deviations: E-Records not "readily" available, impact of equipment failures on batch not investigated, inadequate follow up of complaints, only 5 system suitability test runs instead of 6, reference samples not stored under conditions as recommended by the manufacturer.
  • Examples
    -The 12-page 483 with 12 deviations lists 20 different document types together with the dates when the documents were requested and when they were available. Furthermore, the inspector found that "Stability information provided was not provided in an organized fashion on 06/30/10. I requested that the firm organize the information and bring in a computer on 07/02/10 to view the contents of xxx"..
    - No Quality review was conducted concerning impact on batches that were manufactured during equipment failures. No maintenance records were completed describing what was done to fix the equipment. Equipment failures were not trended by Quality to determine the scope of the manufacturing equipment failures and the overall impact on the manufacturing process and products produced. No deviation report~ were generated, reviewed and approved by the firm's Quality Control Unit regarding the following manufacturing incidents.
    - System suitability conducted for Dissolution Assay per laboratory test methods evaluates only five replicate injections for Relative Standard Deviation (RSD) NMT 3%. USP requires six replicate injections for instrument precision and accuracy
    - Biological Indicators for lot were observed to be stored in Refrigerator on 06/22/10, which is not being monitored for storage at RH per manufacturers instructions.
    - Routine inspection of mechanical and electronic equipment is not performed according to a written program designed to assure proper performance.
    Specifically,
    A. There is no Preventive Maintenance program for the following equipment in
    a. Dissolution Apparatuses
    b. xx for Rapid Resolution
    c. Autotitratiorı
    d. Spectrometer
    e. UV/Vis Spectrophotometer

 

W-238

Keywords: SOPS, Equipment Qualification, OOS, root cause, stability data, expiration date, complaints, software, computer validation

  • Primary deviations: SOP for laboratory testing not followed, no timeline for equipment qualification, OOS not conducted according to SOP, inadequate failure investigation, root cause not determined, expiration dates not supported by stability data, inadequate complaint handling, accuracy of computer input/output data not verified.
  • Examples
    - We also acknowledge that your firm is qualifying the xxx Test System. However, the instrument test methods are under development and you have not provided a timeline for implementation.
    - Your firm failed to check the accuracy of the input to and output from the computer or related systems of formulas or other records or data and establish the degree and frequency of input/output verifications [21 CFR § 211.68(b)]
    - For example, the performance qualification of your xxx system
    software failed to include verification of the expiration date calculations in the xxx system.
    - In addition, there is no established degree and frequency of performing the
    verification. Discrepancy reports have documented that product labeling
    with incorrect expiration dates have been created and issued for use.
    - Your response states that you opened Investigation T-139 and you provide
    a January 29, 2010 through February 26, 2010 completion timeline. You
    have not provided a response to correct this violation and establish a
    corrective action plan to assure that computer systems are properly
    qualified.

 

W-237

Keywords: Raw data, batch records, corrective action, root cause, laboratory records, spreadsheet calculations, method validation, method verification

  • Primary deviations: Batch record raw data written in pencil , erased and rewritten, corrective action not extended to other batches, inadequate review of batch records, root cause for OOS not investigated, laboratory records do not include calculations, accuracy of spreadsheet calculations not verified, analytical method not verified for new equipment
  • Examples
    - Your laboratory records did not include a record of all calculations
    performed in connection with laboratory tests as required by 21 CFR §
    211.194(a)(5). For example, the notebook does not document reference to the spreadsheet calculation used to generate the results
    - Your SOP omits instructions to include in the notebook the reference to the spreadsheet calculation used to generate the results, as well as the raw data and calculations.
    - In addition, you continued to release products based on assay results generated by the spreadsheet that have not been verified for accuracy
    - Your firm's "Batch Record Recording Procedure" states that only blue or black ink can be used to record information in the Batch Record Book. However, for at least six lots, the Master Packaging Instruction sections of the batch records contained reconciliation and disposition data written in pencil, erased, and then rewritten in ink. In addition, some data that had been rewritten in ink was different from the original data that had been written in pencil.
    - You indicated in your response that the Quality Control Unit (QCU) member associated with this practice is no longer working for the firm; however, your proposed corrective action did not include a review of other production and control records to ensure that this practice did not occur in other instances
    - The contract laboratory's investigation confirmed the OOS assay results. However, your firm re-submitted samples for additional testing without conducting an investigation into the root cause of the OOS assay results and invalidating the original assay results
    - You have not established and documented the accuracy, sensitivity,
    specificity, and reproducibility of test methods as required by 21 CFR §
    211.165(e)
    - Your firm has not verified that the preservatives and API test methods using the xxx system is adequate for its intended use.  The xxx system is different from the previously used Perkin-Elmer high Performance Liquid Chromatographic (HPLC) system in make, model,and column.

 

W-236

Keywords: Software testing, raw data, training, servicing procedures, complaint handling

  • Primary deviations: Raw data from software testing discarded, test data not signed, test data incomplete. compliant handling procedures not implemented, servicing procedures not implemented, inadequate training of personnel
  • Examples
    - Verification and Validation test results/raw data for software 4.0,
    Version B, were performed on xxx. Sections of the test
    data were not performed, unsigned, and/or missing as follows:
    - All sequence is entered as pass without supporting data
    to demonstrate the test was performed
    - Verification and Validation report for software version 2.0 is not
    available for review.
    - According to your employee, once the results are
    entered into your electronic report, the raw tests data are discarded.
    Therefore, you have no evidence the sequence testing was performed
    - Failure to establish procedures for verifying that design outputs
    meets design input requirements
    - Failure to implement compliant handling procedures in reviewing and
    evaluating customer reports, Specially, in-house servicing records contain events of reported device failures that were not entered and/or handled as product complaints.
    - Failure to establish Servicing procedures as required by 21 CFR
    820.00(a). Specially, your service manual does not address issues
    related to software failures.
    - Failure to ensure employees are adequately trained to perform their
    assigned duties

 

W-235 (Estabilishment Inspection Report)

Keywords: Dietary supplements, Part 111, EIR

  • FDA Establishment Inspection Reports (EIR) are quite useful to learn about the complete inspection process, e.g., who is interviewed, where the inspection focus is, what documents are reviewed, what questions are asked and if the answers are satisfactory. This is an example of an inspection report related to FDA's GMP regulation for Dietary Supplements.
  • Topics: Initial interview, going through ALL subparts, packaging, general closing discussions with management
  • Discussions
    - Persons interviewed (by function), personnel, training, physical plant and grounds, cleaning and pest control, equipment calibration and sanitation, production and process control, examination of incoming material, quality control, qualification of suppliers, COA, handling returned dietary supplements and customer complaints, review of batch records by QA, laboratory testing, packaging and labeling operation, avoiding product contamination during holding and distribution, closing discussion with QA manager,
    - Final statement: company prepared for implementation of CFR 111. .

 

W-234 (Eleven 483 Inspectional Observations)

Keywords: OOS, failure investigation, raw material, supplier qualification, process changes,  process validation, sampling plans, clean room, cleaning validation, acceptance criteria, risk assessment

  • Primary deviations: Inadequate supplier qualification, inadequate testing of raw material, inadequate SOP for OOS, lack of process validation, inadequate deviation from SOPs before authorization from management, lack of sampling plans, no justification for changing environmental conditions in the Clean Room, test conditions not documented, no justification for only one cleaning validation run, test acceptance criteria not justified, no risk assessment performed to evaluate effect of deviations from SOPs, supplier's test results of components not validated.
  • Examples
    - Your SOP states: "Following a laboratory investigation without an assignable cause, two retests are executed. If the two retests pass, the average of the original OOS result and two retests is reported. Following a laboratory investigation without an assignable cause, the original analyst obtains two failing results, and two additional analysts obtain passing results . The average of the two passing results is reported." There is no scientific justification for invalidating the original analyst's result; it is assumed that the original analyst is improperly trained
    - An out of specification result was obtained for Iron Content assay for xxx. Three analysts executed this assay: the original analyst failed the assay upon retest, two different analysts tested the same samples and they passed . The investigation did not determine the root cause of the out of specification result, training was assumed to be the root cause.
    - Laboratory controls do not include the establishment of scientifically sound and appropriate sampling plans and test procedures designed to assure that drug product containers and closures conform to appropriate standards of identity, strength, quality and purity.
    - Established test procedures are not followed and documented at the time of performance. Specifically analysts in the Quality Control department are not documenting the pH for the xxx sample mixture for drug product release testing
    - The procedure for visual inspection for incoming raw materials, QC of Raw Materials, QSOP 002, version October 18, 2007 and the are inadequate ; they only require Quality Control personnel to verify the color of the raw material. There are no instructions for execution of the visual inspection..

 

W-233 (Three 483 Inspectional Observations)

Keywords: Dietary supplements, equipment cleaning, batch production records, hygienic conditions

  • Primary deviations: Incomplete records of equipment cleaning and sanitation, raw material weight records incomplete, inadequate hygienic conditions
  • Examples
    - You did not make and keep documentation of the date of use, cleaning and sanitizing of the equipment used to prepare coating solutions for dietary supplement tablets
    - Your batch production records did not include the actual results obtained during a monitoring operation, Specifically, records for monitoring raw material in the weight room did not include each partial raw material weight and the identification of the equipment used
    - Your personnel did notuse hygienic practices to the extent necessary to protect against contamination of dietary supplement ingredients. Specifically your personnel did not wear outer garments in a manner that protects against contamination of dietary supplement ingredients
    - Your personnel used gloves that were not clean or stored in a sanitary condition. Gloves used by the associates were stored loose and unprotected on a table covered with raw material dust.

 

W-232 (51 Page with six 483 Inspectional Observations)

Keywords: Dietary supplements, laboratory testing, seal of plastic bottles, packaging specification, pesticides, hand washing facility, corrective actions.

  • Primary deviations: Laboratory examination and test methodology, use method not valid, missing specifications, missing test data as listed in the monograph,  requirements not met in packaging area, not all corrective actions implemented, water temperature not suitable for hand washing
  • Examples
    -The test method using xxx instruments produced negative trends that report equipment drifts, OOS CV standards and/or invalid results that required a re-test on several mineral lots but the test method continues to be used and has not been replaced with a more reliable method.
    - Failure to use an appropriate  scientific valid method to test the seal over plastic bottles,
    - No specifications were established for the amount of pressure and dwell time to apply or use of measurable tool to evaluate the integrity of the seal
    - Specifications for dietary ingredient(ginseng) are listed under Monograph xxx and this monograph requires verification on the supplier's COA that pesticide(tricyclazole) was tested, but COAs for code xxx do not include test results for this pesticide, and was not revised to include the actual name and address of the lab currently responsible for furnishing this information.
    -  Failure to demonstrate that all requirements were met in the packaging area, Specifically as part of Master Packaging Record specifications for cap adjustments (distance from cap to bottom of sealing head) were established to show proper alignment to the sealer; however adjustments were not documented to support proper set-up.
    -  Your hand washing facility does not dispense water at a suitable temperature. The firm's management was advised that cGMPs require that hand-washing facilities furnish running water at a suitable temperature and cold water was not considered suitable, as people would not want to place their hands in cold water.

 

W-231 (483 Inspectional Observations)

Keywords: Stability Chambers, Part 11, authorized access to computer, back-up of computer data, screen saver

  • Primary deviations: Inadequate calibration, re-calibration and maintenance of stability chambers, no screen saver to make the computer screen inactive, no secure access control to computer systems and data, no back-up of HPLC data, no written procedures for production and process controls, failure investigation not extended to other batches, suitability of testing methods not verified under actual conditions 
  • Examples
    -The calibration program for your stability chambers is deficient in that it does not include specific directions and schedules.
    - You do not perform requalification of stability chambers.
    - The original qualification of all chambers only included mapping studies with empty chambers. The chambers were never challenged by filling the storage space and proceeding with mapping studies. These chambers were observed with to be fully loaded.
    - The firm does not have established procedures for stability chamber malfunction, such as unexpected temperature and/or humidity changes. Your written procedure "Operation, Maintenance, and Calibration of Stability Chambers and Walk-in Chambers" does not address emergency procedure
    - There is no procedure to back-up data from the Personal Computer (PC) connected to the HPLC and the UV/Vis Spectrophotometer
    - Appropriate controls are not exercised over computers or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel
    - The dedicated PC attached to HPLC Systems was not secure in that access to the software was not granted by a unique user name and password to avoid any omissions or changes to data.
    - Security measures have not been instituted to prevent the computer screen from remaining active and not protected from unauthorized access
    - No written procedures for this computer system that outlines the responsibilities and privileges of the laboratory personnel who utilize the software

 

W-230

Keywords: IR spectra, electronic raw data, raw material, quality unit, data manipulation, Part 11, 3rd party auditor

  • Primary deviations: Inadequate raw material testing, inadequate data review by quality unit, quality control records manipulated, response to FDA 483 not comprehensive enough.
  • Examples
    - Your firm's laboratory analyst had modified printed raw data related to the IR Spectra test of (b)(4) and (b)(4). We are concerned that the lack of security or system controls allows for this practice.
     - The laboratory control records should include complete documentation of all raw data generated during each test, including graphs, charts and spectra from laboratory instrumentation
    - Your response is inadequate because it fails to completely address how your firm will ensure the integrity of raw analytical data. Your response stated that a computer server will be purchased and installed to save and print the IR spectra by September 30th, 2009
    - We highly recommend that you hire a third party auditor, with experience in detecting data integrity problems, to assist you with this evaluation and assist with your overall compliance with CGMP.
    - Your quality control unit failed to detect that IR spectra were being substituted by a laboratory employee and therefore, misrepresenting the actual results of the tested incoming material. Your response is inadequate in that it does not address the ability of your quality unit to control and detect the manipulation or alteration of laboratory documents.

 

W-229

Keywords: Stability chamber, OOS, process validation, stability testing, stability indicating methods, impurity testing, batch reprocessing, e-audit trail, Part 11

  • Primary deviations: OOS of stability chambers not investigated, inadequate process validation, variation in the amount of components for preparation of dosage forms not justified and documented, stability indicating test methods not followed, impurity specifications not followed, no limited authorized access to electronic records
  • Examples:
    - Out-of-specification (OOS) humidity levels for the controlled room temperature stability chamber were noted on January 27, March 17, and April 5 and 6, 2009. Investigations and corrective actions were not conducted at the time to address these out-of-specification results. During the inspection, however, the Quality Unit presented back-dated service requests to investigators as evidence of proper OOS result handling when in fact, no actual service requests were initiated.
    - Your firm does not have master production and control records that justify variation in the amount of components necessary for the preparation of the dosage form [21 CFR 211.186(b)(4)].
    -- Your firm lacks systems to ensure that all electronic data generated in your Quality Control laboratory is secure and remains unaltered. All analysts have system administrator privileges that allow them to modify, overwrite, and delete original raw data files on the (b)(4) used (b)(4) in the High Performance Liquid Chromatography (HPLC) units.
    - There are no procedures that address the security measures in place for generation and modification of electronic data files for these instruments used for raw material, in-process, finished product and stability testing. In addition, your firm's review of laboratory data does not include a review of an audit trail or revision history to determine if unapproved changes have been made
    - Validated stability indicating test methods are established, but are not followed, to analyze impurity levels for xxx.
    - Impurity specifications have not been established for any of the aforementioned finished product release testing or stability samples as required by 21 CFR 211.160

 

W-228

Keywords:Software validation, training, in-process product control,

  • Primary deviations: Software used after reprogramming before revalidation, acceptance procedures for in-process product not specified, training needs not identified, on the job training not documented, responsibilities for second shift not identified
  • Examples:
    - Failure to adequately validate computer software for its intended use according to an established protocol, as required by 21 CFR 820.70(i). For example, your firm failed to provide documentation detailing the validation o prior to production use. Software on both systems were reprogrammed on August 9-10, 2008, and utilized in production on August 11, 2008. The validation was not completed until October 6, 2008
    - Failure to adequately establish and maintain acceptance procedures, where appropriate, to ensure specified requirements for in-process product are met
    - Failure to adequately establish procedures for identifying training needs and ensure all personnel are trained to adequately perform their assigned responsibilities and the training is documented
    - Your firm fails to document on the job training.
    - Your firm failed to list second shift quality personnel, their positions, and to whom they report within the corporate quality structure.

 

 

 

W-228

Keywords:Software validation, training, in-process product control

  • Primary deviations: Software used after reprogramming before revalidation, acceptance procedures for in-process product not specified, training needs not identified, on the job training not documented, responsibilities for second shift not identified
  • Examples:
    - Failure to adequately validate computer software for its intended use according to an established protocol, as required by 21 CFR 820.70(i). For example, your firm failed to provide documentation detailing the validation o prior to production use. Software on both systems were reprogrammed on August 9-10, 2008, and utilized in production on August 11, 2008. The validation was not completed until October 6, 2008
    - Failure to adequately establish and maintain acceptance procedures, where appropriate, to ensure specified requirements for in-process product are met
    - Failure to adequately establish procedures for identifying training needs and ensure all personnel are trained to adequately perform their assigned responsibilities and the training is documented
    - Your firm fails to document on the job training.
    - Your firm failed to list second shift quality personnel, their positions, and to whom they report within the corporate quality structure.

 

W-227

Keywords: Stability Testing, record review, procedures, process control, complaints, annual product review, equipment maintenance

  • Primary deviations: No written testing program to assess stability characteristics, inadequate number of batches to determine expiration dates, drug production and control records not reviewed by QCU, complaints not reviewed during annul< product review, failure to clean, maintain and sanitize equipment
  • Examples:
    - Failure to place an adequate number of batches of each finished drug product on stability studies to determine an appropriate expiration dating period
    - The liquid pharmaceutical products manufactured at your facility were not placed on accelerated and long-term room temperature stability studies to justify the assignment of a tentative expiration dating period of [redacted]
    - The only accelerated stability data obtained was for development batches (approx. [redacted] liters) that were not representative of routine production batches (approx. [redacted] liters). Our Investigators found no documentation or data to support or
    demonstrate equivalence between development and commercial batches with regards to equipment, components, and manufacturing processes.
    - Your February 5, 2004, response states that development batches will no longer be made and used for accelerated stability studies to support a [redacted] expiration date. The proposal to manufacture pilot batches of [redacted] of the final batch
    size for all new products, and place them on accelerated studies is adequate.
    - However, your response did not address whether the pilot batches will be using equivalent equipment, components, and manufacturing processes. Please provide a
    time frame for completion of the corrective action plans, and a more detailed stability commitment particularly as it relates to assignment of the expiration date

 

W-226 (483)

Keywords: Software validation,  record maintenance

  • Primary deviations: Software supplied by the vendor not verified for intended use, records were not maintained
  • Examples:
    -The performance of computer software has not been verified. Specifically, your firm has not verified the computer software program being used of their donor referral operation to ensure that the electronic records are trustworthy, accurate and reliable.
    - Records were not maintained concurrently with the performance of each step.
  • For the related EIR and company response, scroll down to W-291

 

W-225

Keywords: Dissolution Testing, Stability Testing. FTIR

  • Primary deviations: Dissolution testing not included in stability program, dissolution test method does not detect all active ingredients in the finished product, missing dissolution specifications, FT-IR identity tests for functional groups test did not identify each peak or absorption band.
  • Examples:
    - The written stability program for drug products does not include reliable, meaningful and specific test methods which include dissolution testing and the establishment of controlled-release drug product dissolution specifications for any of the marketed tannate drug products to ensure finished drug product performance at expiry, as required by 21 CFR 211.166(a)(3).
    - The finished drug product, (b)(4) tablets (Phenylephrine Tannate 25 mg and Chlorpheniramine Tannate 9 mg), lot number HRT002, manufactured on January 25-28, 2009, lacks an appropriate dissolution profile specification. The dissolution method tests some of the components, but is not capable of detecting the active tannate ingredients in the finished product. The dissolution specifications are not adequate for use.
    - your firm fails to identify each peak (or absorption band) of spectra obtained using USP <197K> FT-IR identity test for functional groups characteristic of phenylephrine-based and chlorpheniramine-based compounds.
    - Specifically, there are no established dissolution specifications for xxx Suspension

 

W-224

Keywords: Electronic records, data base, source records, source data

  • Primary deviations: Failure to maintain accurate, complete, and current records relating to an investigation, no electronic audit trail, failure to ensure proper monitoring of a clinical investigation,  failure to ensure an investigation is conducted in accordance with the investigational plan
  • Examples:
    - All study data are handled and controlled by your Study Coordinator, who enters the data into an electronic data base. There is no audit trail or log of data changes that are made to the information in the database. Data cannot be verified against source records, since such records are not maintained.

 

W-223

Keywords: Computer validation, data input-output check, records

  • Primary deviations: no checking of input and output data of computer systems, missing records
  • Examples:
    - Failure to check input to and output from the computer or related systems of formulas or other records or data for accuracy as required by 21 CFR 211.68 (b).
    - Failure to maintain donor records as required by 21 CFR 606.160(b).

 

W-222

Keywords: Method validation, electronic records, raw data, instrument information; change control,  computer systems, laboratory notebooks

  • Primary deviations: Missing electronic method validation raw data, missing instrument information, laboratory notebooks not maintained
  • Examples:
    - Your quality unit failed to maintain complete laboratory control records for the analysis of your APIs (including graphs, charts, and spectra from laboratory instrumentation derived from all tests conducted) to ensure compliance with established specifications and standards
    - For example, raw data /e,.g. chromatograms, standard and sample weights, calculations, standards, reagents, and instrument information) for for the Albuterol Sulfate and Lorazepam  related substances. method validation were not available during inspection.
    - Your quality unit personnel informed the investigators that the computer software was upgraded and the raw data was lost during the software upgrade, We have serious concerns about your firms  implementation of changes to your computer system (E.g., software upgrade). It is your responsibility to provide the means of ensuring data protection (e.g., back-up system) for your computerized system to prevent the permanent loss of records.
    - Laboratory notebooks lacked laboratory equipment/instrumentation information (calibration status, system suitability information), standards and reagents information (manufacturer, retest), dates and signatures of persons who performed each test and reviewed the data, reference to the test method
    - Your quality unit failed to establish a control system for the issuance, tracking, and maintenance of laboratory notebooks that are used to record raw data in your QC laboratory.

 

W-221 

Keywords: Test procedures, certified standards, primary standards, failure investigation, HPLC and pH meter qualification, process validation, API, COA, stability testing, review of records

  • Primary deviations: Missing written test procedures, standard for HPLC qualification not certified against a primary standard, batch failures not thoroughly investigated, SOP not followed, missing procedures for process validation, API certificates of analysis (COA) not regularly verified, batch records not always reviewed by QCU prior to release.
  • Examples:
    - No written and approved procedures were available for dissolution and uniformity of dosage unit testing of drug products, prior to release
    - For the testing of incoming components, your firm failed to conduct HPLC system qualification using certified standards and validated procedures
    - Your firm stated that it used the active pharmaceutical ingredient (API) guaifenesin as a standard to qualify the High Pressure Liquid Chromatographic (HPLC) system, prior to testing of drug product samples. Your laboratory failed to certify guaifenesin against a primary standard from an accredited institution and/or to fully characterize the material as a standard
    - your firm failed to document an investigation of this incident, including the root cause and corrective actions for this suspect batch
    . The laboratory pH meter was not calibrated on days of use, as required by SOP 800.7
    - Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed
    - Please note that it is the responsibility of your firm to investigate the cause of the failure of a batch of a drug product to meet its specifications and to include conclusions and follow-up measures to prevent recurrence of these events.
    - Your firm failed to conduct injector and detector performance testing for the (b)(4) HPLC system
     For example, no HPLC injector and detector testing for linearity, accuracy, and precision were conducted, such as: 1) various injection volumes and standard concentration testing; 2) evaluation of detector for noise/drift; and 3) carryover testing to evaluate response at low levels to determine the detection of possible interferences that may affect peaks of interest
    - Your firm does not use primary standards from an accredited institution such as USP.
    - Also, no testing has been performed to certify any of your laboratory standards as secondary standards (e.g., testing against USP primary standards) or fully characterized to be used as a standard.

 

W-220 

Keywords: OOS, Failure Investigations,  training, SOP language, documentation

  • Primary deviations: Individual OOS results inadequately averaged. SOP not provided in English language
  • Examples:
    - Laboratory controls are deficient in that your firm has established procedures that allow for the averaging of out-of-specification (OOS) and within-specification analytical test results from separate samples..
    -  The inspection revealed that results for individual tests are calculated individually by the xxx system and then averaged by your firm's Laboratory Integrated Management System (LIMS). The averaged result (not individual results) is then corrected for water content, if necessary
    - Your firm prepares two to three separate samples, which are assayed individually. We expect you to treat each of these results independently, and not to average an OOS result with a passing individual result. The hiding of an OOS result in the average is an unacceptable practice.
    - We recognize that your SOP has been revised and submitted as a DRAFT. However, most of it is in the German language. Please submit an English translation once it is approved
    - The inspection reported that your analysts had been trained to average passing and OOS results, and to report the average passing results. Please submit the translated training records for all analysts demonstrating that they have been trained in your new revised procedures.

 

W-219

Keywords: Out of Limit (OOL), contract laboratory, training, drug storage, change control, annual review, product registration

  • Primary deviations: OOL (out of limit) and OOS results obtained by contract lab not investigated, Insufficient training, inadequate storage of raw material and drugs, impact of equipment changes (upgrades) not assessed by the quality control unit, no action plan for performance qualification, contract laboratory not qualified, no procedures for annual review, supervisors not qualified for their job., not every product registered with FDA.
  • Examples:
    - Your firm has not established appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, including procedures for validation of any sterilization process
    - It also appears from the labeling that the sterility test described in the United States Pharmacopeia (USP) 30 xxx is not performed for this product; the product is only labeled as complying with the USP 30 ... effectiveness test
    - Unexplained discrepancies and failure of a batch or any of its components to meet specifications are not adequately investigated by the quality control unit-
    - Although results above your alert limits may be an indication of an ongoing uncorrected problem, no investigation was conducted to identify a potential root cause of the problem
    - Your firm invalidated failing microbial test results of ... obtained from your contract testing laboratory and retested four of the five samples without conducting an investigation or providing scientific justification. Your firm's retests were used to inappropriately replace four of five failing samples with the following result
    -  The following five (5) out-of-limit (OOL) microbial test results ... reported by your contract laboratory were discarded without conducting any investigation or justification.
    - Your firm's retests were used to inappropriately replace four of five failing samples
    - Your Firm accepted the passing results obtained by your firm's laboratory without conducting any investigation or providing any scientific justification for invalidating the initial failing results
    -Your firm also lacked a trend analysis of your ... sample results and failed to monitor the ... level prior to or after the .... These issues were discussed during the inspection but not addressed in your response to the 483 observation
    - You indicated that the Installation Qualification and Operation Qualification have been completed and that the Performance Qualification of your ... system is expected to be completed by the end of 2009. You stated that a preliminary study and periodic monitoring of the system has to be done. However, no details of protocol, short term or long term action plan with supportive documentation were included in your response
    - In addition, there is no assurance that the ... used in the preparation of your ... meets the USP requirements for ... because your facility has not completed the requalification of the ... system
    - Adequate laboratory facilities for testing and approval or rejection of components are not available to the quality control unit. Your firm did not qualify the contract laboratories used for the testing off ...
    - It is FDA's expectation that your firm have a quality agreement with the contract laboratories in place. We recommend that this agreement be signed by all parties involved and that it include, as a minimum, specific details delineating the roles and responsibilities of each party. A description of the materials, services, communication, and all testing expected to be performed by each party should also be included. Your firm should ensure that the contract laboratory facility is compelled to produce accurate analytical results for the tested material, conduct adequate laboratory investigations of out-of-specification results, and report to the client such investigations or any changes
    - Individuals responsible for supervising the manufacture, processing, packing, holding of a drug product lack the education, training, experience to perform their assigned functions
    - Our review of your firm's training program disclosed that there was no requirement for on-going CGMP training of employees. The firm only had an initial CGMP training and did not provide regular CGMP training to all employees involved in the manufacture of drug products. There is no reference to CGMP training of supervisors or directors.

 

W-218

Keywords: Design control, documentation control, control of purchased products and services, outside consultant

  • Primary deviations: No or inadequate procedures for design control, no procedures to ensure quality of purchased products and services, no procedures for document control.,
  • Examples:
    - Failure to establish and maintain procedures to control the design of the device in order to ensure specified design requirements are met
    - Failure to establish and maintain procedures to ensure all purchased or otherwise received product and services conform to specified requirements
    - Your firm has not established procedures for purchasing controls which include the evaluation and selection of raw material suppliers and the establishment of specified purchasing data requirements for purchased or otherwise received product

    - Failure to establish and maintain procedures for acceptance activities including inspections, tests, or other verification activities.
    - For example, your firm has not established procedures for document control-
    We are requesting you submit to this office, on the schedule below, certification by an outside expert consultant to state he/she has conducted an audit of your establishment's manufacturing and quality assurance systems relative to the requirements of the device Quality System regulation (21 CFR 820). You should submit a copy of the consultant's report, and certification by your establishment's Chief Executive Officer (if other than yourself) stating he or she has reviewed the consultant's report and your establishment has initiated or completed all corrections called for in the report. The initial certifications of audit and corrections and subsequent certification of updated audits and corrections should be submitted to this office by xxx (dates for initial and final certification)

 

W-217

Keywords: computer validation, equipment maintenance, OOS, FDA Meeting, Reference Material, facility contamination

  • Primary deviations: Computer output not checked for accuracy, failure investigations not extended to other batches, expiration date of reference material extended without supporting data, procedures to prevent facility contamination incomplete, written procedures for equipment maintenance not followed.
  • Examples:
    -
    Failures are not fully investigated and documented, nor extended to other batches as appropriate.
    - You failed to exercise appropriate controls over computer or related systems to assure that changes in master production are instituted and input and output from the computer or related system of formulas are checked for accuracy and maintained
    - There is no documentation to support software change
    - There are no data to support extension of expiration for xxx Reference Standard
    - Written procedures for the use of cleaning and sanitizing agents designed to prevent contamination of your facility are incomplete. Specifically, SOP xxxx does not provide a frequency for performance of the multi-step decontamination
    - Written procedures are not followed for the maintenance of equipment used in manufacture, processing, packing or holding
    - To facilitate your remediation efforts we request a meeting with you and other senior management at Merck to further discuss the issues cited in this letter and your proposed responses to address them.

 

W-216

Keywords: Part 11, electronic records, computer validation, Cleaning verification, media fills, environment monitoring

  • Primary recommendations: Establish and follow time a table for equipment qualification, resolve issues related to electronic records and signatures. Validate any computer system that performs cGMP functions, more detailed environmental monitoring sampling diagrams
  • Examples:
    -A viable timetable for completion of all qualifications and validations should be established and followed
    - Issues pertaining to electronic records and signatures related to the firm's computer systems should be resolved in compliance with 21 CFR Part 11
    - Complete the activities and assessments including upgrades to the current system with high priority.
    - Drawings should be controlled. e.g., stamped signature and date
    - Provide more specific diagrams or locations for environmental monitoring sampling plans

 

W-215

Keywords: Bioburden, computer validation, equipment maintenance

  • Primary deviations: No adequate monitoring of bioburden. written procedures for equipment maintenance not followed, computerized systems not maintained  in validated state
  • Examples:
    - Your firm does not conduct adequate monitoring of bioburden after hold times of intermediates or pooled buffers during purification of xxx
    - Pooled buffers used in purification steps are not adequately controlled for composition
    - Internal surfaces and manual valves on the stainless steel chromatography columns used during drug substance purification are not adequately maintained.
    - Maintenance has never been performed on the interior of columns to prevent adverse impact on cell cultures due to metal contamination.
    - Your firm failed to maintain computerized systems in a validated state. The inspection team noted that this automated system, containing formulas and recipes for buffers was programmed in 1999 and has not been reviewed or updated. We are concerned that other discrepancies in other values may exist. Please comment on how you will assure all values programmed into the automated system, and other automated systems, are consistent with current master batch records.

 

W-214

Keywords: Process validation,  equipment cleaning, laboratory records

  • Primary deviations: , No written procedures for production and process control, Failure, to adequately clean, maintain, and sanitize equipment and utensils at appropriate intervals, no laboratory records that include complete data derived from all tests necessary to assure compliance with established specifications, deviations from written production and process control procedures not justified.
  • Examples:
    -Failure to establish written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess as required by 21 CFR 211.100(a)
    - For example, process validation studies have not been conducted for any of the human drug products manufactured by your firm
    - Failure to adequately clean, maintain, and sanitize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality or purity of the drug product and failure to follow written procedures for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product as required by 21 CFR 211.67(a) & (b).
    - Failure to have laboratory records that include complete data derived from all tests necessary to assure compliance with established specifications and standards, including examinations and assays such as a statement of the results of tests and how the results compare with established standards of identity, strength, quality, and purity for the component, drug product container, closure, in-process material, or drug product tested as required by 21 CFR 211.194(a)(6).

 

W-213

Keywords: Method Verification, Compendial Methods, System Suitability Testing

  • Primary deviations: Compendial methods not verified, no system suitability testing performed .
  • Examples:
    -The test methods performed for heparin sodium USP have not been verified to ensure suitability under actual conditions of use.
    - Specifically, you have failed to conduct adequate verification of USP compendial test methods as applied to the production of your firm's API.
    - The data you provided in your March 17,2008, response did not include information about the suitability, accuracy, and detection limits of certain test methods for API, such as the protein test method, used by your firm
    - In addition, your firm had not conducted suitability testing of the method to determine the limit of detection for the method.
    - You assert that USP <1226>, Verification of Compendial Procedures, states that verification is not required for basic compendial test procedures that are routinely performed unless there is an indication that the compendial procedure is not appropriate for the article under test.
    - We disagree with your assertions that verification is not required for those USP test methods used by your firm

 

W-212

Keywords: Design validation, software validation, acceptance criteria, CAPA, root cause, complaints, documentation

  • Primary Deviations: Incomplete risk analysis, acceptance criteria not complete prior testing, no analysis of of quality data for identifying root cause, obsolete documents not removed
  • Examples:
    - Your firm failed to establish and maintain adequate procedures to control design validation, including software validation and risk analysis, where appropriate,
    - Because you failed to follow your procedure, the acceptance criteria were not complete prior to the performance of validation activities
    -  Risk analysis is incomplete. The risk analysis for the hazard of linking PET/CT scans to the incorrect patient was performed after a June 2006 incident. The risk analysis has not been re-assessed/updated for increased probability given the three subsequent incidents. Your firm's Standard Operating Procedure directs risk analysis be reviewed and updated upon receipt of safety-related complaints. However, no risk analysis was performed for complaints related to incorrect normalization values in [redacted] PET/CT scanners
    - Your firm failed to establish and maintain adequate procedures for implementing corrective and preventive action (CAPA) to ensure the analyzing of sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems and employ appropriate statistical methodology, where necessary, to detect recurring quality problems
    - Failure to establish and maintain adequate complaint procedures for receiving, reviewing, and evaluating complaints
    - Complaints are not handled in a uniform and timely manner as specified by your procedures. Specifically, there are instances where the assignee of a complaint did not notify the complaint coordinator and indicated an expected date of investigation completion after the 60 day due date which is specified by the complaint handling procedures
    - Your firm failed to establish and maintain adequate procedures to control documents and ensure all obsolete documents are promptly removed from use or otherwise prevented from unintended use

 

W-211

  • Primary Deviations: bioburden determination not performed, software not validated, validation not documented, failure to implement sampling plans, QA employees not trained
  • Examples:
    - No software validation or verification was available for the [redacted] planning [redacted] system which is used for managing inventory, distribution of inventory, scheduling, engineering change orders, recalls, complaints, reworks, device master records, product return, procurement, production and sales processes. You provided some documented “scenarios”; however there was no protocol or summary included with those scenarios and no evidence that the tasks listed in the scenarios were ever performed.
    - We have reviewed your response received by the Atlanta District office on October 22, 2007 and have concluded that it is inadequate in that while you indicate that you have performed the [redacted] software verification, no documentation was provided. Documentation provided in your December response is incomplete and does not fully address software verification. While various printouts of output testing were provided, there was no protocol one could follow to assess what your testing is actually accomplishing
    - You did not perform bio-burden determination in the 2005 ethylene oxide (EO) validation study as specified in your protocol. The validation for the EO sterilization process was conducted in May 2005 in order to [redacted]. As part of protocol # 797040273, your firm was to perform a bioburden evaluation study
    - Failure to establish and implement sampling plans based on a valid statistical rationale. You did not have a rationale for the number of packages which are visually inspected every [redacted] hours on the [redacted] packaging machines
    - Failure to ensure that all employees have the necessary training and experience to perform their jobs. Specifically employees who manage, perform, and assess work affecting quality have not been adequately trained as members of your firm’s quality unit. Quality Assurance employees have not performed effectively in conducting complaint investigations, corrective/preventive action activities, design activities, internal audits, risk analysis and/or document reviews.

 

W-210

Keywords:  Computer system validation, CAPA, inspection of incoming products

  • Primary Deviations: Failure to adequately validate computer software, no investigation of complaints, no adequate inspection of incoming products
  • Examples:
    - Failure to adequately validate computer software used in an automated process for its intended use according to an established protocol, as required by 21 CFR 820.70
    - For example, no person from your firm reviewed or approved the third party approval test results for the original "[redacted] Complaint System Validation" used in your firm's quality system.
    - Failure to establish and maintain procedures for implementing corrective and preventive action that include requirements for analyzing processes, work operations, concessions, quality audit reports, quality records, service records, complaints, returned product, and other sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems
    - Failure to maintain a record of an investigation of a complaint by a formally designated unit that includes any corrective action taken
    - Failure to establish and maintain procedures for acceptance of incoming product, and to inspect, test, or otherwise verify incoming product as conforming to specified requireme

W-209

Keywords: Laboratory, computer system validation, computer security, audit trail, test report, signature, OOS, CAPA

  • Primary Deviations: Failure to validate computer systems, failure to secure computer systems, no password control for analysts and supervisors, deficient analyst worksheets, failure to investigate OOS results
  • Examples:
    - Data stored on the computer can be deleted, removed, transferred, renamed or altered (without audit trail)
    - There were no written protocols to assign levels of responsibilities for the system
    - There should be a record of any data change made, the previous entry, who made the change, and when the change was made.
    - There were no written protocols to assign levels of responsibilities for the system
    - Computerized systems should have sufficient controls to prevent unauthorized access or changes to data
    - No reference to analytical test method in the analyst worksheet, no reference to the instruments used
    - There were weights reported without indicating the gross, tare, or net weight
    - Failure of your investigations of out-of-specification (OOS) results to determine if corrections or preventive actions are needed

 

W-208

Keywords: Software validation, software changes, software patches, CAPA

  • Primary Deviations: No documentation of validation of software patches, software correction not verified, failure to establish and maintain adequate procedures for CAPA,
  • Examples:
    - You made changes to versions of the ISOLOC software between November 30, 2004, and April 7, 2006. For example, you released software patches for these various changes to your customers on November 30, 2004; December 30, 2004; April 11, 2005; April 28, 2005; May 31, 2005; January 2, 2006; and April 7, 2006. You have no documentation of validation or justification of verification for the seven patches. You also have no documentation of two incidents where problems were found with the patches that had been released. The ISOLOC 6.5 patch identified as 03102006 and issued on March 24, 2006, was removed from online distribution due to an "error" found in the patch which caused an inaccurate couch printout. You did not validate the patch or document that you had verified the correction
    - Failure to establish and maintain procedures for implementing corrective and preventive action to verify or validate the corrective and preventive action to ensure that such action is effective and does not adversely effect the finished device. Specifically, your Change Order #06-018A documenting a bug in the ISOLOC software version 6.5, which was addressed in the Corrective Action Request Form #06-004 and corrected in the ISOLOC software version 6.6, does not indicate the results of the validation or verification testing and any re-evaluation of the risk analysis to ensure the effectiveness of the corrective action.

 

W-207

Keywords: Process validation, computer validation, OOS, root cause, CAPA, management reviews, supplier evaluation

  • Primary Deviations: Inadequate process validation, validation OOS results not investigated and not reported in the validation report, no verification of effectiveness of CAPA., no evaluation of supplier and contractors, management review procedures not implemented. 
  • Examples:
    - Computer Numerical Control (CNC) Machine #C-4 had out of specification results during operational qualification conducted during validation. These out of specification results were not investigated or addressed in the validation report
    - The ultrasonic cleaning process has not been validated.
    - Failure to analyze all sources of quality data to identify existing and potential causes of nonconforming product
    - Failure to ensure that the corrective and preventive actions are effective
    - Failure to adequately implement your management review procedures
    - Failure to evaluate potential suppliers and contrac

 

 

W-206

Keywords:  Failure investigation, root cause, reporting quality problems, incoming products, complaints, training, internal audits, computer software validation,  test scripts, sampling plan, documentation

  • Primary Deviations: failure to validate computer software, no procedures for failure investigations, missing test scripts for computer validation, no procedures to report and follow quality problems, corrective actions identified but not implemented, corrective action, no acceptance procedures for in-process products, no procedures to verify conformance of purchased products, inadequate complaint investigation, failure to identify training needs, training requirements incomplete, no procedures for internal audits, no sampling procedures, sampling plans not reviewed, wrong procedure in document.
  • Examples:
    -Failure to validate computer software for its intended use according to an established protocol when computers or automated data processing systems are used as part of production or the quality system
    - Training Database software validation used to document employee training was deficient in that the test scripts were not available to show the execution of the software validation protocol. It appears that at least five (5) tests specified in the. approved protocol were not performed.
    - Failure to establish and maintain procedures for investigating the cause of nonconformities relating to product, processes, and the quality system,
    - Management did not implement corrective action for previously-identified deficiencies
    - Failure to establish and maintain procedures for submitting relevant information on identified quality problems
    - Failure to establish and maintain procedures to ensure that all purchased or otherwise received product and services conform to specified requirements
    -  All seven employee training records reviewed had incomplete training requirements
    - Failure to establish and maintain procedures to ensure that sampling methods are adequate for their intended use, to ensure, that when changes occur the sampling plans are reviewed, and that sampling plans are written based on a valid statistical rationale
    - The released updated revision #2 of procedure [redacted] "Drying Procedure for [redacted] Pellets" actually contained a different procedure (Urethane Mixing Solution, SOP [redacted]. This was not noted by any of the six (6) approving officials on December 19-20, 2006, or during employee training on the updated procedure on January 9, 2007

 

W-205

Keywords: Software validation, revalidation, quality policy, water purification

  • Primary Deviations: Inadequate software validation, quality policy not implemented, water purification system not validated, no revalidation after changes, no purchasing control procedures.
  • Examples:
    - Failure to have management with executive responsibility to ensure the quality policy has been fully implemented and maintained [21 CFR 820.20(a)]. Admittedly, you lack a Quality Plan and a management representative and have continued to operate since 2004
    -Failure to validate your software used for fluid delivery and heat disinfection in your water purification systems [21 CFR 820.70(i) and (b)]. For example, implementations of remote changes in operating parameters change the output of the system. These types of changes require re-validation of the system. You failed to follow your own procedure for change controls when critical limits were changed to suit a client's needs.
    --Failure to validate your water purification systems
    -The pre-treatment water purification, fluid delivery, and heat disinfection systems have not been validated . Although you indicate you follow AAMI standards for the fluid delivery system, our inspection did not support your claim . AAMI recommends one continuous loop, but you developed a,A1111101fuid delivery system with no data to support your claims of flow rates and acid levels..

    - Failure to establish and maintain purchasing control procedures [21CFR 820.50].
    - There are no incoming component specifications for acceptance and no supplier quality agreement

 

W-204

Keywords: Software validation, acceptance criteria, validation report

  • Primary Deviations: Inadequate validation. No justification why failed test results have been accepted.
  • Examples:
    - Failure to establish and maintain adequate procedures for validating the device software design to conform to the intended uses. For example: The validation results do not meet the pre-determined acceptance criteria, and there was no documentation why the results were acceptable. The validation reports do not contain an evaluation of the validation data and activities. Nor does it contain validation analyses and conclusion.

 

W-203

Keywords: Stability Testing, failure investigation, data integrity, data authenticity, data security, chromatograms, method validation, method transfer.

  • Primary Deviations: No stability testing program, no written procedures for stability testing, no failure investigation, no procedures to ensure authenticity, integrity, and security of electronic records, system administrator privileges assigned to chemists, chromatograms manipulated, methods used by outside contractor not validated.
  • Examples:
    - Failure to establish a stability testing program which includes reliable, meaningful, and specific test methods'
    - In addition, although your firm conducts impurity testing for [redacted] tablets, [redacted] softgels [redacted] caplets; and [redacted] mg tablets, it does not have written procedures for impurity testing
    - Failure to thoroughly investigate any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications
    - Failure to establish adequate controls and procedures to assure the authenticity, integrity, and security of all electronic records including data generated in the laboratory
    -System administrator privileges were to be assigned to validation chemists, lead chemists, and laboratory supervisors only.
    - These privileges include the ability to modify and delete raw data files and to lock/unlock projects for reprocessing in the chromatographic data acquisitions system which is used in the laboratory for finished product release testing, stability testing, and method validation studies
    - Our investigators documented numerous instances where these privileges were reassigned to other chemists without documentation or justification some of which resulted in extensive manipulation of data with no explanation regarding why the manipulation was conducted.
    - Our investigators documented many instances with extensive manipulation of data with no explanation regarding why the manipulation was conducted. This manipulation would include changing integration parameters or re-labeling peaks such that previously resolved peaks would not be integrated and included in the calculation for impurities
    - Furthermore, our investigators found that numerous products were tested using analytical methods, provided by outside sources, which had not been validated/verified according to SOP CO-S850-001-03, "Laboratory Technology transfer of Analytical Methods" and SOP CO-S880-002-02, "Method Validation Requirements" to determine these methods suitability for their intended use.
    - We acknowledge your corrective action plans. You have suspended production and distribution of drug products at [redacted] sites [redacted] and [redacted] and committed not to resume those operations until you have satisfactorily demonstrated to Atlanta District that the CGMP compliance problems have been addressed and the recall of most products within expiry is complete. We agree with your decision to hire consultants to help you implement corrective actions.

 

W-202

Keywords:  Design changes, design changes, software changes, revalidation, risk analysis, software testing, code testing, incoming products

  • Primary Deviations: No validation to verify effectiveness of software design changes, no revalidation after software change, no safety risk analysis, inadequate software test protocols and procedures, inadequate incoming product testing
  • Examples:
    - Failure to establish and maintain procedures for the identification, documentation, validation or verification, review, and approval of design changes before their implementation
    - There were no validation test protocol and test results to verify the effectiveness of the software design changes. This ECN did not document or reference design inputs (complaints, service requests, internal engineering testing, etc.) that led to these software design changes.
    - We noted that an engineering test protocol entitled "AV1 System Test Specification and Report Form - ECR 20051028," Revision 1, dated 7/24/06, was in still "Draft" at the time of the inspection and did not document specific test instructions, acceptance criteria, and the report summary to verify that the "software bugs" had been fixed.
    - Your firm was unable to produce records of design validation results, including software validation, to prove that the Best Pro 1 device meets its design specifications for the four treatment modes
    - Your firm failed to conduct and document adequate risk analyses that discuss the safe use of your devices with/without their accessories
    - Your firm's "Memo to File" for the software validation of the Best Pro 1 Device, prepared and dated 4/18/07 during the inspection, and the Software Validation Report, Revision 2, dated 11/7/06, for the Med Best, Med Sport, and Best Pro 1 Devices only document the general functional test requirements without attaching or referencing their software codes, software code testing, I/O (Input/Output) interface testing between the hardware and software, and the actual test results for each of the functional test requirements listed in these two documents
    - Failure to establish and maintain adequate acceptance procedures, including inspections, tests, or verification activities, for incoming product and for documenting the acceptance or rejection of the incoming product

W-201

Keywords: Software validation, Spreadsheets, CAPA, Incoming product testing

  • Primary Software not validated, spreadsheets not validated, implementation of corrective action too late, no procedures to ensure the quality of incoming products, CAPA not documented, CAPA not documented
  • Examples:
    -  Software used as part of the production quality system was not validated for its intended use according to an established protocol [21 C.F.R. 820.70(i)]. Specifically,
    (a) Spreadsheets intended to check for outliers and calculate mean, SC, % CV, value assignments for finished devices.
    (b) Complaint handling software
    (c) Quantrol database program
    - Your response to this observation appears to be adequate but we are concerned that the corrections are scheduled for completion in the fourth quarter of 2007. Your response should explain the need for this length of time.
    - Procedures to ensure that all purchased or otherwise received product and services conform to specified requirements were not established
    - Specifically, independent laboratories evaluated production lots for the purpose of contributing to the device value assignments. Those laboratories were not on the approved vendor list.
    - Corrective and preventive action activities were not documented, including the actions needed to correct or prevent recurrence of nonconforming product and other quality problems, and implementation of corrective and preventive actions.
    - Specifically: (b) Temperature recording charts for [redacted] indicated temperatures were outside the acceptable range on at least four (4) occasions. The corrective action required investigating the effect of temperature fluctuations on the product when the freezers were not within the acceptable range. This evaluation was not performed.

 

W-200

Keywords:  Process validation, automated systems, software validation, root cause, bio-burden, environmental conditions not controlled, equipment calibration

  • Primary Deviations: Processes not validated, automated and semi-automated systems not validated, software not validated, root case of failures not investigated, equipment calibration not documented.
  • Examples:
    - Failure to validate a process whose results cannot be fully verified by subsequent inspection and test-
    - The filling, capping, packaging, and sealing processes, which utilize semi-automated and automated equipment, are not validated. In addition, the software applications controlling these processes are not validated for their intended uses.
    - The software controlling the capping processes has not been validated
    - No investigation was conducted under the firm's CAPA system to determine the root cause for spikes in bioburden
    - No investigation was conducted under the firm's CAPA. system to determine the root cause for the process water failing conductivity testing
    - Failure to establish and maintain adequate procedures to control environmental conditions
    -  Failure to document equipment identification, calibration date, the individual performing the calibration, and the next calibration dat

 

W-199

Keywords: Design validation, software validation, risk analysis for risk analysis, testing, code reviews, training, service calls

  • Primary Deviations: No procedure for design validation, software validation and risk analysis, structural testing not documented, validation of compiler not documented, independent code reviews not documented, personnel taking service calls not trained
  • Examples:
    - Failure to establish and maintain adequate procedures that ensure design validation to include software validation and risk analysis, where appropriate, as required by 21 CFR 820.30(g).
    - For example: The firm failed to document structural (white box) testing of its P.I.N. software, including independent code reviews, and the firm lacks documentation of validation of its compiler.
    - Failure to ensure that all personnel are trained to adequately perform their assigned responsibilities, as required by 21 CFR 820.25(b). For example, training of individuals who take service calls is inadequate since they are responsible for identifying complaints and separating them from other issues in a uniform and timely manner; however, they are not accurately identifying all complaints.

W-198

Keywords:  Software validation, failure investigation, computer access, audit trail, cleaning validation,  CAPA, stability testing, impurity testing

  • Primary Deviations: No impact analysis of actual batch problems on distributed products, drug products not tested for impurities or degradation products, suggested time for corrective action too late.
  • Examples:
    - Appropriate controls are not exercised over computers or related systems to assure that changes in analytical methods or other control records are instituted only by authorized personnel [21 CFR 211.68(b)].
    - Specifically, a) There was a failure to validate the [redacted] software to assure that all data generated by the system was secure. This software runs the laboratory HPLC equipment, generates and stores data, and performs calculations during testing of raw materials, in-process materials, finished products, and stability samples.
    - b) User access levels for the [redacted] software were not established and documented. Currently, laboratory personnel use a common password to gain access to the system and there are no user access level restrictions for deleting or modifying data.
    - Furthermore, your system does not have an audit trail to document changes
    - Regarding computer validation and security issues, you did not provide a time frame for writing and implementation of a computer security SOP. Your response regarding data back-up indicated that a separate server was being considered and would be implemented by "[redacted]" We believe this date was to have read [redacted]. Please explain why this correction cannot be completed in a more timely fashion
    - Based upon your response, it appears that investigations of the Out-of-Specification results cited on the FDA-483 have still not been conducted and documented, nor have you assessed whether any of the failures cited may also affect marketed product lots, for instance, in terms of the ability of the marketed lots to meet all specifications throughout the labeled expiry period
    - Evaluations were not conducted at least annually to review records associated with a representative number of batches, whether approved or rejected
    - Drug products manufactured by your firm have not been evaluated for the presence of impurities and degradation products

W-197

Keywords: Software validation, trend analysis, complaint software, non-conforming products

  • Primary deviations:  Trend analysis and complaint software not validated,. use of non-conforming product not justified
  • Examples:
    - The validation of the software used to perform the trend analysis has not been provided to support your firm's claim that the software can be used effectively to prevent the firm from overlooking complaints. In addition, you have not addressed how you corrected the observations that were made during the FDA inspection. Specifically, you have not provided the documentation of the investigation into the complaints that were identified in the FDA-483. Please provide for FDA review the documentation of investigation into the complaints, revised procedure QSP8.2-2 "Customer Complaints," and the software validation that was performed on the complaint handling software used for trend analysis.
    - -Your firm's response dated 11/09/2006 is not adequate. You stated in your response that you have updated QSP 8.2-2 "Customer Complaints" and revised the customer complaint handling software to allow for trend analysis based on malfunction code. You have not provided-a copy of QSP 8.2-2 "Customer Complaints" for FDA review.
    -  Failure to document the justification for use of the nonconforming product and the signature of the individual(s) authorizing the use

 

W-196

Keywords: Software change,  quality policy, quality system, supplier evaluation, consultant evaluation, incoming products, effectiveness of CAPA,

  • Primary deviations:  Effectiveness of CAPA not verified, hardware and software fault conditions during factory testing and clinical use not investigated, quality policy and quality system not implemented, no or inadequate procedures to ensure the quality of incoming products, no or inadequate procedures to evaluate suppliers, contractors and consultants, no follow up of problems with quality of incoming products, source of quality problems not evaluted
  • Examples:
    -  Failure to establish and maintain procedures for verifying and validating the corrective and preventive action
    - Failure to have management with executive responsibility to ensure the quality policy has been fully implemented
    - Simply replace malfunctioned pressure monitors and pumps, or any other defective components during factory testing, site installation, and subsequent service calls of analyzers is not an effective solution, and cannot be effectively verified nor validated without investigating all possible hardware and software fault conditions occurring during factory testing and field clinical use of the analyzers.
    - Failure to establish and maintain adequate procedure to ensure that all purchased or otherwise received product and services conform to specified requirements, and to include evaluation of supplier, contractors, and consultants, as required by 21 C.F.R. § 820.50. For example, your firm rejected defective components during incoming and finished device testing, documented nonconforming material reports for rejected components, and then sent supplier corrective action reports to your suppliers to notify them of quality issues. However, your firm failed to collectively use these sources of information to re-evaluate the overall quality rating your suppliers as required by your procedures. Additionally, despite the fact that your firm documented negative quality data for the pressure monitors and pumps, your firm has not adequately evaluated the ability of the two suppliers to meet your firm's requirements.
    - Failure of the management with executive responsibility to ensure that an adequate and effective quality system has been fully implemented and maintained at all levels of the organization, as required by 21 C.F.R. § 820.20. For example, your firm's management has not effectively implemented adequate and global corrective actions in a timely manner to correct quality issues across your analyzer product lines. The FDA's current inspection involved the issuance of an 11-item FDA-483 to your firm.
    - Failure to establish and maintain procedures for the analysis of all sources of quality data to identify existing and potential causes of nonconforming product or other quality problems

 

W-195

Keywords: Software validation, software retesting, data integrity, data migration, change control, document changes

  • Primary Deviations: No procedures for design changes, incomplete software validation, SW functions not tested without justification, failure to validate data integrity for data file migration, correct functioning of migration from earlier versions not updated, only from immediate predecessor, effectiveness of CAPA not verified
  • Examples:
    - Failure to establish and maintain procedures for the identification, documentation, validation, or where appropriate verification, review, and approval of design changes before their implementation
    - The software verification/validation for the pump operating software version 4.00.04 and MDL software version 5, and the design of the hardware components associated with the PCA/PCEA module were not completed at the time the re-designed Spectrum pump was released for manufacturing
    - There was no documented verification or validation testing of the PCA/PCEA delivery mode software that was integrated into the Spectrum operating software version 4.00.04
    - Validation of MDL software for Sigma Spectrum pumps was either not performed or it was incomplete
    - Additionally, in all software versions above, two tests to support the "library download deployment and download validation", which were consistently performed in validation of previous iterations of the MDL, were excluded from these protocols. Your firm has not provided any justification as to why these tests were removed from the protocol.
    - Failure to validate the data integrity of the MDL library is especially crucial for versions 5.0.0.25 and 5.0.2, which supports the unvalidated PCA/PCEA delivery modules
    - Testing was not performed to verify or validate that newer versions of the MDL could successfully import the drug library data from older versions of the software.
    - Sigma International's engineers stated that MDL software and data files can be migrated into the most current version of the MDL that is installed on any particular device. However, your firm has not validated that this migration can be performed successfully, without compromising the integrity of the data that is transferred from older MDLs to newer MDLs
    - The following test was successfully completed without failures: Importing Drug Libraries from MDL v2.0.0-0002 to MDL v4.00.02 to MDL v5.0.0.25, MDL 5.0.1 to v5.0.2. However, based upon our review, it appears that your firm's tests only verify that any given version of the MDL would successfully import software and data files from its immediate predecessor
    - Failure to establish and maintain procedures for verifying or validating the corrective and preventive action to ensure that such action is effective
    - Failure to establish and maintain procedures for changes to a specification, method, process or procedure
    - Failure to maintain records of changes to documents that include a description of the change, identification of affected documents, signature of approving individual, approval date and when the change became effective
    - Failure of management with executive responsibility to ensure that the established quality policy is understood, implemented, and maintained at all levels of the organization

 

 

W-194

Keywords: GLP, raw data, reason for change, responsibilities of QAU, integrity of study data

  • Primary Deviations: Incomplete study records, no reason for change of study records, QAU not fulfilled its responsibilities, raw data, no assurance of the quality and integrity of study report, no final study report, no or inadequate testing and calibration of equipment
  • Examples:
    - Failure of the study director to assure that all experimental data were accurately recorded and verified and document the reason for any change in the entries
    - For study xxx your study director failed to assure that dosing were accurately recorded to confirm that study animals received protocol-specified doses of the vehicle.
    - Failure of QAU to assure that reported results in the final study report accurately reflected the raw data
    - Failure of QAU to maintain written and properly signed records of each periodic inspection
    - Failure to identify the test and control articles with appropriate characteristics in the final report
    -  Failure to adequately test, calibrate, and/or standardize all equipment used the generation, measurement and assessment of data

 

W-193

Keywords: Batch records, method validation, cleaning validation, equipment calibration

  • Primary Deviations: Incomplete batch records, insufficient documentation of method validation, inadequate documentation of laboratory equipment calibration, shipment of APIs to US from non certified manufacturing site
  • Examples:
    - Batch production records do not include complete information relating to the production and control of each API batch
    - Method validation documentation did not include appropriate data to verify that the analytical method produced accurate and reliable data
    - Production equipment was not adequately cleaned and was not maintained in a good state of repair
    - Laboratory equipment calibration was not adequately documented.

W-192

Keywords: Data security, raw data, passwords, laboratory software

  • Primary deviations: no individual passwords, ability to overwrite raw data.
  • Examples:
    - Validation of the (brand name) laboratory software used to control instruments, generate data, perform calculations, and store data from raw material and finished product testing failed to demonstrate adequate security. Analysts have the ability to overwrite original data, and are not required to utilize the protection of individual passwords.
    - The corresponding EIR further states: During discussions and lab demonstrations, it was determined that neither system prevents analysts from overwriting original raw data. A review of the software validation showed initial failures for modules demonstrating the ability to delete or overwrite data. Documentation in the validation report stated that this capability could not be changed. During the laboratory demonstration, I observed the statement, "Data will be overwritten" with the option to ignore this.
    - In addition to the ability to overwrite original data, the analysts are not required to utilize the protection of passwords since they are considered to have "limited access". I stated that each analyst needs to have their own password to access the system to help ensure data security and to track the usage by individuals.

 

W-191

Keywords: Vendor software, software validation

  • Primary deviations: vendor supplied computer software not validated,
  • Examples:
    -The performance of the computer software has not been verified. Specifically your firm has not verified your computer software program in all aspects of their donor referral operations to ensure that electronic records are trustworthy, accurate and reliable. The related EIR further explained: The firm uses a computer software program called (brand name) that is manufactured by (vendor name).
    - During the inspection, I asked if the computer software has been validation to assure that it performs for it's intended use. I was told that the software was validated by the manufacturer. The managing director provided me a copy of the letter the received from (the vendor). The letter indicated that the software was validated. She also the gave me a copy of validation information that was obtained from (the vendor) during the inspection.
    - I told the managing director I still need to see what they have done to validate the system since the computer was making a decision to accept or reject potential donors. The managing director and the Manager of the Communications Center told me that they were unaware they the company had to validate the software because it was validated by (the vendor) and that was their reason for purchasing the version of software instead of the COTS (Commercial Off The Shelf) version of the software that is also manufactured by (the vendor).  

 

W-190

Keywords: IQ, OQ, PQ, retrospective validation, legacy systems, no review of electronic records

  • Primary deviations: no validation of legacy systems, no formal change control. no design control for customized software elements, no review of electronic records
  • Examples:
    - No IQ, OQ or PQ has been performed throughout the life of the system. No validation reports have been generated historically.
    - Current efforts to retrospectively validate the system have progressed through the approval of an IQ protocol, however, this protocol has not yet been executed. OQ and PQ efforts have not yet been developed as part of these current validation efforts.
    - The (system) has not been maintained under established procedures for change control. This is true throughout the life of this software application.
    - The firm has failed to generate or maintain design control documentation sufficient to define all customized elements making up the (system) configuration (i.e., functional or structural design documentation defining all program making up (the system)
    - Electronic records generated during manufacture of APIs were not reviewed prior to release of validation lots or for any lots manufactured thereafter to include the most recently released API lot.
  •  

 

W-189

Keywords: Microsoft Excel, Microsoft Word, Off-the-shelf software, Validation

  • Primary deviations: Off-the shelf software not validated
  • Examples:
     Failure to assure that when computers or automated data processing are used as part of the production or quality system the manufacturer shall validate computer software for its intended use according to an established protocol, as required by 21 CFR 820.70(i).
    - Electronic records are used but there was no software validation.
    - No procedures are established to validate for its intended purpose the Microsoft Word or Microsoft Excel software used in creating and maintaining nonconformance records, product return records, internal audit corrective records, or corrective action records.

 

W-188

Keywords: Laboratory, Electronic Audit Trail, Chromatographic integration

  • Primary deviations: No or inadequate electronic audit trail, no audit trail for chromatographic reintegration
  • Examples:
    - Operations that could affect the integrity of chromatographic data files … are not controlled by electronic audit trails that maintain who, why and what was changed to any given sample record
    - There are no records of user transactions when data is deleted, copied, renamed or purged
    - The firm can not determine if reintegration of a sample occurred once or several times

 

W-187

Keywords: Stability Testing, Quality Control Unit, Laboratory investigations, electronic audit trail, automated computer time-out, method validation, method transfer

  • Primary deviations: Electronic audit trail not reviewed, electronic audit trail does not identify the the person who made the change, no automated computer time-out, operators and supervisors can delete raw data, raw data from contract testing labs not reviewed, proper functioning of established methods not verified after modifications, no follow-up on unknown chromatographic peaks, failing impurity results not reported, no or inadequate training, responsibilities of quality control unit not in writing, inadequate cleaning and maintenance of equipment, no or inadequate failure investigation
  • Examples:
    - Appropriate controls are not exercised over computers or related systems to assure that changes in master production and control records are instituted only by authorized personnel
    - The audit trail generated within xxx does not truly reflect the identity of the responsible individuals. Individuals have been able to log on to the system under an other individuals account and make changes which then show up on the audit trail to the first individual.
    - Changes made by PERSON 1 are attributed to PERSON 2 on the (electronic) audit trail.
    - The firm's review of laboratory data does not include the audit trail/revision history to determine if unapproved changes have been made.
    - The xxx system computers in the lab do not time-out. If an employee fails to log off a computer and walks away other individuals can easily access the computer under the first employees account.
    - The firm routinely assigned method validation chemists, lead chemist, and laboratory supervisors system administrator status with the ability to modify and delete raw data files in the HPLC data acquisition system
    - Records maintained of any modifications of an established method employed in testing do not include the data to verify that the modification produced results that are at least as accurate and reliable for the material being tested as the established method
    - The firm does not receive and review all raw data from contract testing laboratories
    - The accuracy, sensitivity, specificity, and reproducibility of test methods have not been established and documented
    - The firm failed to perform finished product test method transfers for 34 products
    - The firm has failed to perform method validations, method verifications, or method transfers for any of the laboratory test methods used to test active pharmaceutical ingredients

 

W-186

Keywords: Method validation, method transfer, process control procedure, sampling plans, test procedures

  • Primary deviations: Analytical methods transferred without method transfer or revalidation protocol, no or inadequate product specifications, no or inadequate sampling plans.
  • Examples:
    - Failure to establish production and process control procedures designed to assure your drug products have the required identity, strength, quality and purity. For example, the validation protocols for xxx and xxx do not provide assurance that the manufacturing process quality throughout the production process/
    - failure to establish scientifically sound and appropriate specifications, standards, sampling plans, and test procedure designed to assure products conform to appropriate standards of identity, strength, quality, and purity. For example, there is no scientific justification for testing 30 capsules for content uniformity during process validation.
    - Failure to establish and document the accuracy, sensitivity and reproducibility of test methods employed. for example, methods that were validated at one facility and transferred to xxx site are being used without method transfer or revalidation protocol,.

 

W-185

Keywords: Software and computer system validation, back-up, limited access, audit trail, data encryption, accurate copies

  • Primary deviations: Inadequate storage and back-up, missing ability to discern invalid or altered electronic records, access to computer records without unique user ID and password, no or inadequate validation, inaccurate copies of electronic records.
  • Examples:
    -Failure to store records so as to minimize deterioration, prevent loss and back up of automated data processing systems
    - The electronic data did not correlate with the paper records; you had not established an electronic data back-up procedure; and finally, data was copied onto the server from one system to the next via floppy: therefore, no limited access or data protection had been established
    - You failed to adhere to the requirements established by the stability protocol in that, the method for tracking (i.e. Microsoft Excel) the number of samples placed in the incubator was unauthenticated.
    - You failed to encrypt and/ or physically secure your data back-up system to comply with the requirements to prevent deterioration or deletion of the analyzer data- You failed to encrypt and/ or physically secure your data back-up system to comply with the requirements to prevent deterioration or deletion of the analyzer data
    - Failure to adequately validate the intended use of this PC and its software
    - The dedicated PC [redacted] attached to the [redacted] was not secure in that access to the data on [redacted] was not granted by a unique username and password or equivalent method
    - there as no documentation associated with the electronic data for whom was responsible for collection of the analytical results as several quality control personnel have access to the [redacted] no software changes in the study data could be detected as there was no audit trail capability; and finally, the electronic data did not correlate with the paper records.
    - your response and have concluded that it is inadequate because no system validation was conducted to ensure accuracy, reliability, consistent intended performance, and the ability to discern invalid or altered records

 

W-184

Keywords: IRB, clinical investigations, review procedures

  • Primary deviations: Failure to follow required written procedures, failure to use expedited review procedures.
  • Examples:
    - Review of the inspection report indicates that the IRB failed to follow written procedures for conducting initial and continuing review of research
    - The IRB's written procedures state that "the IRB shall consist of thirteen (13) members." Since October 12, 2005, the IRB membership roster has listed only 12 members.
    - The IRB's written procedures state that "meetings will be held on an as-needed basis, but no less than quarterly." However, the IRB records indicate that the IRB has met at intervals greater than three months on four occasions since August 2004.
    - Failure to use expedited review procedures only for certain kinds of research involving no more than minimal risk or for minor changes in approved research [21 CFR 56.110]
    - Failure to ensure that the IRB reviewed proposed research at convened meetings at which a majority of the members of the IRB were present

 

W-183

Keywords: Clinical trials, investigational plan, investigator agreement

  • Primary deviations: Missing records, inaccurate data corrected, unapproved deviation from investigational plan, no or inadequate
  • Examples:
    - Failure to ensure adequate monitoring of the investigation
    - Data were missing and inaccurate data was corrected for Subject [redacted]
    - Failure to secure the investigator's compliance with the signed investigator agreement, the investigational plan, applicable FDA regulations, and any other conditions of approval imposed by the reviewing IRB or FDA
    - There are repeated deviations from the investigational plan, spanning several years, with no apparent steps taken to bring the clinical investigators into compliance, which indicates failure to ensure investigator compliance

 

W-182

Keywords: Method validation, USP, standard methods, stability testing, method documentation, change control, OOS, batch records

  • Primary deviations: Failure to validate changed USP standard methods, missing validation for stability indicating methods, insufficient documentation of test methods, insufficient documentation of changes, no follow-up of oos situations, failure to release products that do not meet USP requirements, incomplete batch records
  • Examples:
    - Your firm uses USP methods to analyze your products, but changes have been made to the USP methods and no validation has been performed. For example, for Migrazone Capsules, the USP uses three different wavelengths to analyze the three active ingredients. Your firm changed the method to use [redacted] of or all three actives and no validation of the new procedure was performed.
    - Failure to follow your firm's written stability testing program as required by 21 CFR 211.166(a) in that your firm has no validation data to demonstrate that the method used to analyze products for stability is capable of detecting degradation of the products
    - Your firm lacks complete written methods that fully describe the procedures, equipment, parameters and specifications to be used in the analysis of individual products.
    - Written instructions for analyzing products include cross outs and changes to the instructions without any documentation as to why these changes were made
    - Review of chromatograms revealed that, in certain instances, out of specification results which were recorded on the chromatograms had no corresponding reference or raw data recorded in the official laboratory bound notebook. In these cases, the data was recorded in the notebook only when the sample was retested and results found to be within limits. For example...
    - Your firm has released products purporting to meet USP requirements when, in certain cases, they fail to meet such requirements. For example ...
    - Laboratory control results are not included in batch records as required by 21 CFR 211.188(b)(5). Analytical results are only maintained in laboratory notebooks

 

W-181

Keywords: Cleaning records, sampling plans, test procedures, building design

  • Primary deviations: Failure to keep records for the maintenance, cleaning, and sanitizing of equipment. Failure to establish sampling plans, test procedures, or laboratory control mechanisms for testing your finished product Failure to have adequate building design.
  • Examples:
    -For example, your firm lacked an adequate assessment of the cross-contamination risks posed by the manufacture of several potent compounds (e.g. cytotoxic and hormone products, as well as other products of high pharmacologic activity) at your facility.
    - Failure to have adequate building design and construction used in manufacture, processing, packing, or holding of drug products to facilitate cleaning, maintenance, and proper operations
    - There were no equipment cleaning records for several of the product contact, multi-use formulation mixing rods. The investigators observed that there was no evidence to demonstrate that the mixing rods were dedicated to specific products.
    - Investigators observed black colored particles in at least one evacuated sterile vial. The microbiologist performing sterility testing on the vials was observed removing the vial with the black colored particles and replacing the vial. No sampling plan or test procedures were available to justify replacement of the finished product evacuated vial.

 

W-180

Keywords: Cleaning validation, quality control unit, failure investigation, oos, raw data, laboratory notebooks, input-output checking, retesting

  • Primary deviations: Inadequate cleaning validation, quality control units failed adequate investigation, no or inadequate failure investigation, raw data not documented in laboratory notebooks, oos retesting without supervisory approval, electronic data files not routinely checked for accuracy, discrepancies in electronic data
    Examples:
    - Our investigators observed numerous instances where the quality control unit failed to adequately investigate and resolve laboratory deviations and out-of-specification test results involving drug products that ultimately were released for distribution into interstate commerce
    - Our investigators uncovered out-of-specification test results in laboratory raw data that were not documented in laboratory notebooks, and found that products were released based on retesting without any justification for discarding the initial out-of-specification test results.
    - The chromatographic test data reflecting the out-of-specification test results were not recorded in laboratory notebooks. Instead, a new sample preparation was injected within the same chromatographic run without supervisory approval, as required by your firm's SOP
    - A review of the laboratory notebook shows the sample dilution value in the laboratory notebook was overwritten, without being signed and dated.
    - There was a failure to check for accuracy the inputs to and outputs from the "Total Chrom Data Acquisition System," which is used to run your firm's HPLC instruments during analysis of drug products. For example, electronic data files were not routinely checked for accuracy and, as mentioned in the above observations, our investigators found numerous discrepancies between the electronic data files and documentation in laboratory notebook.

 

W-179

Keywords: Computer validation, training, document control, CAPA, root cause

  • Primary deviations: Computer systems nor validated, training needs not identified, failure to follow document controls requirements, no or inadequate CAPA procedures, no validation or verification that implemented CAPA activities are effective
  • Examples:
    - Failure to establish and maintain procedures for implementing corrective and preventive actions. The procedures must include verifying or validating the corrective. and preventive actions to ensure that such actions are effective and do not adversely affect the finished device, as required by ...
    - Failure to investigate the cause of nonconformities relating to product, processes, and the quality system, as required by 21 CFR 820.100a)(2). For example, the following procedures, Complaint Handling, Defect Tracking and Trending, Nonconforming Material and Repair of Equipment, do not include procedures for performing failure investigations.
    - Failure to have production and process controls for automated processes, as required by 21 CFR 820.70(i). when computers or automated data processing systems are used as part of production or the quality system . A manufacturer is required to validate computer software for its intended use according to an established protocol. For example, databases that are maintained for data analysis and other tracking and trending functions, including complaint and services access databases, have not been validated for their intended use.
    - Verification or validation of CAPA is required and no documentation was attached or referenced to CAPA 440C.

 

W-178

Keywords: Ongoing equipment qualification (PQ), procedures, PQ, training, quality control unit, records, failure investigation

  • Primary deviations: No or inadequate performance qualification, no or inadequate written procedures for production and process control, no or inadequate quality control unit, failure to perform investigation, no or inadequate training, procedures not followed, failure to maintain complete equipment calibration records records .
  • Examples:
    -Failure to routinely calibrate, inspect, or check automatic, mechanical, or electronic equipment according to a written program designed to assure proper performance [21 CFR 211.68(a)].
    - Specifically, your cryogenic pumping system lacks qualification according to a written plan to assure all parts of the system, including the pump, power supply, electric components, vacuum hold and cryogenic jacket, will operate properly for their intended use every time.
    - Failure to establish adequate written procedures for production and process control designed to assure drug products have the identity, strength, quality and purity they purport or are represented to possess
    - Failure to establish an adequate quality control unit having the responsibility and authority to approve or reject all drug products, and the authority to review production records to assure no errors have occurred or, if errors have occurred, they have been fully investigated, as required by 21 CFR 211.22(a). Specifically .......
    - Quality control unit personnel failed to perform an investigation into the failure of the filling equipment to fully pressurize the cylinders during a filling operation, in violation of 21 CFR 211.192
    - Failure to maintain complete records of the periodic calibration of laboratory instruments required by 21 CFR 211.160(b)(4) and 211.194(d)

 

W-177

Keywords: Bioequivalence, retrospective review of study data, analytical methods, no procedures, pharmacokinetic profiles, failure investigations

  • Primary deviations: invalid retrospective review of study data, inadequate documentation to demonstrate accuracy of analytical methods, providing incorrect information to the FDA, missing studies in retrospective review, lacking procedures for critical steps in retrospective review, failure to investigate pharmacokinetic profiles with unexpected concentration results, no timely information of study sponsors about invalid data.
  • Examples:
    -Failure to demonstrate that the five year retrospective review is effective and capable of discriminating between valid and invalid data
    - Failure to assure that the analytical methods used for in vivo bioavailability studies could accurately measure the actual concentration of active drug ingredient, or its metabolite, achieved in the body. "Long term use" is not a sufficient assurance of assay accuracy.
    - For these reasons you have not demonstrated that the reported concentration results in Study xxx are accurate.
    - You provided incorrect incorrect information to FDA regarding the status of undergoing retrospective review
    - You failed to appropriately include studies in the retrospective review
    - There is no assurance that reviews were conducted in accordance with original or revised procedures
    - You failed to investigate the cause of anomalous results, or re-assay the affected samples. Contrary to your response, the frequency of occurrence is not a justification for accepting anomalous study results
    - Although you discontinued use of the xxx method in August 2005, you failed to inform study sponsors that the data generated with this method was invalid.

 

W-176

Keywords: Clinical studies, subjects safety, subject rights, supervision of personnel, signatures, review reports, record maintenance

  • Primary deviations: failure to protect the rights, safety, and welfare of subjects under care, failure to personally conduct or adequately supervise the above references clinical trial, no evidence of lab report review, failure ton conduct the study in accordance with the investigational plan, failure to prepare and maintain adequate and accurate records, failure to promptly report to the sponsor any adverse effect that may reasonably be regarded as caused by, or probably cause by, the drug.
  • W-175Examples:
    - You did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations
    - Because this subject had a history of peptic ulcer disease and an incident of gastrointestinal bleeding she was at substantial risk for GI bleed related to treatment with aspirin.
    - The record does reflect that you reviewed the subject screening assessments and related subject records in accordance with the protocol
    - You delegated certain study tasks to an individual not qualified to perform such tasks
    - You permitted an individual with no medical training to evaluate laboratory results for clinical significance. The lab reports were not co-signed by you, therefore thee is no indication that you reviewed them
    - The case history did not contain any other documents to validate the subject's enrollment and completion of clinical investigation

 

W-175

Keywords: Process validation, software validation, design verification, SOPs, incoming product control, complaint handling

  • Primary deviations: Inadequate procedures for monitoring and control of parameters for validated processes, inadequate process control procedures, inadequate procedures for incoming product control and documentation, inadequate complaint handling procedures, no or inadequate software
  • Examples:
    - Failure to establish, and maintain procedures for monitoring and control of parameters for validated processes to ensure that the specified requirements continue to be met
    - Where the process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures.
    - The validation activities and results, including the date and signature of the individual(s) approving the validation and where appropriate the major equipment validated, must be documented. For example, your firm has not validated the software used in the xxx device. The xxx device has a microprocessor programmed with specific -software to control the xxx and alternate the xxx Procedures for validating the device design to ensure that the device conforms to defined user needs and intended uses have not been provided, nor has the software validation been performed
    - Failure to establish and maintain process control procedures, including documented instructions, standard operating procedures (SOPs), and methods, that define and control the manner of production
    - Failure to establish and maintain procedures for finished device acceptance to ensure that each production run, lot, or batch of finished devices meets acceptance criteria
    - Failure to establish and maintain procedures for acceptance of incoming product, including documentation of acceptance or rejection
    - Failure to establish and maintain adequate complaint handling procedures for receiving, reviewing, and evaluating complaints by a formally designated unit

 

W-174

Keywords: CAPA, complaints, training, equipment calibration, process validation, received product testing

  • Primary deviations: training procedures not implemented, no or inadequate procedures for equipment calibration and inspection, no procedures for process validation and monitoring, CAPA procedures not established and implemented, complaint files not maintained, specifications of all purchased or otherwise received products and services not verified
  • Examples:
    -Failure to establish, implement, and control procedures to ensure that equipment used in production and measuring are routinely calibrated, inspected, and checked for accuracy Specifically, no records are maintained for the inspection, checking, adjustment and calibration of scales, production furnace, and filling machine
    - Failure to ensure complaint files are maintained and that all oral and written complaints are documented upon receipt and are processed in a uniform and timely manner
    - Failure to establish, implement, and control procedures for the validation of production processes and control and monitoring of process parameters
    - Failure to implement and control procedures to ensure that all purchased or otherwise received product and services conform to specified requirements
    - Failure to establish, implement, and control procedures for Corrective Action and Preventive Action (CAPA)
    - Failure to ensure that training procedures identifying training needs are implemented and training activities are documented

 

W-173

Keywords: Audit of contract laboratories, certificate of analysis, responsibilities of quality unit, reserve samples, API, repackaging, container closure systems, equivalency

  • Primary deviations: failure to conduct audits of contract laboratories, failure to validate the authenticity of suppliers COAs, reserve samples not retained, equivalency of container closure system not documented
  • Examples:
    - Failure to validate the authenticity of supplier's COAs of a periodic basis in lieu of full compendia testing of APIs that you package
    -Failure to conduct audits of contract laboratories that perform testing-of-incoming API. Your SOPs indicate that these audits are to be conducted every two years
    - Failure to maintain written procedures that describe the responsibilities and procedures applicable to the quality control unit
    - Failure to retain reserve samples of each batch of each API that you repackage. There were a number of instances your firm received complaints regarding product integrity. Your firm failed to conduct complete investigations into these complaints regarding the APIs that you repackage because no reserve samples were available to examine
    - You have not demonstrated that the container closure systems into which these APIs are repackaged are identical or equivalent to those in which the APIs are received

 

W-172

Keywords: failure investigations, contract laboratory, repair, passwords, audit trail, security, method change, signatures on test results, power failure

  • Primary deviations: insufficient written records of failure investigations, investigations not extended to other batches, missing HPLC peak not investigated, no investigation regarding HPLC malfunctions requiring external repair, impact of power failure not investigated, laboratory records not signed by the analyst, analyst not identified, failure to use group passwords to log-on to computer systems, changes of methods by authorized persons not ensured, no review of audit trail, contract laboratory not qualified
  • Examples:
    - Written records are not always made of investigations into unexplained discrepancies, nor did investigations of unexplained discrepancies extend to other batches of the same drug product or other drug products that may have been associated with the specific failure or discrepancies
    - The reference standard injection following assay and content uniformity testing of xxx, failed to show any peaks due to a leaking column. There was no documented investigation of this deviation, there was no assessment of the impact of the leaking column on the xxx analysis or any other analysis conducted with the same column, and the observation was made during the previous inspection, yet no investigation was conducted.
    - There was no documented investigation regarding HPLC malfunctions requiring external repair. Both HPLC xxx and xxx required repair in June 2005; however there is no documentation regarding whether the malfunctions impacted any analyses, and if so, what the corrective actions were regarding those analyses.
    - Power failures occurred during analyses of xxx. Investigations did not document the impact on the analyses, any re-testing or resampling, or if the power outage impacted any other analyses
    - Laboratory records fail to include the initials or signature of the person who performs each laboratory test [21 CFR § 211.194(a)(7)]. Specifically, laboratory analysis records for analyses performed on HPLC xxx and xxx do not indicate which analyst performed the injections.
    - Failure to maintain complete records of any modification of an established method employed in testing [21 CFR § 211.194(b)]. Specifically, the records of laboratory methods stored in the xxx computer system do not include the identity of the person initiating method changes.
    - Appropriate controls are not exercised over computers or related systems to assure that changes in analytical methods or other control records are instituted only by authorized personnel
    - Laboratory managers (QC and R&D) gained access to the xxx computer system through a common password. Analysts were not required to use individual passwords; they operated the system following the login by the laboratory managers.
    - Due to the common password and lack of varying security levels, any analyst or manager has access to, and can modify any HPLC analytical method or record. Furthermore, review of audit trails is not required.
    - Failure to follow written procedures applicable to the quality control, unit [21 CFR § 211.22(d)]. Specifically, the contracted laboratories responsible for performing analyses on Active Pharmaceutical Ingredients and other drug components, used in the finished drug products, such as LOD, nitrogen content; microbial limits, and specific rotation, have not been qualified by the quality unit as per your firm's written procedures.

 

W-171

Keywords: Complaints, service, repair, design, risk assessment

  • Primary deviations: Service records not maintained, inadequate handling of complaints, not all possible risks identified and documented
  • Examples:
    - Failure to establish and maintain procedures to ensure that the design requirements relating to a device are appropriate and documented
    - Your firm failed to identify, approve, and document appropriate design inputs prior to the start of its formal design of the Frye Adjusting Instrument
    - Failure to establish and maintain procedures for validating the device design to ensure that the device conforms to user needs and intended uses
    - Your firm failed to adequately identify and document all possible risks associated with your device and document the results of your firm's risk analysis
    - Failure to establish and maintain complaint handling procedures for receiving, reviewing, evaluating, and documenting complaints by a formally designated unit
    - Failure to maintain service reports for serviced devices, as required by 21 CFR § 820.200(d). For example, your firm failed to maintain service reports for each device returned to your firm for servicing or repair (e.g. the name of the device, the date of service, the individual(s) servicing the device, the service performed, and the test and inspection data).
    - Your firm failed to document the results of its analysis or evaluation of emails of complaints and service reports in order to identify existing and potential causes of nonconforming product. You stated that you mentally evaluated complaints and servicing or repairs of returned devices but that you had not documented any evaluations.

 

W-170

Keywords: process control, change control, training, product identification

  • Primary deviations: no adequate production and process controls, inadequate change control, no performance verification after the change, missing records of communication, training not documented
  • Examples:
    - Failure to establish and maintain adequate production and process controls that include documented instructions, standard operating procedures (SOP), and methods that define and control the manner of production
    - Failure to establish and maintain procedures for changes to a specification, method, process, or procedure, including verification or validation of such changes
    - Failure to promptly remove obsolete documents from all points of use
    - Your firm changed the xxx Cooler-Heater device's internal timer setting in two instances. The reason for the changes, the review and approval for the changes, and the effective date of the changes were not documented
    - Your firm failed to conduct, document, and maintain the results of the verification testing of each change o determine whether or not each change affect operations and performance specifications
    - Your firm failed to maintain records of communication with the specification developer to document who initiated and authorized the changes, the signature of the approving individual(s), the approval date, and an effective date of each approved change
    - Failure to establish and maintain procedures for identifying product during all stages of receipt, production, distribution, and installation to prevent mixup
    - Your firm stated that three individual employees involved in the assembly of the xxx Cooler-Heater devices had been trained but that your firm could not provide any documentation of their training.

 

W-169

Keywords: Buildings, equipment cleaning, maintenance, calibration, laboratory controls, records, signature, failure investigation

  • Primary deviations: Inadequate buildings, no or inadequate maintenance and cleaning of equipment, insufficient intervals for equipment calibration, inadequate laboratory controls, test procedures not followed, incomplete laboratory records, initials or signature of a second review person missing, inadequate failure investigation
  • Examples:
    -Buildings used in manufacture of injectable products are not always maintained in a good state of repair,
    -Equipment and utensils are not always cleaned, maintained and sanitized at appropriate intervals to prevent malfunction or contamination
    - The calibration of instruments was not always conducted at suitable intervals
    - Deviations from written procedures not justified
    - Test procedures were not always followed
    - Laboratory records did not always include a description and identification of the sample received for testing, the date the sample was taken, the date the sample was received for testing and the data derived from testing.
    - Laboratory did not enter the date on which the results are read into the logbook.
    - There were not always the initials or signature of second person showing that the original records have been adequately reviewed by a second person
    - The investigations did not always extend to other batches of the drug or other drug products that may have been associated with specific failure or discrepancy

 

W-168

Keywords: supplier evaluation, process validation, complaints, computer validation, training, quality system

  • Primary deviations: No or inadequate procedures for design control, no documentation that products have been developed in accordance with design control, inadequate review of complaints, no procedures for evaluation of suppliers, contractors, and consultants, no notification of changes by the supplier, effective and complete procedures for implementing corrective and preventative action operations, no validation of the manufacturing processes, no or inadequate validation of computer systems, insufficient controlling the storage of product in order to prevent mix-ups, no or insufficient training, quality system not fully implemented
  • Examples:
    -written procedures for controlling the design of the Hemoglobin Alc Reagent and formulation changes to the Liquid Glucose Hexokinase Reagents were not adequately established during the implementation of these design projects
    - design history files do not demonstrate that these devices were developed in accordance with the design control requirements
    - Your firm failed to ensure complaints involving possible failures are adequately reviewed and evaluated to determine if investigations are necessary
    - Your firm failed to establish procedures for the evaluation of suppliers, contractors, and consultants
    - For example, there is no documentation to demonstrate that your firm has evaluated the importer or is aware of the manufacturer from Asia supplying the reagents used to produce the Hemoglobin Alc Reagent
    - In addition there are no clear agreements from the suppliers to notify you of changes
    - Your firm failed to validate computer software used to control automated production and quality system operations, as required by 21 CFR 820.70(i). For example, your firm has not validated the software used to produce labels and manage your complaints
    - Your firm failed to follow procedures for controlling the storage of product in order to prevent mix-ups, damages, or other adverse effects

 

W-167

Keywords: Part 11, electronic records, integrity, stability testing, documentation, storage conditions, people resources

  • Primary deviations: Electronic raw data not saved, laboratory records incomplete, inadequate documentation of storage conditions of samples, insufficient personnel and equipment in the quality control unit for testing
  • Examples:
    - Laboratory records do not include a complete record of all data in the case of each test, including graphs, charts, and spectra from laboratory instrumentation, properly identified to show the specific product lost tested. (21 CFR 211.194(a)(4)).
    - Review of stability data by our investigation team disclosed that prior to November 2004, your form did not maintain documentation of xxx operating conditions and settings for xxx analysis nor the complete raw data.
    - After November 2004 the operating parameters were maintained with the relevant xxx. However, the electronic raw data was not saved.
    - According to the director of Quality assurance, Ranbaxy began saving xxx electronic raw data just recently at the beginning of February 2006. However, that was not observed during inspection.

    - The SOP allows "discarding" data due to variation in the xxx area or any other reason
    - Your firm failed to establish and follow an adequate written stability testing program design to assess the stability characteristics of drug products.
    - Storage condition for samples retained for stability testing are not adequately documented
    - The Quality Control Unit lacks adequate laboratory resources (personnel equipment) for conducting stability testing of drug products

 

W-166

Keywords: Part 11, electronic records, raw data, method validation, USP methods, SOP, paper notebooks

  • Primary deviations: No FDA-483, Inspectional Observations, issued to the firm. Several items have been discussed verbally with management:
  • Examples:
    - I explained that computerized records that the firm keeps to make it easier to sort or find certain information would not necessarily have to comply with Part 11 regulations. As an example, I explained that if the firm has a database for complaints, but still records everything on paper (and the paper copy is the official record), the database would not have to comply with Part 11. However, if the database was their only record, the database would have to comply with Part 11
    - if not using the methods listed in the USP, firm's methods have to be validated and/or shown to be as good as or better than the USP methods.
    - firm needs to have a system for accountability for raw data. Raw data was recorded onto a loose leaf piece of paper. The firm must have a a system of accountability in place to assure that raw data is being lost. I further explained that the firm could use bound laboratory notebooks or pre-numbered laboratory worksheets to fulfill this requirement.
    - firm needs to either update SOPs so that they reflect what is actually being done at the firm or follow SOPs as written.

 

W-165

Keywords: Part 11, electronic records, integrity, API, calibration
Includes 483 - Establishment Inspection report (EIR) - Company's response letter - FDA's answer

  • Primary deviations: Failing integrity of QC results, no testing of bulk solvents prior to receipt, failure to retain and review alarm history printout and equipment cleaning:
  • Examples:
    - There is no system for assuring the integrity of blank sheets used in the recording of results in the paper documentation system
    -  The computerized system is not secure in that it is possible for data entered to be changed. This was observed following a request during inspection for a challenge to be performed during which it was determined that previously recorded input including sample gross and net weights and the final result could be changed..
    - There is no written procedure regarding the documentation and review of deviations which occur during sterility testing
    - Testing which is performed on incoming lots of solvent to the tank farm is limited to identity testing
    - The xxx used in the manufacturing in-process laboratory and the QC laboratory was not calibrated .

 

W-164

Keywords: Equipment qualification, IQ/OQ/PQ, procedures, cleaning validation, failure investigation, washing facilities, testing, preventive maintenance

  • Primary deviations: Equipment not performing, procedures not followed, inadequate equipment qualification, PQ protocol missing, validation protocol not followed, inadequate cleaning validation procedures, missing failure investigation, master production and control records not signed, inadequate washing facilities, insufficient testing, missing preventive maintenance, forms inadequate to record complete IQ information, IQ/OQ not performed
  • Examples:
    - Failure to ensure that automatic, mechanical, or electrical equipment or other types of equipment will perform a function satisfactorily. For example.....
    - Failure to follow your standard operating procedure
    - For example, , Inspection and Testing of Manufacturing Equipment, which applies to all activities for testing and inspection of equipment at Cody Labs, and the Installation Qualification Manufacturing Equipment form do not fully describe the requirements for equipment qualification, including environmental conditions for equipment operation.
    - There is no requirement for a Performance Qualification protocol
    - The Validation Master Plan does not contain an operational qualification for xxx
    - In addition, the validation protocol should be followed and any deviations or variations from the approved protocol should be investigated
    - Written procedures for cleaning and maintaining equipment used in the manufacture, processing, packing, or holding of a drug product, are inadequate
    - There is a failure to investigate a batch that did not meet specifications
    - Failure to test each batch of API to determine conformance to specifications
    - The forms contained in the SOP are not designed to allow recording of the information that they are required to contain under the SOP. For example, there are no provisions in the form to record or check the specifications against which the Installation Qualification (IQ) is to be performed.
    - There was no Preventative Maintenance (PM) on this equipment
    - In fact, the IQ and OQ were not performed

 

W-163

Keywords: Process control, procedures, environmental monitoring equipment, batch records, log book, documentation, signature

  • Primary deviations: procedures and protocols not followed, location of equipment used for environmental monitoring not documented, drawing prepared from memory, batch records not complete, incomplete log-book information
  • Examples:
    - Written production and process control procedures not always followed and documented at the time of performance-
    - The samples that were taken were documented as 115g, 3.5 g and 115g which are all outside the range allowed in the protocol
    - Relying on the recollection of of an employee eight months after protocol was executed is not good practice
    - Lob-book did not contain complete and/or accurate documentation
    - We expect that all entries in logbooks, batch records, laboratory documentation and all other documentation be signed by the person who performed the operation.
    - Having a supervisor sign does not give the same level of accountability
    - Your response did not contain a global evaluation of other logbooks where entries may be performed similarly
    - Complete, true and accurate records are the foundation for good GMPs. Reliable documentation is a control which raises assurance of the quality of the product manufactured.
    - Practices such as back dating and signing for actions not performed are a serious violation

 

W-162

Keywords: Reference standards, method validation, change control, stability testing, cleaning validation, quality control unit, sampling, process, validation, retrospective validation, analytical equipment calibration, glass wa

  • Primary deviations: No adequate quality control unit, inadequate cleaning methods, collected samples not representative, no written validation plan or written validation protocols plan, inadequate change control for analytical methods, failure to maintain records of method modification, inadequate method validation
  • Examples:
    - Failure to have a quality control unit adequate to perform its functions and responsibilities.
    - Failure to establish and follow validated sampling and testing procedures of in process materials and drug products
    - There is no data available to establish the purity of the reference standards used to assay finished products
    - The calibration of analytical instruments is not being conducted in accordance with your established program
    - All methods do not include system suitability tests to ensure that the system is operating properly
    - Volumetric glassware is not always used to take volume measurements during assays of active ingredients in drug product
    - There is no data available to establish that analytical methods used to assay finished products meet appropriate standards for accuracy and reliability
    - Failure to maintain complete records of any modification of an established method employed in testing, including the reason for the modification and data to verify that the modification produced test results at least as accurate and reliable for that material being tested as the established method

 

W-161

Keywords: Laboratory, calibration, equipment qualification, equipment testing, balance, HPLC, GC, acceptance criteria, outside contractor

  • Primary deviations: Calibration performed by an outside contractor not verified. Insufficient testing for operational qualification, SOP not followed for testing, no procedures for HPLC and GC performance verification, no specific directions and limits for accuracy to assure chromatography performance, incomplete documentation of GC system calibration, acceptance criteria not included in GC system calibration documents
  • Examples:
    - The laboratory does not perform an adequate testing and /or calibration to verify its performance and accuracy.
    - The laboratory does not verify that the calibration performed by an outside contractor is complete and performed as required by the established standard operating procedure "HPLC Maintenance and Operational qualification". This SOP requires four tests for the operational verification: power up, diagnostics, accuracy, reproducibility and linearity tests. The reproducibility and linearity tests have not been performed.
    - - The xxx class mass used for balance calibration did not comply with the USP 0.1% requirement for mass measurement uncertainty
    - The balance used to weigh more than 20 mg did not comply with the USP 0.1% requirement for balance measurement uncertainty
    - The firm does not have a written procedure that includes requirements for the performance verification of HPLC and GC systems. They do not have specific directions
    - During the inspection, the firm did not provide an SOP for the performance verification of the HPLC and GC systems. Actually, they are contracting services for the verification of those systems, and then they are adopting contractor's SOP. Each of them has different SOPs, which includes different types of tests that does not compare. The firm should establish a procedure to assure uniformity providing specific directions and requirements for all GC Systems. Also, it will apply to HPLC systems.
    - Documentation of the GC system calibration performed by an outside contractor is incomplete. It does not include the following information: xxx

 

W-160

Keywords: OOS, CAPA, IQ, OQ, PQ, equipment, calibration, maintenance, design verification, design review, document approval

  • Primary deviations: No procedures for CAPA established and maintained, root cause for non-conforming product not identified, effectiveness of CAPA not verified, IQ and OQ not documented, settings for PQ not documented. Lack of adequate procedures for equipment calibration, checking and maintenance. No documented design verification. Approval of documents not documented.
  • Examples:
    - Your firm failed to establish and maintain procedures for implementing corrective and preventive action. In particular, you do not have a procedure to identify the action(s) needed to correct and prevent recurrence of non-conforming product and other quality problems as required by xxx
    - Your firm failed to analyze processes, quality records, service records, and other sources of quality data to identify existing and potential causes of non-conforming product
    - Your firm's corrective and preventive action (CAPA) procedure does not include a requirement that each CAPA be verified or validated to ensure that such action is effective and does not adversely affect the finished device
    - Where the results of a process cannot be fully verified by subsequent inspection and test, the process must be validated with a high degree of assurance and approved according to established procedures
    - Lacks documentation of installation and operation qualification of equipment,
    - Failed to document settings used for the Performance Qualification
    - Your firm failed to establish and maintain procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained
    - In particular, your firm did not establish and maintain procedures for calibrating temperature and speed controls on xxx

 

W-159

Keywords: GLP, electronic raw data, audit trail, automated data entry, study report, study protocol, system identification

  • Primary deviations: insufficient documentation of changes, insufficient information in the study report, study protocol not followed, no identification of automated systems
  • Examples:
    - Failure of testing facility management to assure that test articles or mixtures were appropriately tested for identity, strength, stability, and uniformity, as applicable (21 CFR 58.31(d))
    - Failure to include a description of all circumstances that may have affected the quality or integrity of the data in final study reports
    - Specifically in your summary and conclusion section of the final report you did not communicate that you have lacked critical data, or that you had reservation about drawing study conclusions
    - The final reports prepared by your study director for studies xxx did not include characteristics of the test article such as strength, purity, and composition.
    - Failure to indicate the reason for change in automated data entries. In several instances, entries in the xxx collection/notes and audit trails failed to provide the reason for changing the raw data. For example, audit trail entries for study xxx demonstrate that observation of "normal' were removed without explanation.
    - Failure to have approved written protocols written for each study
    - Not all nonclinical laboratory studies were conducted in accordance with the protocol
    - In various instances, the protocols for studies xxx did not identify the automated systems that were used for data collection.

 

W-158

Keywords: Quality control unit, OOS, failure investigations, annual reports, NDA-field alert report, laboratory test results, computer system audits, training, retesting, manufacturing investigations

483, 12 items

  • Primary deviations: no review of computer audit trail, no failure investigations, incomplete annual reports, NDA-Field Alert report not submitted, incomplete laboratory records, missing computer system audit, lack of training on SOPs and GMP, missing conclusions and follow up from failure investigations, procedures not followed, inadequate manufacturing investigations
  • Examples:
    - The quality control unit lacks authority fully investigate errors that have occurred
    - The quality unit failed to review electronic data as part of batch release
    - The quality unit failed to review computer audit trails
    - Resampling after OOS results without failure investigations
    - An NDA-Field alert Report was not submitted within three working days of receipt of information concerning a failure of distributed batches
    - OOS results were substituted with passing results by analysts and supervisors. The substitution of data was performed by cutting and pasting of chromatograms, substituting vials, changing sample weights and changing processing methods
    - Laboratory records do not include complete data from all tests, examinations and assay necessary to assure compliance with established specifications and standards, e.g., OOS data, chromatograms, sample weighs
    - Audits were not conducted of the data acquisition system used to run the HPLC instruments during analysis of drugs
    - There was no documentation of the number of retests to be performed as required by the SOP
    - Manufacturing investigations into rejected batches of drugs did not include an evaluation of the validated manufacturing process

 

W-157

Keywords: Change control, design, risk analysis,, testing, incoming product testing, device master records, internal audits, CAPA

  • Primary deviations: inadequate change control procedure, no documentation of risk analysis, inadequate testing and documentation, failure to maintain device master records, no procedures for quality audits.
  • Examples:
    - Failure to establish and maintain procedures for the identification, documentation, validation or verification, review and approval of design changes before their implementation
    - Your firm failed to provide documentation explaining whether your firm or the specification developer has conducted and documented any risk analysis of the design change or the rationale for not conducting a design risk analysis. There is no documentation documenting all possible risks that can adversely affect the patient and the controls that can be implemented to reduce the probability and severity of risks
    -The "Pass/Fail" portion of the power unit testing was filled out before the power unit testing was actually conducted
    - The test results were not documented in sufficient details to demonstrate how the power unit passed its finished product testing. The test results were simply recorded as either "Pass" or "Fail". For example, your firm failed to explain and document quantitative test results and specific acceptance criteria for the power unit's test parameters, such as the electrode temperature, safety alarm functions, current and voltage output, elapsed timer, and stimulation counter.
    - Recommendation: Due to the serious and repeat nature of the inspectional observations cited by the FDA and Texas DSHS, we suggest your firm use a qualified quality system consultant to help identify any gaps in your firm's quality system in order to establish and implement complete and comprehensive quality system procedures that will (a) correct the inspectional observations issued at the conclusion of the inspections on November 2002 and 2005, and the items identified in this warning letter, and (b) prevent a recurrence of CGMP violations 

 

W-156

Keywords: Water systems, diagrams, process validation, cleaning validation, batch record review, training, instrument calibration, reserve samples, testing, product specification, distribution records, analytical method, USP standard, failure investigation, labeling, SOPs

  • Primary deviations: missing diagrams, no installation qualification, no operation qualification, no batch record review, inadequate GMP training, inadequate equipment calibration, inadequate storage of reserve samples, SOPs not approved, inadequate procedures for sampling and testing
  • Examples:
    -There was no diagram of the water system
    - Batch records not reviewed by QC,
    - Routine calibration not performed according to a written program
    - Conductivity meters not calibrated to an NIST traceable device
    - Batch records lack a description of name of the equipment
    - No reference in analytical method to recognized standard method.
    - Current SOPs not reviewed and approved by QCU

 

W-155

Keywords: Electronic records, electronic signatures, Part 11, Equipment calibration, equipment qualification, certificate of analysis, review of records

  • Primary deviations: missing Certificate of Analysis, inadequate equipment calibration, failure to review production and control records by QA, no recalibration after equipment move.
  • Examples:
    - Electronic records are used but the do not meet employee accountability responsibility and signature manifestion requirements to ensure that they are trustworthy, reliable and generally ewquivalent to paper records-
    -Failure to establish laboratory controls which include the calibration of instruments, apparatus, gauges and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision and remedial action in the event the accuracy and/or precision limits are not met [21 CFR 211.160(b)(4)].
    - Specifically, your firm does not have a Certificate of Analysis (COA) for ...
    - The procedure is unclear and is inconsistent with the manufacturer's recommendation which advises to calibrate the [redacted] Oxygen Analyzer each time the analyzer is moved.
    - Failure to routinely calibrate, inspect, or check automatic, mechanical, or electronic equipment according to a written program designed to assure proper performance [21 CFR 211.68(a)]. Specifically, your firm has not performed any equipment qualification on the "mobile" cryogenic pumping system.

 

W-154

Keywords: Equipment calibration, equipment qualification, certificate of analysis, review of records

  • Primary deviations: missing Certificate of Analysis, inadequate equipment calibration, failure to review production and control records by QA, no recalibration after equipment move.
  • Examples:
    - Failure to establish laboratory controls which include the calibration of instruments, apparatus, gauges and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision and remedial action in the event the accuracy and/or precision limits are not met [21 CFR 211.160(b)(4)].
    - Specifically, your firm does not have a Certificate of Analysis (COA) for ...
    - The procedure is unclear and is inconsistent with the manufacturer's recommendation which advises to calibrate the [redacted] Oxygen Analyzer each time the analyzer is moved.
    - Failure to routinely calibrate, inspect, or check automatic, mechanical, or electronic equipment according to a written program designed to assure proper performance [21 CFR 211.68(a)]. Specifically, your firm has not performed any equipment qualification on the "mobile" cryogenic pumping system.

 

W-153

Keywords: capa, process validation, change control, quality systems

  • Primary deviations: inadequate corrective and preventive actions, inadequate process validation, inadequate change control procedure
  • Examples:
    -Failure to establish and maintain an adequate corrective and preventive action procedure which ensures identification of actions needed to correct and prevent the recurrence of nonconforming product and other quality problems, as required by 21 CFR 820.100(a)(3).
    - Failure to validate changes to your manufacturing process with a high degree of assurance to ensure that specified requirements are met as required by 21 CFR 820.75(c).
    - Validation did not include verification assurance that the changes did not affect the device
    -Failure to identify the acceptance status of product throughout manufacturing, packaging, labeling, and servicing of the product to ensure that only product which has passed the required acceptance activities is distributed or used.

 

W-152

Keywords: root cause, capa, compliant handling, management responsibility

  • Primary deviations: no root cause analysis, insufficient complaint handling
  • Examples:
    - You are responsible for investigating and determining the causes of the violations identified by the FDA. You also must promptly initiate permanent corrective and preventive action of your quality system. Failure to promptly correct these deviations may result in regulatory action being initiated by the FDA without further notice. These actions include, but are not limited to, seizure, injunction, and/or civil penalties. Additionally, no premarket submissions for Class III devices to which QSR deficiencies are reasonably related will be cleared until the violations have been corrected. Also, no requests for Certificates to Foreign Governments will be approved until the violations related to the subject devices have been corrected.
    - You have failed to establish complaint handling procedures sufficient to ensure that all complaints are documented and processed in a uniform and timely manner, as required by 21 CFR 820.198(a).
    - Management with executive responsibility has failed to ensure that an adequate and effective quality system has been fully implemented and maintained at all levels, as required by 21 CFR 820.20
    - You have also failed to establish a policy of overall intentions and direction of your firm with respect to quality

 

W-151

Keywords: stability testing, failure investigation, batch reprocessing, missing records

  • Primary deviations: No adequate stability test program, missing failure investigation, missing procedure for the reprocessing of batches, missing records regarding unexplained discrepancies
  • Examples:
    - You have failed to establish an adequate stability testing program to determine appropriate expiration dates for all your drug products (21 CFR 211.166(a) and (b)
    - You have failed to investigate failures of a batch or any of its components to meet their specifications (21 CFR 211.192).
    - You do not maintain any written records regarding unexplained discrepancies and batch failures as required by 21 CFR 211.192
    - Batches are routinely reprocessed when initial release specifications fail.
    - None of the stability failures, described above, were the subject of an investigation as required by 21 CFR 211.192
    - You have not established written procedures for the reprocessing of batches to ensure that they will conform to all established specifications (21 CFR 211.115).

 

W-150

Keywords: CAPA, complaints, audits, document control, quality system, training

  • Primary deviations: No or inadequate CAPA system, inadequate complaint handling procedures, no quality audits, inadequate organizational structure, inadequate document control, failure to review effectiveness of quality system by management with executive responsibility, insufficient personnel with necessary education.
  • Examples:
    Significant deviations include, but are not limited to, the following
    - Analyzing processes, work operations, complaints, returned product and other sources of quality data to identify existing and potential causes of nonconforming product
    - Investigating the cause of nonconformities relating to product, processes, and the quality system
    - Identifying the actions needed to correct and prevent recurrence of nonconforming product and other quality problems
    - Verifying or validating the CAPA to ensure that such action is effective and does not adversely affect the finished device

 

W-149

Keywords: API, testing, impurity testing, supplier testing, certificate of analysis, solvent recovery, labeling system

  • Primary deviations: Insufficient testing of individual batches, supplier testing not verified, no procedures for solvent recovery, inadequate proof of incoming labels.
  • Examples:
    - The laboratory did not have an adequate impurity profile that identifies organic, inorganic and solvent impurities to monitor unidentified and apparent impurities in the API
    - The microbiological laboratory fails to document the lot number and expiry date of xx
    - The reliability of the supplier's certificate of analysis (COA) was not established in that a complete analysis was not performed with the COA at the appropriate intervals.
    - Procedures for solvent recovery have not been established to ensure that solvents are controlled and monitored
    - Incoming labels received from the vendor are not proofed against the master label

 

W-148

Keywords: API, testing, raw data, failure investigations, equipment design, English language, equipment maintenance

  • Primary deviations: Insufficient testing of individual batches, insufficient recording of raw data, inadequate failure investigation, inadequate equipment design, inadequate equipment maintenance
  • Examples:
    - The individual batches are not tested for residual solvents
    - Laboratory records do not include all raw data. For example, weights determined during the preparation of standard solutions were not recorded
    - Critical production deviations may not have been investigated and documented.
    - Production equipment was not designed to minimize contamination
    - Equipment was not maintained in an adequate state of repair.
    - If you whish to to continue to ship APIs to the United states, you should evaluate all equipment and written procedures and your employees adherence to written procedures, for compliance with this standards.
    - Failure to promptly correct these deficiencies may result in the refusal to permit entry of these APIs or finished products made from these APIs into the United States.
    - Please submit documentation, with English translation, of these corrections.

 

W-147

Keywords: Audits, CAPA, risk assessment, complaint handling, validation, test equipment, training

  • Primary deviations: no audits of records, inadequate validation of workstation test equipment, inadequate compliant handling, inadequate procedures for CAPA, inadequate risk assessment.
  • Examples:
    - There is no indication that your firm conducted periodic checks or audits of the records during this time to assure the validity of the data.
    - Failure to establish and maintain procedures for implementing corrective and preventive actions (CAPA ) to include requirements for analyzing processes, work operations, concessions, quality audit reports, quality records, service records, complaints, returned product, and other sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems, as required by 21 CFR 820.100(a)(1)
    - For example, your firm performed risk assessments for product failures without documenting how the severity or likelihood of occurrence used in the assessment was determined, in violation of your own procedures.
    - For example, the validation of the workstation test equipment used as part of the final device testing system; did not include a process capability challenge, did not ensure that the test equipment used was capable of functioning as necessary to capture results at both the high and low ends of the test specifications, and did not include challenges with known failures to ensure the equipment detected fault conditions.s.

 

W-146

Keywords: audits, CAPA, risk assessment, complaint handling, validation, test equipment, training

  • Primary deviations: no procedures for validating the device design, no formal risk analysis for software changes, no procedures for finished device acceptance, inadequate installation, inadequate inspection, no procedures for supplier assessment.
  • Examples:
    - Failure to establish and maintain adequate procedures for validating the device design to ensure that the device conforms to user needs and intended uses and include risk analysis, as required by 21 CFR 820.30(g) (FDA 483, Item 151.
    - For example, a formal risk analysis of the original system design and software changes to correct software bugs that caused incorrect functionality or performance problems, and to enhance the product, has not been documented. Although your software release notes briefly describe the nature of unresolved software bugs in a particular software version, they do not explain the impact of these software bugs on user needs and intended uses. For example, in the workflow release notes, dated 6/24/04, software version 2.Otr17 described that "the scores for the left eye and right eye was reversed, and the macular edema value used previously was confusing."
    - Status of design changes was not documented to explain why certain design changes were not implemented to correct Software bugs
    - The "Workflow Release Notes by xxx has no status information or discussion of the test releases of software versions v2.xx36 through v2.xx40
    - Failure to establish and maintain procedures for finished device acceptance to ensure that each production run, lot, or batch of finished devices is not released for distribution until all the requirements are completed as required by 21 CFR 820.80(d) [FDA 483 item 3]. For example, your firm has not documented the signature(s) of approval needed to release xxx for distribution
    - Failure to establish and maintain procedures for adequate installation and inspection, as required by 21 CFR 820.170(a) and document the installation activities and inspection results, as required by 21 CFR 820.170(b) [FDA 483 Item 5]. For example, your firm's device installation procedure was in the draft form at the time of our inspection, and your firm has not maintained records of installation activities and inspection results of the retinal image acquisition subsystem of the 3DT system at the clinical sites.
    - Failure to establish and maintain procedures to ensure that all purchased or otherwise received product and services conform to specified requirements, as required by 21 CFR 820.50 [FDA 483, Items 10, 11, 12, and 13). For example, your firm has not (a) evaluated the suppliers for their ability to meet your firm's requirements; (b) defined the quality requirements that each supplier must meet; (c) defined the frequency of supplier evaluations; and (d) documented supplier evaluations.

 

W-145

Keywords: Part 11, electronic records, electronic medical record (EMR) system, computer validation, audit trail, accurate and complete copies, invalid and altered records

  • Primary deviations: missing documentation for validation and other part 11 requirements
  • Examples:
    Our review of the inspection results also noted that you use an electronic medical record (EMR) system to maintain medical and other clinical data for your patients, including study subjects . You told Mr. xxx that data obtained during study visits are entered directly into the EMR, and no paper records are used. A follow-up letter from you to Mr. xxx, dated January 31, 2005, detailed the name of the EMR system and the means by which study subject information is entered
    Please note that Title 21, Code of Federal Regulations, Part 11, "Electronic Records; Electronic Signatures" outlines specific requirements that must be met for any system that is being used to maintain required records . In addition to the information requested above, please submit the following:
    - documentation of the validation of your EMR system to ensure accuracy, reliability, and the ability to detect invalid or altered records;
    - documentation of the ability to generate accurate and complete copies of records suitable for inspection, review, and copying by the agency;
    - documentation of a secure, computer-generated, time-stamped audit trail that can independently record the date and time of operator entries and actions that create, modify, or delete electronic records, and to verify that record changes do not obscure previously recorded
    information.

 

W-144

Keywords: complaints, suppliers, contractors, software validation, change control

  • Primary deviations: no or inadequate software validation, no quality requirements for suppliers, contractors and consultants, no supplier audits, inadequate change control
  • Examples:
    - Failure to perform software validation, as required by xxx. Specifically, the xxx controller unit, software version xxx was changed to xxx. The change in the software allowed for adjustment in the speed of the water pump, and inverse pulsing from the A valve to the B valve when the speculum was clogged. Your firm did not have any documentation showing that the current software version was validated.
    - Failure to establish and maintain the requirements, including quality requirements, that must be met by suppliers, contractors, and consultants, as required by xxx. Specifically, your firm did not have any documentation showing audits of the contract manufacturer responsible for manufacturing the disposable xxx which is used with the xxx. Your firm also did not define the type and extent of control to be exercised over the product, suppliers, and contractors.
    - Failure of management with executive responsibility to ensure that an adequate and effective quality system has been fully implemented and maintained at all levels of the organization, as required by 21 CFR 820.20(a). Specifically, management with executive responsibility has failed to ensure that an adequate and effective quality system has been established. There was no management oversight for employees responsible for manufacturing, finished device release, distribution, and for maintaining quality system records.

 

W-143

Keywords: System suitability testing, process validation, part 11, method validation, OOS, laboratory controls, impurities, QA procedures, training, vendor qualification, refractive index detector, electronic records, stability testing

  • Primary deviations: no or inadequate failure investigation, inadequate process validation, inadequate method validation, inadequate instruction for testing, insufficient justification for impurity specifications, QA procedures not followed, insufficient training on cGMP and operations, failure to establish controls and procedures to establish authenticity, integrity and security of all electronic records, failure to qualify suppliers, IQ/OQ or equipment not performed or data not reviewed, no records for refractive index detector qualification, incomplete laboratory records, inadequate stability
  • Examples:
    - Drug products failing to meet established specifications are not rejected
    - The xxx solution used in the xxx assay test did not meet USP suitability test specification during the analysis of Sample lot...
    - Control procedures are not established which validate the performance of those manufacturing process that may be responsible for causing variability in the characteristics of in-process material and the drug product.
    - Initial OOS results for accuracy and intermediate precision were retested with no laboratory investigation conducted; a revised analytical method was developed, the samples retested, and only the passing results reported.
    - The analytical method report was not signed off as approved until it had been used to test released batches
    - Appropriate controls are not exercised over computers or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel.
    - The firm has failed to establish controls and procedures to assure authenticity, integrity and security of all electronic records including data generated in the QC laboratory.
    - All laboratory analysts and supervisors have system administration privileges in the firm's HPLC and GC acquisition systems which allow them overwrite original raw data files.
    - Refractive Index Detector used for component testing , sugars, there is no record that the equipment has been qualified.

 

W-142

Keywords: SOPs, complaints, annual product reviews, failure investigations, laboratory controls

  • Primary deviations: missing SOP to handle drug quality complaints, missing labels, not following written procedures, inadequate corrective actions regarding failure investigations, failure to follow laboratory procedures
  • Examples:
    - Your QCU also failed to extend the investigation into other similar lots
    - Laboratory failed to properly label sample preparations in your laboratory refrigerator and workbench areas
    - Failure to follow written procedures for Annual Product Reviews
    - Failure to follow established Standard Operating Procedures regarding the handling of written and oral drug product quality complaints
    - Failure to follow established laboratory control procedures

 

W-141

Keywords: bioequivalence study, contamination, procedures, policy, failure investigation

  • Primary deviations: equivalency of analytical method not demonstrated, inadequate approach to investigating sources of contamination, lack of procedures and policies
  • Examples:
    - You failed to demonstrate that the analytical method used in this in vivo bioavailability study was accurate to measure the accurate concentration of loratadine and its metabolite
    - Your approach to investigating sources of contamination in bioequivalence studies is inadequate and has resulted in the submission of invalid data to the agency. You should have conducted a systematic and thorough evaluation to identify and correct the source of contamination when it was first observed.
    - The manner in which (company name) investigated the contamination problem in this study causes FDA to have concerns with the validity of other bioequivalence data generated by (company name).

 

W-140

Keywords: number of people, stability testing, laboratory records, data integrity, equipment maintenance

  • Primary deviations: no adequate number of trained people, laboratory records missing, inadequate change of raw data, no adequate equipment maintenance
  • Examples:
    -Written control procedures not always followed when changes were made to test methods and validated system
    - No positive control has been used while conducting the USP test since December 2002
    -The inappropriate change to test method was made without Quality Control unit review. as a result, batches of product were released for export to the US based on invalid USP test results
    - Written procedures for investigating deviations were not followed on at least six occasions in 2004, when recording charts showed malfunctions
    - no adequate number of trained people to carry out the responsibilities of your quality assurance department, ... only one person conducted the dual functions of quality control and quality assurance.
    - Maintenance performed on the xxx in September and October 2003 was not correctly recorded

 

W-139

Keywords: quality control unit, training, stability testing, water purification, batch production and control records, batch record review

  • Primary deviations: QC unit did not follow written responsibilities, employees not trained on CGMP, no microbial analyses/or preserve analysis on finished drug products, water qualification, no batch record review
  • Examples:
    - SOPS have not been approved by the quality control unit, and the review of any complaints involving the possible failure of a drug product to meet any of its specifications has not been performed per SOP.
    - According to the Executive Director of the firm, the employees have never received any type of CGMP training
    - Your firm failed to conduct microbial analysis and/or preservative assays on finished drug products as a criteria for release.
    - The firm does not have a sampling and test procedures designed to assure that the water from the purification system conforms to appropriate standards
    - Failure to have all drug product production and control records reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed.

 

W-138

Keywords: computer validation, data integrity, acceptance levels, method validation, process validation, revalidation, OOS

  • Primary deviations: No acceptance and/or rejection levels for theoretical and actual batch yields, no test method validation, lab computer software not validated, no process revalidation, no OOS investigation
  • W-137Examples:
    -The process validation for the product Syncro-Mate-B Implants is inadequate in that your firm’s 1994 retrospective validation report evaluated batches that were manufactured and tested at a different manufacturing facility. Your firm failed to perform any new process validation or revalidate the manufacturing process, at your current site. Additionally, your firm failed to validate the testing methods used to analyze the batches in your retrospective validation report and the equipment used to manufacture and test the validation batches was never qualified.
    - The firm’s computer software programs which operate all of the lab during the analysis of raw materials and xxx finished product, have not been qualified and/or validated. The software programs do not secure files from accidental alteration or losses of data. The functions that modify and delete partial or whole data files are available for use by all analysts. In addition, the firm has not established any security procedures for the laboratory computer systems. There are no procedures for backing-up data files and no levels of security access established.

 

W-137

Keywords: stability testing, certificate of analysis, quality assurance unit, product testing

  • Primary deviations: No written testing program designed to assess the stability characteristics of drug products. No or inadequate stability test program. Lots not withhold from use before released by QAU. Missing Certificate of Analysis.
  • Examples:
    -Failure to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile. For example, there are no written procedures designed to prevent the products, labeled as sterile, from microbiological contamination.
    -Failure to have, for each batch of drug product purporting to be sterile, appropriate laboratory testing to determine conformance to such requirements.
    - Failure to withhold from use each lot of components, dru
  • - No written testing program designed to assess the stability characteristics of drug products.

 

W-136

Keywords: software validation, revalidation, stability testing, test, failure investigation, cleaning validation

  • Primary deviations: No or inadequate documentation of for revalidation of computer software, no or inadequate failure investigation to determine the route cause of the failure, failure to assure that test procedures are scientifically sound, failure to reject drug products to meet established standards or specification, no or inadequate scientifically sound specifications, standards, sampling plans, inadequate stability test program, no or inadequate cleaning validation.
  • Examples:
    -Your response indicates that the computer software was initially validated in April 2001 and that it was going to be revalidated in May 2004. You also included the validation report of the software used for maintenance of the complaint. However, the adequacy of the challenges to the computer systems cannot be fully assessed since the validation protocols were not provided.
    - The original test results that the analyst invalidated should have been documented and reported to the laboratory supervisor. Only the data from the repeated analysis was recorded in the laboratory notebook.
    - You indicated that an investigation was made to explain why the area of the unknown peak was included in the calculation with the fructose peak and that the product was sent to a contract laboratory for analysis of total sugars. However, this laboratory has not been qualified and the test methods have not been validated for Guardian’s product; therefore, any results generated by the contract laboratory are suspect.

 

W-135

Keywords: Test results, records integrity, results of internal audit, training, people qualification,, storage of reference samples, microbiological test

  • Primary deviations: No adequate qualification of QA and QC personnel, missing test data, missing computer files, integrity of test records, and inadequate storage of reference samples, inadequate microbiological testing.
  • Examples:
    - Qualifications of those working in the Quality Assurance (QA) and Quality Control (QC) units have not been demonstrated to be adequate
    - No one on the organizational chart, including supervisors in QA and QC, are identified as having academic or other suitable training in chemistry or microbiology
    - A supervisor and QC manager could not explain how the calculation was done for the xxx assay determination
    - In your recent correspondence you offered to provide our office a copy of the internal audit that resulted from this inspection. We would like to see your audit findings.
    - The microbiological test records all appear to be recently written in spite of the fact that some date back as far as two years
    - Compendial and secondary reference standards were not properly stored D

 

W-134

Keywords: Quality system, organizational structure, quality policy, review of quality system, document control, corrective and preventive actions (CAPA), complaint handling

  • Primary deviations: No adequate quality system, quality policy not established, inadequate organizational structure, inadequate control of documents, inadequate procedures for receiving, reviewing, and evaluating of complaints
  • Examples:
    -Failure to adequately establish and maintain a quality system that is appropriate for
    -Management has not ensured that quality system requirements have been effectively established and maintained
    - Failure of management with executive responsibility to establish its policy and objectives for, and commitment to, quality as required by
    - Failure to adequately establish and maintain an adequate organizational structure
    - Failure for management with executive responsibility to review the suitability and effectiveness of the quality system at defined intervals
    - Failure to establish and maintain procedures to control all documents

 

W-133

Keywords: Process validation, HPLC upgrade, system suitability testing frequency, solvent recycling, water purity, reserve samples

  • Primary deviations: System suitability testing not frequent enough. Strip chart recorded based HPLC system needs to be upgraded.
  • Examples:
    -The SOP requirement for the assay analysis of xxx was not followed in that the HPLC system suitability test was only performed weekly per firm SOP, instead of the actual time of testing
    - "Recovered xxx solvent used for the production bulk API xxx is not tested with a specific assay for purity".
    - The firm needed to upgrade several pieces of their equipment. Principally, the old HPLC being used still was using the equivalent of a strip chart recorder. This made accurate determination of the related compounds, etc, very difficult unless additional standard and sample injections were made with the scale set a pre-determined setting. The system didn't have the capability of reprocessing data, etc.

 

W-132

Keywords: Process validation, raw data, system suitability , impurities, documentation, laboratory instrument calibrations, cleaning validation, laboratory procedures, equipment  qualifications, validation of computer data integrity

  • Primary deviations: No raw data for assay and impurity tests for validation data, no impurity testing for (API) stability studies, inadequate (API) process validation, no equipment qualifications, failure to validate computer data integrity
  • Examples:
    - There was no logbook or raw data documentation of standards used, standard preparation, sample preparation used for assay and impurity testing
    - There are no impurity tests performed for the (API) stability studies as required by their acceptance criteria in SOP xxx
    - Laboratory instrument calibrations are inadequate by the following:
    - There is no documentation that analytical data reported for xxx samples is verified by a second person.
    - Purity tests were performed to determine xxx with only one sample and no quantification with a certified standard
    - No System Suitability performance before running testing
    - Firm lacks to validate computer data integrity acquisition for the use of the xxx. Also stress of the computer has not been tested proven that the system can run in parallel at the same time.
    - Testing does not follow USP requirements

 

W-132

Keywords: GLP, SOP, protocols, retaining samples, handling deviations from SO

  • Primary deviations: No raw data for assay and impurity tests for validation data, no impurity testing for (API) stability studies, inadequate (API) process validation, no equipment qualifications, failure to validate computer data integrity
  • Examples:
    - There was no logbook or raw data documentation of standards used, standard preparation, sample preparation used for assay and impurity testing
    - There are no impurity tests performed for the (API) stability studies as required by their acceptance criteria in SOP xxx
    - Laboratory instrument calibrations are inadequate by the following:
    - There is no documentation that analytical data reported for xxx samples is verified by a second person.
    - Purity tests were performed to determine xxx with only one sample and no quantification with a certified standard
    - No System Suitability performance before running testing
    - Firm lacks to validate computer data integrity acquisition for the use of the xxx. Also stress of the computer has not been tested proven that the system can run in parallel at the same time.
    - Testing does not follow USP requirements

 

W-131

Keywords: GLP, SOP, protocols, retaining samples, handling deviations from SOP

  • Primary deviations: No SOPs or SOPs not adequate, protocol not followed
  • Examples:
    - The testing facility management failed to establish standard operating procedures (SOPS) adequate to ensure the quality and integrity of the data generated during the course of a study, to limit unauthorized and undocumented procedural deviations, and to establish controls to ensure accountability of SOPS. Examples of this failure include but are not limited to .....
    - If exceptions from laboratory’s SOPS apply for the study, then those exceptions should be described in the protocol
    - Failure to conduct studies per approved protocol
    Examples of this failure include but are not limited to the following:
    - Failure to retain reserve samples from each batch of test and control articles from studies longer than four weeks
    - Failure to prepare the reporting of nonclinical laboratory study results
    - Failure to have protocols that clearly contain information to conduct the nonclinical laboratory studies

 

W-130

Keywords: Out of specification results, SOPs, root cause analysis, complaint procedures, change control, computers, software validation

  • Primary deviations: Invalidation of results without documented causes or adequate rational, procedures not followed, inadequate SOPs, no management review of laboratory test data, no or inadequate failure investigations, inadequate complaint handling procedures, custom-made calculations of automated systems not verified with manual calculations.
  • Examples: Original OOS results obtained during the residual solvent analysis of xxxx were invalidated without documented assignable causes or adequate scientific rationale. Lots were originally rejected, but later were re-sampled, retested, and released for distribution based on the retest passing results.
    - Retesting was performed with additional new samples from the lot rather than with the original sample, as required by the procedure
    - Several 00s test results were attributed to analyst or instrument error without documented evidence of the error.
    - A revised SOP submitted in response to this observation is still not adequate because the procedure does not require a production level investigation to rule out manufacturing error in those instances where laboratory error is inconclusive.
    - Your firm failed to evaluate the need for revalidation of the QC Lab Data Acquisition System (which performs instrumentation control, data acquisition, data processing and report generation for all the a activities performed at the xxxx QC laboratory after the addition of xxx new acquisition servers, xxx new chromatographic systems and changes in the acquisition server configuration.
    - You continued to utilize this revised QC Lab data acquisition system without ensuring that the system would perform as intended
    - In addition, prior to the Data Acquisition System Formula Validation, protocol xxx your firm relied on the not yet validated system for automated calculations, obtained by using custom-made formula fields, in making release decisions without manual verification.

 

W-129

Keywords: Equipment calibration, quality systems, quality audits, software validation, complaint procedures, CAPA, service records

  • Primary deviations: calibration not done according to specified intervals, software transfer process not validated, no procedures for quality audits, quality system not in compliance with established quality system requirements
  • Examples:
    -Specifically, the software transfer process using your firm’s xxxx has not been validated to assure that it is capable of reproducing and completely copying the master software program onto a blank xxxx.
    - Failure to establish procedures for quality audits and to conduct such audits so as to assure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system as required by xxxx
    - Specifically, on 01/14/2004, it was noted that xxxx, displayed a calibration sticker which revealed the last calibration date of 07/02/99 although the unit should have been calibrated on a yearly basis. Further, the xxx was used in the repair department to perform voltage and safety tests and no further action was taken to evaluate whether there was any adverse effect on the (product) quality.
    - Failure to establish and maintain instructions and procedures for performing and verifying that servicing meets the specified requirements as required by xxxx. Specifically, no written procedures were established directing the maintenance of service records.

 

W-128

Keywords: Quality systems, training, quality audits, software validation, complaint procedures, testing, sampling plans

  • Primary deviations: missing records of acceptable suppliers, no quality audits, training needs not identified, missing software validation, test results not documented, established sampling plans were not followed.
  • Examples:
    - No quality audits have been conducted since the establishment of your quality system procedures in July 2000.
    - Procedures for identifying training needs have not been followed [21 CFR 820.25(b)].
    - Specifically, employee training needs were not addressed and training was not documented.
    - Software validation activities for computers or automated data processing systems used as part of production have not been performed or documented. Specifically, the Eng xxxx software used for engineering and servicing of the xxxx System has not been validated.
    - Records of acceptable suppliers were not maintained

 

W-127

Keywords: Training, training records, documentation of disposal, SOPs, reporting deviations to FDA

  •  Primary deviations: Insufficient training, insufficient training records, SOPs not followed, insufficient documentation, no reporting of deviations to the FDA

  • Examples:
    -Your plasma processing employees were observed performing plasma collection duties, such as disconnecting phlebotomies, for which they are not trained or prior to completing their training;
    - You did not retain employee competency test documentation as required by your standard operating procedures (SOPS).
    - Your employees did not document the disposal of unit 076162
    - Your employees did not follow your SOP’s pertaining to review of records
    - Your firm reported 11 Biological Product Deviation reports to the U.S. Food and Drug Administration 

 

W-126

Keywords: Training, procedures, failure investigation

  • Primary deviations: not standardizing refractometer, inadequate recording of data, no investigation of unacceptable quality control test, no use of checklists for training records 

  • Examples:
    - Numerous deficiencies were documented related to your firm’s failure follow written standard operating procedures (SOPS):
    - Your firm failed to standardize the refractometer on each day of use was not documented or reported, as required by your firm’s "Variance Report" procedure
    - Your firm failed to maintain records concurrently with the performance of each significant step in the collection, processing, compatibility testing, storage, and distribution of xxxx
    - Your firm failed conduct and document an investigation of unacceptable quality control (QC) tests on units
    - Several deficiencies were documented in your firm’s training program including associated written procedures and employee training records
    - Our investigator noted the training record checklists for two production laboratory employees did not use the defined checklists. One employee’s record had three checklists, which differed from the procedure’s checklist, while the other employee’s record had two lists that differed. Your firm’s Training Program, dated June 15, 1998, specifically defines the training record checklists to be used for training of production laboratory employees.
    - There is no evidence an annual written test has been given to all laboratory personnel as required by the "Training Program" procedure for the production laboratory
    - There is no evidence that all laboratory personnel have been observed annually for performance competency as required by the "Training Program" procedure for the production laboratory and the "Training Program" procedure for the compliance department dated October 5, 1998

 

W-125

Keywords: Excel, software validation, quality systems, organizational structure, management review, CAPA, document control, change control, part 11

  • Primary deviations: inadequate software validation, inadequate change control, Excel spreadsheets not validated for intended use, no or inadequate procedures for corrective and preventive actions, inadequate process validation, inadequate management controls

  • Examples:
    - Failure to establish and maintain an adequate organizational structure, review the suitability and effectiveness of the quality system by management, and establish quality system procedures and instructions
    - Procedures for management review are not complete and implemented nor have an such reviews been conducted.
    - Failure to validate computer software for its intended use according to an established protocol. For example; the Microsoft 2000 Excel spreadsheet software program was not validated for formulation of reagents and was seen to give incorrect data
    - Microsoft 2000 Excel spreadsheet software used manufacturing has not been validated for the purpose of generating a worksheet for formulation of reagents. No documentation was found to establish or verify corrections made to the program.

 

W-124

Keywords: method validation, change control, laboratory records, stability testing

  • Primary deviations: incomplete laboratory records, no adequate documentation of method validation, methods used outside established USP method without checking equivalent accuracy and reliability, no specifications for cleaning validation, no stability testing, no protocols of HPLC testing
  • Examples:
    - Failure to include in laboratory records complete records of any modification of an established method employed in testing
    - There is no documentation that identifies the reason for the modifications and no data to verify that the modifications produce results that are at least as accurate and reliable as the established USP method
    - The cleaning validation documents did not include a sampling, test method for analyzing samples, and specification limits.
    - The firm failed to maintain any background data to verify that testing of laboratory HPLC’s identified as [redacted] and [redacted] had been performed or produced acceptable results. Also, ....

 

W-123

Keywords: OOS, chromatographic reprocessing, content uniformity, blend uniformity, HPLC, impurity testing, laboratory records

  • Primary deviations: OOS invalidation without thorough investigation: chromatographic and content uniformity testing, no or inadequate specifications, incomplete laboratory records, missing calculations in laboratory records
  • Examples:
    - Out-of-specification (OOS) results were invalidated, without a thorough investigation, supporting data, documentation, or justification. For example....
    - Confirmed OOS results for xxx assay used in xxx were invalidated by Quality Assurance, that concluded that the chromatographs were incorrectly integrated. The Chromatographs were reprocessed with adjusted baseline parameters, yielding acceptable results, and the lots were released for distribution. However, the laboratory investigation concluded that the results could not be invalidated and that no problems were observed during the chromatographic run.
    - Not all analytical test methods detect known impurities for all raw materials. For example...
    - Laboratory records do not include complete data derived from all tests including a record of all calculations performed in connection with the test [21 CFR 211.194(a)(5)]. For example,....

 

W-122

Keywords: management responsibilities, quality system, quality policy, quality objectives, CAPA for quality systems, quality audits

  • Primary deviations: Failure to establish, maintain and control a quality system, no corrective and preventive actions to address quality problems
  • Examples:
    - Management with executive responsibility has not ensured that quality system requirements are effectively established and maintained
    - Management with executive responsibility has not established a quality policy and objectives
    - No quality plan defining the quality practices, resources, and activities
    - No quality system procedures and instructions have been established and implemented

 

W-121

Keywords: procedures, training, responsibilities, quality control unit, product testing, cleaning validation, stability procedures, handling of complaints, handling of samples

  • Primary deviations: no finished product testing, responsibilities of QC unit not specified, missing written procedures, failure to determine acceptance or rejection of active ingredients and other incoming components
  • Examples:
    - Failure to establish and validate written procedures that describe the manufacturing processes for all drug products
    - Failure to establish procedures that describe the responsibilities of the quality control unit on the acceptance or rejection of procedures, specifications, or any other criteria that may impact the identity, strength, purity, and quality of finished drug products
    - Failure to perform finished product testing for the identity and strength of active ingredients and their conformance to established specifications for any of your drug products
    - Failure to conduct training in current good manufacturing practices for employees involved in the manufacturing...

 

W-120

Keywords: food, dairy creamers, records, filling and packaging, review of production param

  • Primary deviations: insufficient records of critical filling and packaging parameters, no or insufficient temperature recording, no review of production and processing parameters, products were released by your firm prior to completing record review
  • Examples:
    - During our inspection of your plant, our investigators observed that your firm’s [redacted] aseptic filling and packaging system operators fail to record critical filling and packaging parameters (lint speed, hot air manifold temperature, laboratory verification of the hydrogen peroxide concentration, cup/lid stock hydrogen peroxide flow rate, aseptic zone overpressure, and other critical factors identified in the scheduled process for the w aseptic filling and packaging system in the Supplemental Information
    - Your firm failed to always make, and record on a written operator’s form, observations of the temperature-indicating device in holding tube outlet; temperature recorder in holding tube outlet; temperature recorder controller in final heater outlet

 

W-119

Keywords: aseptic media fill, lyophylization, video taping, batch records, smoke studies, IQ/OQ, change control, diagrams, evaluation, revalidation, cross contamination, accurate copy, reuse of discs, storage of discs, sterilization validation protocol

25 pages

  • Primary deviations: batch records do not document the names or initials of the aseptic filling operator, failed to comply with written procedures, no procedures for video taping process, no established procedure to describe common practice, batch records verified for accuracy one day before calculations were made, inadequate smoke studies, no comprehensive review of changes to assure that ... does not require re-qualification or revalidation, no procedure to prevent cross-contamination, no record to document that the protocol was reviewed and approved, no formal evaluation that printed measurements are an accurate reflection of the data on the ...disc, when the capacity of the disc is filled, original electronic data are not retained, inappropriate storage of discs, no review of inventory records by second person
  • Examples:
    -
    The Quality Unit has failed to put in place procedures to coordinate and control updates to structural diagrams when modifications are made
    - The Air Handling System was initially qualified in xxx. Since then, there have been multiple additions or modifications. Modifications include addition of a computer monitoring system.
    - While the individual changes have been reviewed during the change control process, a comprehensive review of all the collective changes has not been performed in order to assure that the initial IQ/OQ remains to be valid and to assure tat the Air Handling Unit does not require requalification or revalidation.
    -  During lyophylization simulation process, temperature thermocouples are placed inside of the media fill vials
    - Preceding observation points out that the firm has failed to comply with written procedure in that there is "no data or appropriate literature references" concerning the justification for the incubation.
    - There is no written procedure for the video taping process which was explained to be a common practice of the media fill operations.
    - There were filling operators with head covers worn in a manner such that the side of their face or neck could be observed during some of the aseptic filling activities.

 

W-118

Keywords: Clinical trials, toxicity data, IND, study protocol, dosing rational

  • Primary deviations: missing animal toxicity data, missing study protocol, no summary of previous human studies. no dosing rational, no adequate description of clinical procedures, failed to notify and obtain IRB approval, failed to protect the safety and welfare of subjects under your care
  • Examples:
    - You failed to submit an IND for the conduct of a clinical investigation with an investigational new drug as required by 21 CFR 312.20(a)
    - You also failed to submit supporting data and a study protocol with required elements specified in 21 CFR 312.23 including chemistry, manufacturing, and control information for the drug substance.
    - You did not provide adequate animal toxicity data

 

W-117

Keywords: CAPA, procedures, specifications, methods

  • Primary deviations: No or inadequate CAPA procedures, CAPA open for too long time, no verification of CAPA procedures, no procedures for changing specifications, methods and and processes
  • Examples:
    - Failure to establish CAPA procedures that assure all relevant information on identified quality problems, as well as corrective and preventive actions, are submitted for management review, as required by ....
    - For example, procedures do not assure that all sources of quality data are identified, reviewed, tracked or trended.
    - Failure to establish and maintain procedures for corrective and preventive actions (CAPA) to include requirements to assure corrective actions are implemented and changes in methods and procedures to correct and prevent identified quality problems are recorded, as required by ...

 

W-116

Keywords: failure investigation, root cause, corrective action, preventive action, test methods

  • Primary deviations: no investigation to find the rot cause of the problem. no corrective action, no preventive action, inadequate test methods, inadequate procedures to prevent microbiological contamination of sterile drugs

  • Examples:
    - In the last two years there were 11 product sterility failures involving the organism .. Investigations into these routine results found no assignable cause or the sterility failures.
    - There were no corrective actions identified in these investigations and the batches were released on the basis of the ..test.
    - The production department conducted no investigations, although the production system could not be ruled out as the potential cause of the product contamination.
    - The response stated that no probable cause was identified in four investigations, i.e., no conclusive evidence that the failure was due to either laboratory or production error, therefore corrective action could not be documented.
    - The firm failed to implement any corrective actions to insure that the laboratory errors would not occur in the future.D

 

W-115

Keywords: equipment calibration, failure investigation, SOPs, biological products, deviation report

  • Primary deviations: no equipment calibration, no follow-up on unexplained discrepancy, no maintenance of SOPs for testing, biological product deviation report not submitted
  • Examples:
    - Failure to observe, standardize, and calibrate equipment on a regularly scheduled basis to assure that it will perform in the manner for which it as designed
    - Failure to perform a thorough investigation and make record of the conclusions and follow-up of unexplained discrepancy
    - Failure to maintain written standard operating procedures (SOPS) including all steps to be followed in the compatibility testing of ....
    - Failure to submit a biological product deviation report

 

W-114

Keywords: quality system, quality policy, documentation

  • Primary deviations: no documentation, no quality policy, no quality plan, no procedures for acceptance of incoming products
  • Examples:
    - Failure of management with executive responsibility to ensure that an adequate and effective quality system has been fully implemented and maintained at all levels of the organization
    - Your firm has not established (a) a quality policy, a quality plan ....
    - Failure to establish and maintain procedures for acceptance of incoming product
    - You verbally stated to our investigator that you had received some complaints of device defects, retrieved the defective devices, returned them to the contract manufacturer for repair, and then returned the repaired devices to the customers. There was no documentation of these activities

 

W-113

Keywords: design control, design verification, risk analysis

  • Primary deviations: no procedures for design control, no design and development plan describing the design and development activities, no verification of design input requirements, no adequate risk analysis to identify and document possible hazards, device design not correctly transferred to production
  • Examples:
    - Failure to conduct a thorough risk analysis to identify and document any possible hazards associated with the design of the devices in both normal and fault conditions
    - Failure to establish and implement procedures to control the design process of devices to ensure that specified design requirements are met.
    - Failure to establish and implement a design and development plan describing the design and development activities, defining responsibility for implementation of these activities, and providing the identity and description of the interfaces with other groups or activities as appropriate
    - Failure to establish and implement procedures to ensure that a device’s design input requirements are appropriate and address its intended use, including user/patient needs.
    - Failure to establish and implement procedures for defining and documenting design output in terms that allow an adequate evaluation of conformance to design input requirements

 

W-112

Keywords: production record reviews, instrument calibration, laboratory records, in process test

  • Primary deviations: insufficient production records, no production record reviews, inadequate instrument calibration in the routine, insufficient laboratory records, no procedures for in-process testing
  • Examples:
    - Manufacturing equipment used in the production are not labeled or identified in the batch record.
    - The dates and times of finished product testing are not recorded on the batch record.
    - Instruments utilized in the manufacturing and testing of finished product are not calibrated on a routine basis
    - Failure of laboratory records to include complete data derived from all tests, including...
    - Failure of laboratory controls to include written procedures for in-process testing of drug products;

 

W-111

Keywords: content uniformity, process validation, OOS, re-testing, dissolution testing

  • Primary deviations: inadequate laboratory controls, continue testing after OOS results, no colection of content uniformity samples
  • Examples:
    -No content uniformity samples are collected after the product is mixed and prior to being transferred to the holding tanks
    - The manufacturing process validation for Questran Powder does not address the capability of the process to produce a homogeneous drug product in that the mixing time of the powder product is not established
    - Failure to have adequate laboratory controls in that once stability samples are found out of specifications and confirmed by re-test, you continue testing additional samples until passing results are obtained to conclude that the lot is within specification
    - The OOS results were observed during stages one and two of solution test but not in the re-test results when a new and sealed bottle was used

 

W-110

Keywords: API, impurities, scientifically sound procedures, unknown peaks, process control, HPLC gradient accuracy, detector linearity, equipment cleaning, cleaning validation, cross contamination

  • Primary deviations: insufficient detection of impurities, inadequate analytical methods validation, missing raw data, Lack of scientifically sound test procedures, Failure to identify unknown peaks during the Organic Volatile Impurities, Lack of adequate training for laboratory analysts and manufacturing employees
  • Examples:
    -Failure to have an analytical method capable of detecting the presence of impurities found in Metformin HCI batch;
    - Your analytical method used for determination of impurities fails to detect all five (5) of the impurities listed in the product’s specifications. Therefore, there is no assurance that...
    - Failure to have adequate process controls. Examples are as follows...
    - Inadequate laboratory procedures and records to assure that the APIs have the appropriate quality and purity
    - Failure to identify impurities greater than 0.1 %
    - Failure to have a complete calibration program for the HPLCs in that the gradient accuracy and detector linearity is not being verified

 

W-109

Keywords: security, computer validation, QA procedures, cleaning of equipment, HVAC, Sterilize

  • Primary deviations: QA unit not following procedures, automated equipment not validated, no restricted access to authorized personnel, no procedures for cleaning and maintenance of equipment
  • Examples:
    -Failure of the Quality Assurance Unit to follow written procedures, which require oversight and review responsibilities
    - Failure to assure that automated equipment will perform a function satisfactorily during the manufacturing process for your drug products [21 CFR 211.68]. For example
    - Process control computer not validated
    - Equipment not validated (HVAC, Sterilizer, Water Purification System)
    - Failure to restrict access by unauthorized personnel from entering areas designated as limited access areas

 

W-108

Keywords: quality system, management, corrective action, preventive action 

  • Primary deviations: no management procedures, no corrective and preventive action, no quality system procedures
  • Examples:
    - Failure to establish procedures for management with executive responsibility to review the suitability and effectiveness of the quality system
    - Failure to establish and maintain procedures for implementing corrective and preventative action, as required by...
    - Failure to establish and maintain quality system procedures

 

W-107

Keywords: validation of spreadsheets, data integrity, intermediate and long term storage of e-records, deletion of e-records, cleaning validation, method validation, process validation, OOS, failure investigation, training

To download click on: W-107   W-106   W-105  W-063

Now with full Inspection Reports (EIRs), more to come.

This shows a complete sequence starting with a 483 (W-105) and followed by a full inspection report of the initial inspection (W-106), a Warning Letter (W-063) and the EIR of the follow-up inspection (W107). The follow-up inspection report describes very much in detail how deviations have been corrected according to FDA requirements.

EIR's They describe very much in detail how the inspection went, what the inspectors were looking at, what they were asking and what the firm's response was. EIR's will be reviewed, e.g., by the regional headquarter office and will be used as input to issue a warning letter or not. Most useful is to have the 483, the EIR, and the warning letter from the same inspection. When thoroughly read this information is ideal to prepare firms for inspections. Most useful are the type of questions and whether the firm's answer was successful, so they not only help to avoid FDA warnings but also avoid to overreact.

 

 

W-104

Keywords: aseptic parenteral manufacturing operations, part 11, audit trail, global correction action plan, environment validation

  • Primary deviations: missing e-audit trail, no action plan for part 11, no validation of environment for aseptic filling machines
  • Examples:
    - In addition, we further request details regarding steps your firm is taking to bring your electronic cGMP records into conformance with the requirements of21 CFR Part 11; Electronic Records; Electronic Signatures. Part 11 establishes requirements to ensure that electronic records and electronic signatures are trustworthy, reliable and generally equivalent substitutes for paper records and traditional handwritten signatures. Electronic records and electronic signatures may be used to meet record and signature requirements of21 CFR Parts 210 and 211 when Part 11 requirements are met.
    - In addition to a response to the deficiencies noted earlier in this letter, please outline your firm’s global corrective action plan, including timeframes for correction, to address this Part 11 issue.
    - This inspection disclosed deficient controls in the laboratory electronic record keeping system, which is used for maintaining chromatography and audit trails.
    - Failure to collect a sufficient number of samples to evaluate for particulate matter based on a validated statistical plan.
    - Failure to validate the environment in which the xxx aseptic filling machines are located.
    - Failure to provide sufficient detail describing the methods used to clean the firm’s mix tanks.

 

W-103

Keywords: Employee training and qualification, computer systems, installation records, validation

  • Primary deviations: incomplete or no training of employees on computer systems, incomplete installation records of computer systems, incomplete validation of computer systems
  • Examples:
    - Employee training on the use of the new [redacted] computer system, which is used in donor screening and product processing, was not-complete.
    - The center director had not received any training on this computers system even though he retains a high security level for data entered on this computer system
    - The validation and installation records for the [redacted] computer system were incomplete. Installation of this system was performed on 11/1 7/2000, however the validation study was not formally approved until 4/1 9/2001. The testing was noted in the following areas: ...

 

W-102

Keywords: API, OOS, documentation, process validation, method validation, critical process parameters, change control

  • Primary deviations: OOS not documented, manufacturing process not validated, analytical method not stability indicating, no change control procedures for analytical methods, critical process parameters not identified
  • Examples:
    - There are no documented investigations of process deviations or out of specifications (OOS) laboratory results.
    - During the inspection, our investigation requested to see investigations of process deviations and out of specification laboratory results. She was informed that these investigations are conducted but not documented
    - The protocol did not identify critical process steps, critical process parameters, in-process tests or specifications

 

W-101

Keywords: Networks, WAN, LAN, validation change control, diagrams, IT personnel training, revision control, change control

  • Primary deviations: failure to validate and document initial set up and upgrades of networked systems , failure to train IS personnel on GMP
  • Examples:
    - The program is not controlled via revision number
    - Complete software structural design descriptions have not been maintained or updated from original design specifications
    - Complete diagrams and text descriptions identifying all other network program interfaces with XXX, and which specify the data being exchanged between the XXX and other programs have not been maintained or updated from original design specifications
    - Wide Area Network diagrams (WAN) with appropriate definition documentation identifying corporate sites on the network that use XXX have not been included in any XXX validation documents.
    - These diagrams are not dated, have no document controls number, and have no indication of review or approval.
    - The firm has failed to incorporate a revision control system for the firm's custom configurations of release 9.8
    - There are no records to document that the Information Technology (IT) service provider staff personnel have received training that include current good manufacturing practice regulations and written procedures referred by the regulations.

 

W-100

Keywords: equipment qualification, boundary testing, CAPA, personnel, training, statistical analysis

  • Primary deviations: inadequate follow up of non-conformance, equipment not tested for all parameters, no boundary testing, potential cause for non-compliance not evaluated, insufficient personnel with adequate training, statistical analysis
  • Examples:
    - There are no records to demonstrate that all the operating parameters (e.g. maximum, minimum and nominal parameters) were verified and that all the sample were collected and tested in accordance to the validation protocol
    - Your firm failed to analyze, identify and document existing and potential causes of non-conforming product and other quality problems, as required by ....
    - There is no procedure for the statistical and non-statistical analysis of the product and quality problems.
    - Your firm fails to have sufficient personnel with the necessary training to assure that all activities required by ... are correctly performed,

 

W-099

Keywords: Networked systems, environmental monitoring, record maintenance, structural and functional design, code review, dead code, code annotations, Part 11

  • Primary deviations: inadequate retrospective validation of networked computer systems, inadequate software version control, code review not complete, no structural and functional design, inadequate environmental monitoring, inadequate record maintenance, code lacked annotations, code included 'dead' and unused code
  • Examples:
    - inadequate retrospective validation of networked computer systems used for overall quality assurance/quality control operations and for the control and release of raw material, in process material and finished products. For example....
    - there was no structural and functional design included in the validations for the program
    - only a small fraction of each program underwent a detailed review
    - there was inadequate software version control

 

W-098

Keywords: process validation, OOS, microbial testing, API, method validation, stability testing, maintenance of records

  • Primary deviations: no manufacturing process validation, failure to establish and maintain written records of investigations into unexplained discrepancies, failure to establish release criteria for API, failure to validate the performance and reliability of test methods, failure to maintain records of calibration checks and inspections of automatic equipment
  • Examples:
    - For example, there is no manufacturing process validation in place for drug products and the associated equipment utilized in drug manufacturing.
    - A total of ...microbial tests were conducted for this product, yet there was no documented investigation into these discrepancies nor was there any conclusion or follow-up.
    - Failure to maintain records of calibration checks and inspections of automatic, mechanical, or electronic equipment

 

W-097

Keywords: API, stability testing, raw data, HPLC, detector linearity, temperature accuracy of column heater, integrator linearity

  • Primary deviations: results of stability testing not traceable to the batches produced at the manufacturing site, missing raw data, no testing of detector linearity, no testing of accuracy of temperature settings for column heater and detector, inadequate calibration procedure for GC's and GC headspace unit, calibration raw data and results obtained for performance qualification of analytical instruments not checked for accuracy and completeness by a second analyst or supervisor
  • Examples:
    - Stability samples for ... that were tested to provide stability data for the DMF amendment 97-001 were not traceable to the batches produced at the manufacturing site.
    - No distinction is made between active pharmaceutical ingredients and finished pharmaceuticals, and failure of either to comply with CGMP constitutes a failure to comply with the requirements of the Act.
    - During the inspection of your facility, you were unable to present records of raw data pertaining to the subject stability batches submitted
    - The calibration procedure for HPLC systems is inadequate in that it did not include integrator and detector’s linearity, injector’s reproducibility, and accuracy of temperature settings for column heater and detector.
    - Until FDA has re-inspected this facility and confirms compliance with CGMPS and correction of these deficiencies, this office will recommend withholding approval of any new drug applications listing this facility as the manufacturer of active pharmaceutical ingredients (APIs). Failure to promptly correct these deficiencies will result in the refusal to permit entry of these products into the United States.

 

W-096

Keywords: API, cleaning validation, microbiological specifications, HPLC, method validation, stability testing, import alert

  • Primary deviations: API manufacturing not in compliance with CGMP, cleaning procedures not validated, failure to establish microbilogical specifications, HPLC analytical methods not adequately validated, failure to test stability samples at required time intervals
  • Examples:
    - This letter concerns FDA inspections of your active pharmaceutical ingredient manufacturing facilities located in .... During both inspections, our investigators documented significant deviations from current Good Manufacturing Practices (cGMPs) in the manufacture of active pharmaceutical ingredients (API’s).
    - Cleaning procedures for non-dedicated reaction vessels, holding vessels, re-crystallizers, centrifuges, and dryers used to produce APIs and intermediates have not been validated.

 

W-095

Keywords: sterile manufacturing, aseptic process, sanitizing equipment, microbial contamination, import alert

  • Primary deviations: length of time critical equipment is issued without re-sterilization, qualification of procedures for sanitizing equipment surfaces not adequate, frequency of monitoring procedures too long
  • Examples:
    - The aseptic powder fill process simulation (media fills) did not adequately address several critical issues such as the lengths of campaign and the length of time critical equipment is issued without re-sterilization
    - qualification of procedures for sanitizing equipment surfaces not adequate to ensure an aseptic processing environment
    - If you whish to continue to ship your products to the United States, it is the responsibility of your firm to assure compliance with U.S. standards for CGMPs.
    - This office will recommend withholding approval of any new applications listing your firm as the manufacturer of sterile products.

 

W-094

Keywords: qualification of vendors, contract laboratories, returned goods, storage of finished products, change control

  • Primary deviations: no SOP for the qualification of vendors and contract laboratories, no documented qualification of vendors, no audit of contract laboratories, returned goods not identified as such, no change control SOP for documentation and manufacturing processes
  • Examples:
    - The firm has no SOP for the qualification of vendors and contract laboratories, nor has such documented qualification been conducted.
    - The firm has been using the service of .... for the testing of Purified Water, however there has been no audit conducted at this contract laboratory

 

W-093

Keywords: GCP, meeting minutes, research review

  • Primary deviations: no initial and continuing review of research, no reporting of changes in research activities, no reporting to the FDA of any unanticipated problems, no maintenance of meeting minutes
  • Examples:
    - failed prompt reporting to the IRB, appropriate institutional officials, and the FDA of any unanticipated problems involving risks to human subjects or others, any issues of serious or continuing noncompliance with these regulations or the requirements or determinations of the IRB, and any....
    - The IRB failed to review proposed research at convened meetings at which a majority of members are present including one member whose primary concerns are in the non-scientific area

 

W-092

Keywords: management responsibilities, management reviews, CAPA, validation

  • Primary deviations: inadequate management responsibility, no procedures for management reviews, no procedures for corrective and preventive actions
  • Examples:
    - Failure to appoint, and document such appointment of a member of management who irrespective of other responsibilities shall have established authority over and responsibility for ensuring that quality system requirements are effectively maintained and to report on the performance of the quality system to management with executive responsibility
    - Failure to establish and implement procedures for conducting management reviews;
    - Failure to establish procedures for implementing corrective and preventive action addressing the analysis of sources of quality data to identify existing and potential causes of nonconforming product or other quality problems
    - Failure to ensure that all inspection, measuring and test equipment is suitable for its intended purposes and is capable of producing valid results

 

W-091

Keywords: API, raw data, maintenance of data, training

  • Primary deviations: API's not manufactured in compliance with cGMP, no raw data, no SOP for maintenance of data, training does not include GMP,
  • Examples:
    - This letter concerns an inspection of your facility located at...During the inspection our investigators documented significant deviations from current Good Manufacturing Practices (cGMPs) in the manufacture of Active Pharmaceutical Ingredients (APIs).
    - Your formalized training program is inadequate in that it does not address current good manufacturing practices.

 

W-090

Keywords: raw data, API, method validation, impact of deficiencies on other procedures, local language SOPs, microbiological contamination, microbiological testing

  • Primary deviations: raw data not recorded, impurity standards were not properly identified, one internal standard was four months old with no data on it's stability over that period, in-process testing inadequately performed, impact of deficiency on other procedures not evaluated, inadequate validation of analytical methods, only Chinese versions of validation protocol and final validation reports available
  • Examples:
    - laboratory procedures are inadequate in that raw data was not always recorded
    - The response does not document that all other laboratory procedures have been reviewed for similar deficiencies, that the new SOPs are now followed
    - Laboratory tests for assay, impurities and … were not performed according to established procedures described in the individual Drug Master Files (DMF) which specify the USP methods
    - Until .... the facility is in compliance with CGMP, this office will continue to recommend disapproval of any applications listing your firm as a supplier of API's.. WE also recommended that your firm's API's be placed on import alert and denied entry into the United States.

 

W-089

Keywords: Bioanalytical test lab, calibration standards, acceptance criteria, analytical balance, freezer, refrigerator, pipettes, micro-pipettor

  • Primary deviations: SOP permits to delete calibration standards, precision data did not include the standards and QC's which failed to meet acceptance criteria, acceptance criterion not specific enough, inadequate purity data on 'certificate of analysis' , analytical balances are used outside specified range, inadequate expiration date, reproducibility of a chromatographic system checked only at the beginning of the chromatographic run, temperatures of freezer and refrigerators not monitored, 'out-of-spec' pipettes used for analytical purposes, no SOP for the calibration of multiprobe micro pipettor.
  • Examples:
    - The SOP #F-001 entitled "Analytical Run Acceptance Criteria" is not objective in that it permits calibration standards to be deleted so that quality control (QC) values will fall within the acceptable limits. Examples include....
    - Reference standards used by the firm for analysis are inadequate and used as 100% pure, although certificates of analysis, in certain instances, do not contain adequate data on the purity or potency of the standard.
    - Calibration records show many instances where examination of the pipettes found them out-of-specification. There is no way to determine when the (pipettes) units in question have been in use for analytical purposes while out of specifications.

 

W-088

Keywords: GLP, master schedule, QAU

  • Primary deviations: no review of GLP documentation by QAU , copy of master schedule not maintained
  • Examples:
    - you failed to maintain a copy of a master schedule of all non clinical laboratory studies
    - you failed to assure QAU oversight during the preparation of histology slides for all GLP studies

 

W-087

Keywords: OOS, spreadsheets, time stamps, recirculation of HPLC solvents, audit trail, e-records, paper copies as raw data, Part 11

  • Primary deviations: no testing of re-circulated HPLC solvents, no audit trail, inadequate password protection, deleting electronic records
  • Examples:
    - Three retests by two different analysts were conducted, however only data obtained by the third analyst was reported and the lot was subsequently released.
    - There is no assurance that re-circulated HPLC solvents have the purity, potency and strength as reported.
    - There is no audit trail to track the number of templates accessed to generate data calculations.
    - Password protection can be bypassed in the system.
    - Data files are automatically deleted after a hardcopy is generated.
    - There is no requirement to identify the analyst or time/date stamping of spreadsheet hardcopies.
    - Alternate methods were used in the re-qualification of working standards without demonstrating equivalence to current USP methods, for example...

 

W-086

Keywords: active ingredients, stability testing, equipment cleaning, records, calibration data

  • Primary deviations: incomplete testing, inadequate stability testing, no records of calibration data, no regular instrument cleaning
  • Examples:
    - Failure to perform laboratory testing on each batch of drug product prior to release, to determine satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient [21 CFR 211.165 (a)]. Specifically, you did not .....
    - Failure to implement a written testing program designed to assess the stability characteristics of drug products, using reliable meaningful and specific test methods [21 CFR 2 11.166 (a)(3)]. Specifically...
    - Failure to include in laboratory records complete records of the periodic calibration of laboratory instruments there are no calibration, records available for the FTIR Spectroscope and the HPLC laboratory instruments, both of which are used in production and testing of human drugs.
    - Failure to clean and maintain equipment and utensils at appropriate intervals

 

W-085

Keywords: Validation, revalidation, boundary testing, worst case testing, raw data, laboratory records

  • Primary deviations: most complex process not validated, batches distributed before validation run completed, reason for OOS not thoroughly investigated, laboratory records do not include raw data
  • Examples:
    - Laboratory records do not always include raw data for all the laboratory testing performed
    - Drug product samples are not adequate or representative of the entire batch, in that...
    - Revalidation protocols do not cover the largest batch size or the most complex manufacturing process;

 

W-084

Keywords: Software validation, spreadsheets, CAPA, OOS, training, internal audits, design reviews

  • Primary deviations: inadequate software validation, inadequate procedures for the review of design changes before their implementation, inadequate procedures for quality audits
  • Examples:
    - failure to maintain adequate procedures for implementing corrective and preventive actions (CAPA) such as analyzing data to identify existing and potential causes of nonconforming product or other quality problems
    - software validation plan does not address the user requirements of inputting data into the [redacted] spreadsheet used as a tool for trending.
    - Failure to maintain adequate procedures to control environmental conditions

 

W-083

Keywords: GLP, toxicology, bioresearch monitoring, study director, testing, study report

  • Primary deviations: inappropriate testing of test articles, incomplete test records, incomplete study report, replacement of the study director not in time
  • Examples:
    - You failed to assure that the test articles and dosing formulations for studies #224 and #323 were appropriately tested for identity, strength, and stability. (21 CFR 58.31(d))
    - Different methods were used for initial and periodic testing, and records were incomplete and/or unavailable for method validation, chromatograms mass spectra, and sources and amounts of reference materials used for calibration.
    - You failed to assure that protocol deviations and QAU inspection reports for study #323 were evaluated by a replacement study director.

 

W-082

Keywords: Validation of automated systems, inspection and test equipment, contingency plan, complaint investigation, out of specification

  • Primary deviations: failure to validate automated systems
  • Examples:
    Failure to validate all automated systems used in conjunction with manufacturing or quality systems.
    Failure to assure that all inspection and testing equipment is suitable for its intended purposes and is capable of producing valid results. The inspection revealed that the automated simulator test has not been updated to keep current with hardware and software changes made to the C2000 device.

 

W-081

Keywords: Quality Assurance Unit, Method validation, Laboratory records, analytical equipment qualification, spreadsheets, data review, overlapping chromatographic peaks, Part 11

  • Primary deviations: no or insufficient procedures, training documentation, incomplete worksheets, missing design and control Part 11
  • Example:
    - In addition to the above listed violations, our Investigator noted that the laboratory is using an electronic record system for processing and storage of data from the atomic absorption and HPLC instruments that is not set up to control the security and data integrity in that the system is not password controlled, there is no systematic back-up provision, and there is no audit trail of the system capabilities. The system does not appear to be designed and controlled in compliance with the requirements of 21 CFR, Part 11, Electronic Records.
    - Failure to document training of the laboratory person involved in drug testing as to specific methodology, instruments used and current Good Manufacturing Practices relevant to...

 

W-080

Keywords: Quality Unit failed, process validation, revalidation, software validation, security validation. validation protocols, validation acceptance criteria, IQ and OQ of equipment, method validation, operating ranges not evaluated, cleaning validation, HVAC systems not qualified, preventive maintenance, laboratory data, computer validation, validation after data migration, change control, test review and approval, inappropriate master validation plan, Part 11

To download click on: W-075, W-076, W-077, W-078, W-079, W-080

FDA Sets Clear Sign to Continue Enforcement

After multiple GMP problems since 1998 Schering-Plough signed a consent decree with FDA May 16 and agreed to pay over $500 million in fines. This was the largest ever assessed on an FDA regulated company. The decree affects about more than 100 different prescription and over-the-counter drugs as part of the decree, the company has agreed to suspend manufacturing 73 other products (Ref: Validation Times, May 21, 2002). Schering received at least five warning letters and 483's. You can download five warning letters (D2 to D6)and an 18 page 483 inspectional report (D1). The 483 is quite comprehensive and can almost be used as a checklist in preparation for FDA inspections.

 

 

W-074

Keywords: Process validation, revalidation, external auditor

  • Primary deviations: quality system, no or insufficient process validation, no revalidation after changes
  • Example:
    Your firm failed to demonstrate adequate documentation that justifies the decision for not revalidating the ...process after making these changes;
    In order to facilitate FDA in making the determination that such corrections have been made and thereby enabling FDA to withdraw its advisory to other federal agencies concerning the award of government contracts, and to resume marketing clearance for class III devices for which a 5 1 O(k) premarket notification or Premarket Approval application (PMA) has been submitted, and Certificates to Foreign Governments for products manufactured at your Billerica and Burlington, MA facilities, we are requesting that you submit to this office on the schedule below, certification by an outside expert consultant that he/she has conducted an audit of your establishment’s manufacturing and quality assurance systems relative to the requirement of the device Quality System regulations (21 CFR Part 820).

 

W-073

Keywords: Validation, Spreadsheet, Excel, MS Access, Excel, Word, Part 11

  • Primary deviations: no validation of Excel, Access, Word
  • Example:
    Failure to validate computer software used as part of the quality system for its intended use according to an established protocol as required by 21 CFR 820.70(i). For example: Software such as Excel, Access, and Word used to create and maintain data bases (rejects, complaints, and concessions) and electronic documents, is not validated.
    In their response dated April 3, 2000, your firm stated that by May 31st, they will have identified what software is used for data processing, and identified a method or methods for validation and/or verification of the software. This response is not adequate since ...

 

W-072

Keywords: Validation, Spreadsheet, MS Access, Excel, effect on other program, Part 11

  • Primary deviations: insufficient validation of Access, no validation of impact on other software
  • Example:
    You failed to investigate the failure of the ... when operating in MS Access. The system locks up at random and it is unknown whether the software which controls the .... during off of MS Excel, could be similarly affected.

 

W-071

Keywords: Spreadsheet, validation, change control, validation of corrective action, Part 11

  • Primary deviations: no validation of spreadsheet, no validation of corrective action, no documentation of changes
  • Examples:
    - Failure to validate computer software used as part of the quality system for its intended use according to an established protocol as required by 21 CFR 820.70(i). For example, the data in the Excel spreadsheet identified as a "Hit List" of top non-conforming components contains 16 record counts for part number 8601618 DC converter failures compared to 18 record counts for part number 860168 DC converter failures in the dbase database. The spreadsheet is used for management review of component suppliers for all components.
    - Failure to verify or validate corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device, as required by 21 CFR 820.100(a)(4). For example, ....
    - Failure to maintain records of changes to documents as required by 21 CFR 820.40(b). For example, ..

 

W-070

Keywords: Spreadsheet, validation, Part 11

  • Primary deviations: no validation of spreadsheets
  • Example:
    Your response indicated that Braun is currently changing the complaint handling system from tracking complaint information on an ... spreadsheet to using an off-the-shelf database system, ... Tracker. As required by 21 CFR 820.70(i), Automated Processes, this off-the-shelf software shall be validated for its intended use if Braun has not already done so.

 

W-069

Keywords: Excel, documentation, protection of electronic records, back-up, Part 11

  • Primary deviations: no documentation of Excel application software, no protection of electronic records
  • Example:
    There is no documentation covering Excel application software, or any procedures instituted covering the protection of electronic records or an established back-up system

 

W-068

Keywords: validation, accurate and complete copies, limited access, Part 11

  • Primary deviations: inadequate validation, inaccurate and incomplete copies, no limited access to the system,
  • Examples:
    - review of your electronic complaint files reveals they have not been properly validated, there is no ability to generate accurate and complete copies of records in human readable and electronic form, there is no protection of records to enable their accurate and ready retrieval, access to your system has not been limited, as well as other significant deficiencies.
    - We strongly encourage you to perform a thorough and complete evaluation of all your electronic records in accordance with 21 CFR Part 11 as well as any guidance generated by FDA to assure conformance to our requirements. Do not limit your evaluation solely to the examples cited above. Only electronic records and electronic signatures that meet 21 CFR Part 11 may be used to satisfy the requirements of 21 CFR 820.198, Complaint Files.

 

W-067

Keywords: networks, testing, critical test, Part 11

  • Primary deviations: design not suitable for intended use, insufficient performance testing
  • The network ... module design limitations, which can only support up to four chromatographic acquisition systems, had up to five chromatographic systems connected. There was no validation showing this configuration to be acceptable
  • Examples:
    - The network ... module design limitations, which can only support up to four chromatographic acquisition systems, had up to five chromatographic systems connected. There was no validation showing this configuration to be acceptable
    - System testing was not conducted to ensure that each system as configured could handle high sample rates.
    - Validation of the system did not include critical system tests such as volume, stress, performance, boundary, and compatibility

 

W-066

Keywords: internal quality audits, quality policy, management reviews, compiler, structural validation, Part 11

  • Primary deviations: inadequate quality unit, inadequate number of qualified people, missing batch production and control records, incomplete laboratory records, inadequate stability program
  • Examples:
    - Failure to have, and/or to follow, laboratory controls which include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality and purity, as required by 21 CFR 211.160
    - Failure to maintain laboratory records that include complete data from all tests necessary to assure compliance with established specifications and standards, as required by 21 CFR 211.194.

 

W-065

Keywords: internal quality audits, quality policy, management reviews, compiler, structural validation, Part 11

  • Primary deviations: incomplete structural software validation, compilers were not validated, inadequate internal quality audits, inadequate quality policy, no ESD reduction procedures, inadequate corrective and preventive action plan, training needs not established, training not documented
  • Examples: Your firm failed to adequately validate software integral to the IVD, IVD wireless and ...devices as required by 21 CFR 820.75. For example, structural testing o the software is not completed or documented, there are no software validation protocols available, and the compilers were not validated
  • Failure to have a quality control unit adequate to perform its functions and responsibilities. Your failure to have an adequate quality control unit is demonstrated by the number and types of inspectional observations made during this inspectio
    Failure to have an adequate number of qualified personnel to perform and supervise the manufacture, processing, packing, or holding of a drug product
  • Failure to ensure that each person engaged in such activities has the education, training, and experience, or any combination thereof, to enable them to perform their assigned functions, as required by 21 CFR 211.25. Your failure to have a staff adequate perform their assigned functions, is the number and types of inspectional during this inspection.
  • Failure to maintain adequate control over air handling and exhaust systems

 

W-064

Keywords: limited access, accurate and complete copies, protection of records, computer validation, change control, quality audit, complaint handling, environmental monitoring, Part 11

  • For example, drawing .... collection set is considered an electronic record. There is no documentation to establish that the system by which these records were produced has been properly validated.
  • There is no ability to generate accurate and complete copies of records in human readable and electronic form. There is no protection of records to enable their accurate and ready retrieval. Access to your system has not been limited and there are other significant deficiencies as well. Do not limit your evaluation solely to the example cited above. Only electronic records and electronic signatures that meet part 11 requirements may be used to satisfy record and signature requirements of 21 CFR $820.30(d), Design Output.
  • During the FDA inspection it was discovered that electronic records are used to establish portions of your design output, 21 CFR 820.30(d). However, there is no documentation to establish that these records meet the requirements of 21 CFR Part 11, Electronic Records; Electronic Signatures. The requirements of 21 CFR Part 11 are designed to ensure that electronic records are trustworthy, reliable, and generally equivalent to paper records.
  • Failure to validate computer software for its intended use according to an established protocol to when computers or automated data processing systems are used as part of production or the quality system as required by 21 CFR 820.70(i). For example: your firm’s ... is computer-controlled. It uses software programs to record data from measurements of the radius of curvature and corneal refraction of the eye. However, your firm has not validated the software and computer system used to record this data for its intended uses. Your firm has no documentation to assure that they perform as intended
  • Also, there is no validation and documentation of subsequent changes to the software
  • Quality audits are inadequate to assure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system, as required by 21 CFR 820.22. For example, your firm’s quality audits did not document or justify your failure to validate the ... software and the ... process.
  • Failure to establish and maintain complaint handling procedures that ensure that all complaints are evaluated to determine whether a complaint represents an event which is required to be reported to FDA under Medical Device Reporting (MDR), as required by 21 CFR part 820.198(a)(3). For example...

 

W-063

Keywords: validation of spreadsheets, data integrity, deletion of e-records, cleaning validation, method validation, process validation, OOS, failure investigation, Part 11

  • Failure to have an adequate validation procedure for computerized spreadsheets used for in-process and finished product analytical calculations. The current validation procedure uses only the values that result in within specification findings, aberrant high findings, and aberrant low findings [21 CFR211. 165(e)]. For example, SOP 644.00, QA/QC Spreadsheet Validation, is deficient in that only a small range of values are being used to challenge computerized spreadsheet mathematical calculations.
  • Failure to use fully validated computer spreadsheets to calculate analytical results for in-process and finished product testing [21 CFR 211.165(e)]. For example, the computer spreadsheets used to calculate analytical results for... have not been validated.
  • Failure to have appropriate controls over computerized laboratory systems to assure that changes in or deletions of records are instituted only by authorized personnel [21 CFR211. 165(e)]. For example, instrumentation where data is stored on the interfacing computer hard drive up to thirty days prior to being written on a compact disk for storage is available to all analysts. While the data exists on the hard drives, any analyst can access, print, or delete the data.
  • Products were manufactured and shipped in interstate commerce before process validation was successfully completed.
  • Batch records do not accurately reflect the actual manufacturing process. For example, there was no documentation, in the batch record that powder blend was reclaimed from the vacuum system of the - Encapsulator and added back into the virgin blend for process validation batches was successfully completed [21 CFR211.110(a)].
  • The investigation of OOS data for validation batch 0000498 Q-Capsules was not extended to batch 98058190 capsules that was also manufactured using ....

 

W-062

Keywords: corrective and preventive action procedures, missing non conformity evaluation, process validation

  • Failure to control your firm’s corrective and preventive actions procedures to ensure that all data from quality data sources are analyzed to identify existing and potential causes of nonconforming product and other quality problems
  • ... and there was no documentation describing any evaluations of the returned goods or their quality problems as they related to your customer complaints
  • Failure to ensure that a process whose results cannot be fully verified by subsequent inspection and testing, has been validated and approved according to established procedures
  • Specifically, your firm has no documented evidence that provides a high degree of assurance that the manufacturing specifications and processing controls used in the automated and software controlled ...operations of your ... will consistently produce a product meeting its pre-determined specifications and quality attributes (traditionally termed validation).

 

W-061

Keywords: cleaning validation, method validation

  • Adequate cleaning procedures have not been established in that FPL has not conducted cleaning validation studies for non-dedicated manufacturing equipment. For example, the cleaning procedures have not been validated to demonstrate removal of API residues, cleaning agents, and impurities in buildings 1,2 & 7.
  • Cleaning verification testing methods for Ammonium Lactate, Inulin, and Decitabine are not validated.
  • Manufacturing processes have not been validated for several products.
    Investigations are not completed in a thorough and timely manner. For example, investigations were not completed for several incidents of Purified Water not meeting specifications for microbial contamination and endotoxin levels during...
  • Representative samples of components are not collected for testing and examination. For example, the inspection revealed that the microbiological samples of Purified Water collected at the points of use are not drawn through the same equipment as water used in product.

 

W-060

Keywords: electronic records, data base, audit trail, training, Part 11

  • It is also noted in the inspection report that you do not have adequate control over the receipt of study data and its subsequent input into the database.
  • There are no records to show when study data is received and when it is entered into the database.
  • There is also no audit trail for changes made to the database. No data queries or clarifications have ever been generated and sent to the sites to verify missing information or to clarify discrepancies...
  • Electronic records, the subject of SOP-100-720, Electronic Database Maintenance, are subject to 21 CFR Part 11- Electronic Records; Electronic Signatures, as well as to the record keeping regulations found in 21 CFR 812.140, a guidance document regarding this regulation, Computerized Systems Used in Clinical Trials, dated April 1999.
  • There is no documentation to show that investigators or their personnel were trained in the use of the ... regarding the investigational plan, or in how to complete the CRFs
  • There is no documentation of the number on the number of ...and ... the number manufactured and distributed, the number of copies of the controlling software made, or the disposition of each copy of the software. There are no records showing to which sites the device was shipped or whether the required software was supplied.

 

W-059

Keywords: Data back-up and archiving, laboratory tests, method validation, change control, Part 11

  • Failure to maintain complete data from all laboratory tests as required by 21 CFR 211.94 (a).
  • There is no back-up file for laboratory UV spectrophotometer test results for some tests. The spectrophotometer does not automatically back-up data and the analyst is required to assign an identification number to each individual chromatogram in order for it to be saved. In some cases, original data was lost and the tests had to be performed again to determine final distribution of the lots.
  • Failure to have documentation of Method Validation for the stability assay method for ... Injection.
  • Failure to document changes to written specifications and to have the changes approved before implementation as required by 21 CFR 211.160 (a). For example...

 

W-058

Keywords: Software validation, security, audit trail, data integrity, failure investigation, laboratory records, training, Part 11

  • The computer software your firm uses to determine metals analysis is deficient. It has no security measures to prevent unauthorized access of the software, no audit trails, and data can be copied or changed at will, with no documentation of the copying or changes
  • Your procedures do not require the documentation of calculation or entry errors.
  • There is no documentation to indicate that analysts are trained in the software and its applications.
  • You or your employees performed repeat testing on products without first conducting an investigation. No explanation into the reason for repeat testing and invalidating the previous results was documented. Further, the initial results were not communicated to your customers; only the repeated and passing results were communicated. Specific examples include.....
  • You (specifically) are not documenting raw data when you perform inductively coupled plasma emission spectrograph or high-pressure liquid chromatography analyses. This raw data includes....
  • Following flood damage in September, 1999 to your facility and equipment, you or your employees failed to evaluate the raw data storage conditions, recalibrate or re-qualify repairable analytical equipment, or implement any procedures or changes to existing procedures to alleviate future damages.
  • Your firm does not have a quality assurance program in place to: a) qualify analytical equipment prior to their use, and b) calibrate and maintain analytical equipment according to manufacturers’ specifications.
  • Your firm has no system for the receipt and storage of standards and analytical chemicals. Expired standards were used in the calibration of equipment. Working solutions were not properly labeled or documented in laboratory notebooks or other records in that the data did not bear complete information, including the analyst or preparer’s identity, solution designation, strength, and expiry dates.
  • The integrity of raw data produced by various laboratory instrumentation is questionable. For individual pieces of equipment, including ...either no equipment qualification was performed, no calibration was performed prior to their use, audit trail exists for data collection and entry, or their inclusion in method or system validation was not made.
  • Your firm’s laboratory records and recordkeeping are deficient. corrections to laboratory raw data were noted to be obscured with white correction fluid or improperly voided (no initials, date, reason or explanation of change). Laboratory worksheets did not contain information of the analytical method used to perform the analysis in question. Analytical calculations were not recorded in laboratory notebooks. There is no other demonstrable record of said calculations.
  • Laboratory records did not contain documentation of a second individual’s review and verification of the original data.
  • You and your employees performing analyses of drug products are not trained in Current Good Manufacturing Practices applicable to your operation. Further, your supervisory employees have not documented any of their subordinates as being qualified to execute the analytical work to which they have been assigned.

 

W-057

Keywords: Data integrity, authorized changes, manufacturing deviations, Part 11

  • Your firm failed to implement appropriate controls over your High Performance Liquid Chromatography (HPLC) to assure that only authorized changes can be made. It was noted during the inspection that there is an option on the HPLC that allows analysts to delete results after they are processed.
  • There is no assurance that all manufacturing deviations are recorded and justified. It was noted that ...

 

W-056

Keywords: Data integrity, unauthorized access, out of specifications, director of quality control, Part 11

  • Failure to maintain the integrity and adequacy of the laboratory’s computer systems used by the Quality Control Unit in the analysis and processing of test data.
  • For example a) There was a lack of a secure system to prevent unauthorized entry in restricted data systems.
  • Data edit authorization rights were available to all unauthorized user not only the system administrator
  • The firm ignored initial out-of-specification results, performed retesting, and released product for distribution without conducting adequate laboratory investigations. In one instance, the Director of Quality Control crossed out the analyst’s statement of true results and determined the low results were due to laboratory error without any evidence or investigation of the results.
  • The Director of Quality Control crossed out the analyst’s statement "This proves that there was not an analyst error." The Director concluded....
    Laboratory controls are deficient in that the firm established a written procedure, which allowed for the averaging of out-of-specification and within-specification analytical test data results, as was done with ...

 

W-055

Keywords: Statistics, quality problems, investigating non-conformities, complaint procedure

  • Not analyzing all significant sources of quality data, and using appropriate statistical methodology where necessary to detect recurring quality problems, as required by 21 CFR 820. 10O(a)(l). For example, your firm does not conduct ....
  • Not investigating the cause of nonconformities relating to product, processes and the quality systems, as required by 21 CFR 820. 10O(a)(2). For example, ....
  • Failure to adequately evaluate and document complaints, as requiredby21 CFR 820.198. Our inspection revealed that the PIR’s are considered to be customer complaints and are handled via your sales/distribution personnel, RMA’s are considered to be product returns, including defective goods that are handled by your customer service department. Review of your records

 

W-054

Keywords: Batch production record, training, calibration procedures, certificate of analysis

  • There is no documentation of the Batch Production Records being reviewed and approved by the Quality Control Unit since January 1, 2001 [21 CFR 211. 192].
  • There is no documentation that members of the Quality Control Unit possess the education, training and/or experience to perform this function [21 CFR 211.25(b)].
  • The calibration procedures and documentation for the ... Analyzer are inadequate in that the frequency for calibration to be performed is not specified and the standards used for calibration are not certified cylinders of nitrogen and oxygen as specified in your procedures [21 CFR 211.68(a)].
  • There is no documentation that you receive a Certificate of Analysis, as your procedures indicate, upon receipt of each cylinder of incoming source oxygen [21 CFR 21 1.84(d)(2)].
  • There is no documentation of a complaint received regarding released product [21 CFR211.198(b)].

 

W-053

Keywords: Method validation, effectiveness testing, stability testing

  • Your firm has not validated the analytical methods used for in-process, stability and product testing
  • Your firm does not perform preservative effectiveness testing as part of your release testing and stability program for dl prescription and OTC drug preparations.
    Failure to follow the Standard Operating Procedure ... "Acceptable Testing Time Intends", which states stability samples are to be tested within 60 days of their scheduled pull date. Your Stability Testing Log documented total of 67 out of 378 stability samples that did not meet the 60-day testing time frames since August2000.

 

W-052

Keywords: Scientifically sound specifications, stability characteristics, verification of calculations by a second person

  • Failure to establish scientifically sound and appropriate specifications for raw material and finished product testing.
  • Failure to have a written testing program to assess the stability characteristics of the .... products.
  • Failure to determine theoretical and actual yields, and failure to have the calculations performed by one person and independently verified by a second individual.

 

W-051

Keywords: Quality control unit, drug manufacturing records, SOPs, identity and purity tests, cGMP training

  • Failure to establish and operate an effective quality control unit in conformity with requirements of 21 CFR 211.22. There re no written procedures concerning individual responsibility for quality control operations.
  • Drug manufacturing records (...) contained numerous errors and omissions, although they had undergone quality control review.
  • Written standard operating procedures covering .... were inaccurate, incomplete, and contained no documentation of origin, review or approval.
  • Failure to follow written production and process control procedures as required by 21CFR 211.100. A significant example is the failure to conduct identity and purity testing of some .... as required by SOPS.
  • Failure to establish and implement an effective employee cGMP training program. Employee training records contain no reference to cGMP
  • There ore no cGMP traini

 

W-050

Keywords: Management reviews, quality audits, destruction of records

  • Failure to conduct management reviews as required by21 CFR 820, 2O(c) and as called for in your procedure QOO1 "Quality System", to assure that the your firm is in compliance with the regulations.
  • Failure to conduct quality audits requiredby21 CFR 820.22, and in your procedure QO02, "Audits" to assure your firm is operating in compliance with the regulations.
  • Your procedure QO02, "Audits", Section 3,3.2, provides for the destruction of the audit reports when corrective action is completed. This represents a failure to document the dates and results of the quality audits as required by 21 CFR 820.22.

 

W-049

Keywords: Software validation, cleaning and maintenance of equipment, Part 11

  • Failure to validate computer software used to control the ... to ensure the software will perform for its intended use. 21 CFR 820.70(i).
  • Failure to adequately validate processes which cannot be fully verified by subsequent inspection and test, 21 CFR 820.75, for example, the ....
  • Other deficiencies found during the inspection include failure to follow procedures for the cleaning and maintenance of manufacturing equipment, and failure to report Medical Device Regulation (MDR) reportable events in a timely manner.

 

W-048

Keywords: Missing meeting records, quality audits, supplier qualification, preventive and corrective action

  • Failure to establish management review procedures and failure to document the dates and results of management reviews [21 CFR 820.20(c)]. For example, your firm has reportedly held management meetings to discuss product quality but has not kept documentation of such meetings
    Failure to document the dates and results of quality audits. For example, your firm has .....
  • Failure to establish and maintain the requirements, including quality requirements, that must be met by suppliers [21 CFR 820.50]. For example, your firm has not specified quality requirements for suppliers, maintained lists of approved suppliers, and developed written procedures describing how suppliers are evaluated for quality acceptance requirements.
  • Failure to establish and maintain procedures for implementing corrective and preventive action [21 CFR 820.100]. For example, your firm has not....

 

W-047

Keywords: QA review, employee competency audits , people qualification, out of range values

  • Failure to perform QA review of the .... results on the Laboratory Requisition for testing forms from 2/2/01 through 7/26/01.
  • Failure to review In Process Failure (error and accident) forms.
  • Failure to perform competency audits of employees
  • Failure to perform daily QA review of the refractometer records, refrigerator/freezer records, donor files and reactive unit log;
  • Failure to perform annual re-certification of the center physician and physician substitute.
  • Failure to document the initial out of range values on ....

 

W-046

Keywords: representarive sampling and testing, validation of supplier analysis, micrbial contamination

  • CGMP deviations noted during the inspection included, but are not limited to: The active pharmaceutical ingredient (API) for the covered product is not sampled for testing in a representative manner prior to use [21 CFR 211.84(b)].
  • Reliability of suppliers’ analyses supporting drug component acceptance is not appropriately validated for all components [21 CFR 211.84(d)(2)].
  • Appropriate written procedures to prevent objectionable microbial contamination from environmental sources are not established and followed [21 CFR 211. 113(a)]
  • The active pharmaceutical ingredient (API) for the covered product is not sampled for testing in a representative manner prior to use (W-046).

 

W-045

Keywords: Supply chain audit, stability testing, method validation, cleaning validation

  •  (Raw) material was accepted based only on review of import documents such as the shipper’s declaration and certificates of origin of the materials. No audit of the supply chain was conducted to verify the certificates. Your March 29, 2001 response provides a commitment to audit the supply chain for new material by the end of 2001, but does not address the material already manufactured.
  • Validation of the batch release and stability test methods for assay and impurities was inadequate in that your study did not include demonstration of accuracy, specificity, range, ruggedness, robustness and system suitability.

Cleaning validation studies for the multi-use process equipment were inadequate in that l The cleaning procedure did not specify the quantity and time for rinsing thee ... machine components therefore any organic residue found can not be quantified l Swab sampling was not representative of the total surface area ..., no recovery data for swab samples was available.

 

W-044

Keywords: responsibilities of QC unit, failure investigation, out of specifications

  • Failure to have a document, which delineates the responsibilities and procedures applicable to the Quality Control Unit. [21CFR 21 1.22(d)]
  • Failure to adequately investigate batches, which did not meet specifications. [21 CFR 211.192]
  • Failure to have an Out of Specification procedure, which addresses the disposition of data not found to be in error from testing or inconclusive from the laboratory investigation. [21CFR 21 1.165]

 

W-043

Keywords: Validation, laboratory data systems, training, responsibilities of QC unit, cleaning validation, Part 11

  • For example, you have failed to establish and document in writing the responsibilities and authority of a Quality Control Unit designed to assure the quality and purity of each batch of drug product (21 CFR 211.22)
  • You have failed to train employees in cGMPs relative to their job functions in drug production [21 CFR 211.25(a)].
  • You have failed to validate, for example, the drug production processes (21 CFR 211.100); computerized control systems used for maintaining laboratory data and drug product distribution information (21 CFR 21 1.68); and the cleaning process for common equipment used in drug and cosmetic production processes (21 CFR 21 1.67).

 

W-042

Keywords: Stability testing, software change control, method validation, laboratory records, laboratory, calculations, equipment calibration, Part 11

  • There were inadequate laboratory procedures and records to assure that APIs have the appropriate quality and purity. The inspection reported deficiencies regarding the following laboratory procedures and records:. Analytical methods validation, systems suitability testing, incomplete laboratory records, inaccurate laboratory calculations, inadequate calibration of laboratory equipment
  • Written procedures for production, process control, and laboratory operations were not always followed to assure that APIs have the appropriate quality and purity. The inspection reported numerous instances regarding the following operations which present a general practice of not following written procedures: Stability testing, Storage of quarantined and released materials, making software changes, drying of finished API

 

W-041

Keywords: Failure investigation, corrective action, filtration, cleaning validation

  • Failure to thoroughly investigate any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications [21 CFR211. 192], as follows....
    2.Failure to establish and follow written procedures for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product[21 CFR211 .67(b)] in that....
  • The cleaning of the ultrafiltration/diafiltration (UF/DF) unit used in the manufacture of ... has not been adequately validated.
  • Failure to ensure that reprocessed batches of product will conform with all established standards, specifications, and characteristics [21 CFR 211.115(a)] in that there were no written procedures and validation data that support the reprocessing and reworking of Albumin for both proteinaceous material (PM) and potential glass fragments.
  • Failure to maintain and/or follow written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to posses and to assure that such procedures, including any changes, are drafted, reviewed, and approved by the -appropriate organizational units and reviewed and approved by quality control. For example.....

 

W-040

Keywords: Validation protocols, Part 11

  • Failure to establish and implement adequate computer security and data integrity in that during this inspection is was observed that an employee was found to have utilized another person's computer access into the ..... computerized record system. Review of 21 CFR Part 11 pertaining to the utilization of electronic records and signatures, and security controls pertaining to both.
    Deviations included: lack of validation protocols and the maintenance of complete and accurate documentation of the performance of the validation protocols and an analysis of the results for the computerized systems.

 

W-039

Keywords: Laboratory test procedures, method validation, raw data, Part 11

  • Laboratory tests and procedures were inadequate in that Laboratory test methods fail to show that all batches of ( ) conform to appropriate specifications in that the method used is not scientifically appropriate. Specifically, the method used is substantially different than the method described in current compendia. The method used has not been demonstrated to be equivalent to the current compendia method to determine that the product meets current compendia limits. Furthermore, ( ) equipment needed for the appropriate analytical method was not available.
  • The analytical methods used for stability testing of ( ) have not been demonstrated to be stability indicating methods. Additionally, stability samples were not stored under controlled conditions
  • Raw data for the preparation of standards and reagents, sample weights, and dilution factors were not always recorded; laboratory worksheets were not always checked by a second individual and crossed-out data on the worksheets was not always observed to have been initialed and dated by the person changing the data.
  • Furthermore, there was no documentation that analysts were trained to perform the laboratory analyses
  • The ( ) system has not been validated
  • There are no records showing that ( ) manufactured by this facility, or purchased from a supplier, tested for microbiological specifications.

 

W-038

Keywords: Management responsibility, audits, software validation, corrective actions, Part 11

  • Failure to implement and control a quality system that is appropriate for the specific devices manufactured by your company. For example....
  • Appropriate management representatives do not review audit reports.
  • No design and development plan has been established.
  • No documented evidence to support the validation of design changes made to the ( ) system despite changes made to this device
  • No procedures for the development of software used to control devices.
  • The software used for the operation of the ( ) system was not properly validated.
  • Failure to establish and control procedures for implementing corrective and preventive actions. For example...

 

W-037

Keywords: Corrective actions, preventive actions, trend analysis

  • Failure to establish and maintain adequate corrective and preventive action procedures.
  • Not all sources of quality data are analyzed to identify existing and potential causes of nonconforming product and other quality problems.
  • For example,...Other failures/problems noted in the complaint system such as ( ) are not evaluated/analyzed and processed through your firm’s corrective and preventive action system.
  • There is no rationale why other events are not trended and analyzed
  • Failure to establish and maintain an adequate complaint handling program. Complaints received by your firm are not processed in accordance with your firm’s SOP in that there was missing information on the complaint form
  • Also, in your firm’s response to the FDA 483, you stated that your firm consistently files MDR reports within 30 days of becoming aware that an event is reportable. FDA generally considers that a manufacturer becomes aware of an adverse event whenever an employee becomes aware of an adverse event. The 30-day time frame begins

 

W-036

Keywords: Legacy systems, retrospective evaluation, software validation, analytical equipment, calibration stickers, Part 11

  • The software programs have not been verified or validated".
  • You indicate that you will develop a complex software validation schedule in cooperation with the software vendor by December 31. However, the validation schedule will not be approved until January 21, 2001, and the software validation exercise will not be completed until June 30, 2001. It appears that you are proposing to continue to use these … systems for testing of … without having completed the calibration of … or validation of its software. This is unacceptable".
  • Written procedures had not been established for the calibration of analytical instruments and equipment in quality control laboratories used for .....
  • Furthermore, calibration data and results provided by an outside contractor were not checked, reviewed and approved by...
  • Most instruments lacked calibration stickers indicating ...

 

W-035

Keywords: Networks, WAN, LAN, LIMS, computer validation, retrospective evaluation, documentation, Part 11

  • The network program lacked adequate validation and/or documentation controls
  • System design documentation has not been maintained or updated throughout of the software dating back to 1985 despite significant changes and modification that have taken place. These include program code, functional/structural design, diagrams, specifications and text descriptions of other programs that interfere with (this program)
  • The program was not controlled by revision numbers to discriminate one revision from the other
  • There was no assurance that complete functional testing had been performed in the ... system. For example you failed to assess all historical testing and compare it with current functionality to ensure that all ... functionality has been adequately evaluated
  • The software validation documentation failed to adequately define, update and control significant elements customized to configure the system for specific needs of operation.
  • You make no commitment to retrospectively put historical documentation together
  • Validation documentation failed to include complete and updated design documentation, and complete wiring/network diagrams to identify all computers and devices connected to the ... system
  • The Quality Control Unit failed to ensure that adequate procedures where put in place to define and control computerized production operations, equipment qualifications, documentation review and laboratory operations.

 

W-034

Keywords: Database, networks, audit trail, computer validation, retrospective evaluation, documentation, Part 11

  • Lack of audit trail function of the database to ensure against possible deletion and lost of records
  • Absence of documentation defining the database, operating system, location of files and security access to database
  • Validation documentation did not address signal lines between detection devices and computer
  • Documentation control deficiencies were reported such as review, approval, and maintenance of records
  • The ... network program lacked adequate validation and/or documentation controls.
  • The following had not been maintained or updated from original release/design specification back to approximately
    - revision control system
    - validation records
    - structural and functional diagrams and design descriptions
    - complete diagrams with text description identifying other network programs which interface with ...
  • Inadequate standard operating procedures to ensure that records are included with validation documentation, maintained and updated when changes are
  • Your response fails to trace back to source code, and the related document cycle which establish evidence that all software requirements have been implemented correctly and completely and are traceable back to system requirements
  • Your response fails to discuss extending the retrospective evaluation to other elements of the system needing to be defined and controlled as part of the overall configuration management.

 

W-033

Keywords: Action plan for part 11, environment validation, cleaning validation, Part 11

  • No action plan to correct for deficiency of 21 CFR Part 11 for a record keeping system, which is used for maintaining chromatography and audit trails.
  • Insufficient environment validation
  • Inadequate cleaning validation

 

W-032

Keywords: Computer validation, security, modem access, data review, change control, Part 11

  • Lack of proper validation of computer software.
    Failure to establish and implement adequate security in allowing the software vendor unrestricted modem access and not consistently documenting this access
  • Not conducting a secondary review of software modification
  • Lack of computer hardware and software change control SOP
  • Lack of verification that software modifications validated on the 'test' system are identical to the modifications implemented later in the 'live' system

 

W-031

Keywords: Laboratory records, electronic records, failure investigation, security procedures, Part 11

  • Failure to maintain laboratory records to include complete data derived from all tests necessary to assure compliance with established specifications and standards
  • Specifically, your firm failed to properly maintain electronic files containing data secured in the course of tests from 20 HPLCs and 3 GLCs.
  • Additionally, no investigation was conducted by your company to determine the cause of missing data and no corrective measures were implemented to prevent the recurrence of this event.
  • Additionally, please provide copies of your written procedures describing system security, system maintenance, and data file backup procedures for assuring backed up automated laboratory files are retrievable.
  • Failure to establish procedures to assure equipment and utensils are sanitized at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality or purity of drugs beyond the official or other established requirements (more specifics to follow)

 

W-030

Keywords: Computer system validation, maintenance, data review, laboratory notebook entries, LIMS, autoclave validation

  • The computer system, used to monitor and maintain critical systems has not been validated. The computer system is used to monitor temperature, conductivity, water pressure and time (in hours) Additionally, this system monitors the differential pressure between... (examples follow)
  • The unit, used to compare the computer line’s air pressure measurement readings with equipment air pressure measurements, has not been calibrated.
  • There has been no periodic maintenance to assure that the unit is operating appropriately.
  • Failure of the Quality Control Unit to establish a system for reviewing microbiological laboratory data to assure completeness and accuracy.
  • Reviews of multiple entries in microbiology laboratory notebooks were not performed in a timely manner. For example…
  • Data (from this testing) was entered into the Laboratory Information Management System (LIMS) prior to the documented review of the data.
  • Validation of the autoclave, used to sterilize equipment, stoppers and filled syringes, is inadequate in that:a. The worst case load configuration has not been established. (other examples follow)

 

W-029

Keywords: Client/server system, chromatography data system, user requirement specifications, change control, audit trail, file security and integrity, system security, back-up and recovery, WAN backup

  • Data transfer of a (chromatographic) client server system not validated
  • No documented evidence of validation of user requirement specifications
  • No validation after hardware and software upgrades and configuration changes
  • Insufficient security controls to prevent analysts from submitting modified data
  • User can select programmable functions without record or documentation in the QC network system that could circumvent system and data integrity
  • Each analyst has access to read/write, purge, copy, rename files
  • Audit trail was intentionally disabled
  • Client/server passwords to access the system never expired and had only four characters
    Authorized LAN access through corporate WAN users was not validated
  • No documented evidence to demonstrate the WAN was capable of properly performing backup and recovery of data on the QC server

 

W-028

Keywords: Computer maintenance, computer validation, worst case testing, change control

  • Failure to maintain a computer system with validated program capabilities
  • No testing of the computer system after installation at the operating site.
  • No testing under worst case conditions
  • The protocol mentions without explanation or supportive documentation, "historic experience" with terminals, but doesn’t specifically identify the terminals
  • The protocol lacks change control procedures

 

W-027

Keywords: Laboratory records, data integrity, equipment maintenance, Part 11

  • Laboratory records are incomplete and inadequate. Data in numerous records were altered, erased, not recorded, recorded in pencil, or covered with white-out material. For example…
  • Altered values were written under computer generated values. Review of electronic data confirmed the incorrect values
  • Two pages of laboratory notebook written in pencil were erased
  • Typewritten dates were pasted over computer generated dates
  • The use log has no entries from Aug to Dec 17, 1999.
  • It is not possible to trace computer generated xxxx because they were not stamped
    Equipment was nor properly maintained (explanation is given)
  • The qualification and maintenance of equipment used in, and the process validation of the xxxx system is inadequate.

 

W-026

Keywords: security, data integrity, audit trail, equipment calibration, Part 11

  • An employee user name and computer password were publicly posted for other employees to ‘access the xxxx data management.
  • Unauthorized access to a running system
  • Access of previous employees to critical Data Management System functions
  • Changes made to critical data base entries not electronically recorded or controlled by procedures
  • The RPM calibration and timer check of the centrifuge was not performed every 60 days as required in the written procedure and operator’s manual.

 

W-025

Keywords: security, data integrity, database access, file privileges, equipment validation, training, Part 11

  • Inadequate controls over computers and related systems to assure that changes in the master production and control records or other records are instituted only by authorized personnel
  • No current listing of individuals who have access to the database program or to what level of access each individual has;
  • No procedure in place to grant, modify or remove access privileges to software
  • There is no audit trail within the computer that identifies how many worksheets have been generated for a given sample number
  • Worksheets and logs used to record raw data were available in the appropriate laboratories without any mechanism controlling their use
  • Procedures allow for managers to approve their own work. Work they perform and approve does not require the initials and signature of a second person showing that the work has been reviewed for accuracy, completeness and compliance with standards
  • There were no raw data indicating that cold spot mapping as part of steam sterilization autoclave revalidation was ever performed
  • The validation of the Biotech Suite was inadequate in that there were no pre-defined criteria describing what the requirements of the suite, other than that of environmental monitoring, were to be, nor were there any pre-defined criteria describing what the requirements for the equipment of this suite were to be.
  • There are no procedures defining training, qualification, disqualification and re-qualification of sterility suite operators when they exceed the microbial limits defined

 

W-024

Keywords: scientifically sound methods, cleaning validation

  • Laboratory controls have not established that the test method for assay of xxxx content of xxxx ‘is scientifically sound to assure that this product conforms to specifications of strength, quality and purity (examples: insufficient separation, no verification of method suitability under actual conditions etc)
  • The calculation for assay fails to include a correction factor for the actual purity of the reference standard
  • Cleaning procedures for process equipment used interchangeably to manufacture pharmaceuticals, including cosmetics, and invitro diagnostic solution. lack sufficient detail to assure contamination will not occur that could alter the safety. quality or purity of pharmaceutical products. (examples follow)
  • There is no provision to document what cleaning chemicals are actually used.

 

W-023

Keywords: Clinical investigation, FDA access control

  • You failed to permit an FDA officer to have access to and copy and verify records and reports relating to a clinical investigation conducted under Part 312. [21 CFR 312.58(a)].
  • You failed to provide access to the records for each subject you described in your Investigational New Drug Applications (INDs).
  • You failed to provide a copy of the protocol to the Immunogenetics’ Investigational Review Board during their review of your study, citing concerns about proprietary information.
  • You failed to withhold administration of an investigational new drug until an IND is in effect.

 

W-022

Keywords: out of specification results, cleaning validation

  • Investigations and follow-up of out of specification results inadequate or incomplete and complaints are inadequate or incomplete.
  • Equipment cleaning procedures used for cleaning multiple use been validated.
  • The computer systems used to control and/or monitor production, reconcile raw materials, assign batch numbers, and control solvents, have not been validated.
  • Qualification of processing equipment has not been completed.

 

W-021

Keywords: failure investigation. Retesting, OOS, cleaning validation

  • Failure to perform a thorough investigation, including conclusions and follow-up, when your drug products do not meet their finished product specifications.
  • There is no documentation available to demonstrate that an appropriate investigation is conducted to determine the root cause of batch failures.
  • Failure to follow your own SOP, "04-003 – Retesting 00S Results" for the investigation of out of specification results for your drug products.
  • Failure to establish procedures for the cleaning of your drug manufacturing equipment that include a description, in sufficient detail, of the methods, equipment, and materials used to assure that the equipment is adequately cleaned. For example, …..
  • Failure to have written master production records that include complete manufacturing and control instructions, and sampling and testing procedures. For example (examples follow)

 

W-020

Keywords: out of specification results, cleaning validation, stability testing

  • The Quality Control Unit failed to identify and evaluate out-of-specification results received for routine stability testing of finished products within expiry. None of the failing results were investigated. For example …
  • Cleaning validation studies and procedures were found to be inadequate to assure prevention of cross-contamination for products manufactured and filled with non-dedicated equipment. For example ….
  • No cleaning validation studies have been conducted for products using non-dedicated equipment to assure the prevention of cross-contamination, such as…
  • The cleaning validation studies which were conducted failed to evaluate the removal of all active ingredients and all cleaning agents.
  • Critical agitation times were not documented during mixing operations or were non-specific in validation studies
  • Analytical test methods used to assure product potency throughout shelf life have not been demonstrated to be stability indicating
    Stability sampling was not conducted in accordance with SOP 13-001-02. Drug Product Stability Testing, which specify testing every three months for the first year, every six months the second year and then yearly.

 

W-019

Keywords: Quality control unit, USP testing, equivalency, storage conditions, documentation, laboratory notebooks, maintenance logbooks, API

  • No quality control unit
  • Failure to perform the required USP testing on each production ‘batch" of the product Anhydrous Caffeine USP. For example: …
  • The (HPLC test) method currently used to assay Caffeine, has not been shown to be equivalent to, or better than the current USP method.
  • The primary Caffeine USP reference standard is not used. The secondary reference standard in use has not been qualified.
  • The reference standards used to perform the Caffeine tests are not stored under adequate conditions.
  • Laboratory notebooks do not document critical information including test methods, reagents used, weights of samples, and drying times and temperatures achieved during testing.
  • The equipment xxxx used to analyze the Caffeine product was not calibrated prior to use.
    The laboratory hood is not certified.
  • Laboratory equipment maintenance logbooks are not maintained.
  • The laboratory bench, sample jars, and equipment were dirty. They were covered with a white powdery material.
  • No validation plan in place that identifies and evaluates the processing steps, operating ranges, critical processing parameters, required equipment, sampling and testing data to be collected.
  • There is no established GMP training program for the firm’s employees.

 

W-018

Keywords: conformance to specifications, record retention, training, Part 11

  • Failure to determine conformance to written specifications. [21 CFR 21 1.160(2)] For example, (examples follow)
  • Failure to retain all production, control, or laboratory records to assure that drug products adhere to established specifications. [21 CFR 211.180 and 21 1.1.94] For example, Raw data printouts from the chloride, potassium and sodium tests … were not available.
  • Failure to effectively train employees in laboratory operations to assure that original records are accurate, complete and in compliance with established specifications.

 

W-017

Keywords: method validation, detection of unknowns, laboratory notebooks

  • Inadequate validation of the analytical method for detecting residual solvents in xxxx in that an unknown xxxx was determined above the limit
  • Accuracy of the test for xxxx was determined at a higher concentration than the limit
  • Linearity and limits of detection were determined above the limit of the test
  • Assay methods for xxxx are not purity indicating
  • Facilities and equipment used in the production of API's are not designed or maintained in a clean and sanitary manner to prevent extraneous contamination of API's with dust, rust, paint chips, metal and insects. With detailed examples to follow.
  • Laboratory standards used for the analysis were not identified in the analyst notebooks (e.g., lot number of secondary working reference standard, analytical balance used for the analysis) With explanations to follow.

 

W-016

Keywords: Method validation, system suitability testing, raw data recording, records, microbiological tests, equipment calibration

  • No or insufficient method validation, expiration dates and storage conditions
  • No chromatographic system suitability testing
  • Missing laboratory records, missing chromatograms and spectra, missing stability test records
  • Standard weights, sample weights and calculations are not recorded
  • No microbial limits testing.
  • No written procedures for any microbiological tests performed
  • No procedure and tests to monitor environment
  • Balances not calibrated against ASTM conforming weights
  • No established calibration specifications for the infrared spectrophotometer when the spectrum of polystyrene is recorded.
  • Rawdata not reviewed and maintained
  • Release of test records before review and approval
  • The filtering apparatus used in the performance of the Particulate Matter test does not have a vacuum system capable of maintaining the required vacuum range,
  • Wearing clean clothing appropriate for the duties they perform not ensured

 

W-015

Keywords: method validation, compliance with procedures, bioburden specifications

  • Failure to establish and document the accuracy, sensitivity and reproducibility of test methods employed. For example, the method used to determine the microbiological quality of Water for Injection does not reflect actual sample values and there are no or vague inspection parameters/specifications for particulate matter in your product.
  • Failure to follow and appropriately document written production and process control procedures. For example, you did not perform annual re-qualification of stability incubators or investigate non-conforming product as required by Standard Operating Procedures that you established.
  • Bulk bioburden specifications were increased without justification the change, the change was not supported by historical data
  • Failure to establish and document the accuracy, sensitivity and reproducibility of test methods employed. For example, the method used to determine the microbiological quality of Water for Injection does not reflect actual sample values and there are no or vague inspection parameters/specifications
  • Failure to follow a written testing program designed to assess the stability characteristics of drug products For example, ….
  • Failure to ensure that complete data derived from all tests necessary to ensure compliance with established specifications are maintained For example, data is recorded on uncontrolled worksheets. The use of the uncontrolled worksheet allows data to be discarded without your knowledge.
  • Failure to document laboratory control procedures at the time of performance. For example, test data such as temperature of heat block incubator, sample identification number, and order of sample loading into the heated block incubator was not recorded during the actual performance of testing
  • Failure to retain a reserve sample that is at least twice the quantity necessary for all required tests (except …)

 

W-014

Keywords: Out of specification result, non identified HPLC peaks

  • xxxx injection failed to meet established specifications for in-process tests for protein concentration and effluent activity, and finished product tests for protein concentration and final yield.
  • Microbiological analyses for environmental samples of your Purified Water System failed action level specifications at two sampling sites
  • Extraneous HPLC peaks continuously explained to be autoinjector contamination, no further investigation

 

W-013

Keywords: Failure investigation, chromatographic split peaks, acceptance testing, expiration dates, cleaning validation

  • Incomplete failure investigation
  • Failure investigation not extended to other batches
  • No investigation of chromatographic split peaks,
  • Missing acceptance criteria for validation testing
  • No data to support storage expiration
  • Insufficient cleaning validation

 

W-012

Keywords: device accountability, investigational study, IRB, investigational plan, records

  • Failure to obtain signed and dated study informed consent documents from all study subjects
  • Several study subjects had not signed the study informed consent document at the time of the inspection.
  • Failure to maintain device accountability records.
  • Failure to conduct the study in accordance with the investigational plan.
  • Failure to maintain accurate, complete, and current subject records.

 

W-011

Keywords: Cleaning validation, identity test, API

  • Failure to ensure that cleaning procedures are adequate to prevent contaminationCleaning validation is inadequate
  • Failure to conduct a specific identity test for active pharmaceutical ingredient.

 

W-010

Keywords: Control of active pharmaceutical ingredients, stability testing

  • Low levels of organic volatile impurities which are not part of the reaction process are found in the finished Active Pharmaceutical Ingredient (API). Source not determined, amount can not be controlled in API
  • Stability samples not stored under controlled temperature
  • Analysis method has not been demonstrated to be stability indicating by degradation studies

 

W-009

Keywords: Bioburden validation, procedures

  • Failure to have and follow written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity h they purport or are represented to possess. For example, ….
  • Bioburden validation was not representative of manufacturing microbial load.
  • Failure to have an appropriate written procedure that would prevent objectionable microorganisms in your drug products. For example, your environmental control procedure does not include any action to be taken when the biological limits are exceeded.

 

W-008

Keywords: quality control unit, conformance to specifications, scientifically sound specifications, equipment validation

  • Failure to have a quality control unit adequate to perform its functions and responsibilities. Your failure to have an adequate quality control unit is demonstrated by …
  • Failure of the quality control unit to review all drug product production and control records to determine compliance with established written procedures before a batch is released or rejected, and to perform an investigation when a batch or its components fails to meet specifications.
  • Failure to make an appropriate laboratory determination of satisfactory conformance of each batch of drug product to its final specifications prior to its release, as required by …
    Failure to have, and/or to follow, laboratory controls which include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures
  • Failure to assure that equipment is of appropriate design for its intended use, as required by …. (examples follow)

 

W-007

Keywords: out of specifications, OOS, not following procedures, modification of methods

  • The significant cGMP deviations noted are as follows: Failure to comply with your own procedures for documenting Laboratory Investigations (SOP WI-QT130009-OOG), concerning the invalidation of test results. For example: ....
  • Failure to comply with your own procedures for completing investigation reports concerning out-of-specification results and/or not conducting investigations on a timely basis. For example:
  • Out-of-specification results were not included in the validation report covering the April 1997-June 1998 cycle. For example:. Microbiological testing results on 2/4/98 and 7/7/98, exceeded the total cfu/ml specification, without resampling, or investigating a potential contamination.
  • Daily qualification of the water system resulted in 17 occasions during validation and 20 times since validation, in which the resistivity fell below the established range of 16.3 -18.1 mega ohms. There was no documentation or shutdown of the system, in accordance with SOP WI-QE090063 -OOD,to investigate these occurrences.
  • Original test methods were modified without further study or documentation to justify the changes made. For example: . Agitation time was changed from 45 to 75 minutes for Diltiazem HCI 120mg, when it failed to originally meet the percent difference between replicate samples and ....

 

W-006

Keywords: responsibilities, quality assurance unit, out of specification results, missing documentation

No written procedures that would clearly define and describe the responsibilities and procedures applicable to the quality control functions associated with the manufacture of this product.

Neither your firm, nor xxxx had clearly assumed the responsibilities of a quality control unit for such critical functions as in-process review testing, review prior to product release, review of third party laboratory results, and initiation o investigation into out-of-specification (00S) results.

Product lots shipped to contract packager without testing

Release testing conducted seven months after the lots were manufactured.

No procedures in place for the analytical lab to forward OOS results to xxxx in a timely manner.

There was no record available to substantiate the claim that these results had been forwarded to xxxx

 

W-005

Keywords: quality control unit, records, process control procedures

  • No quality control unit
  • Failure to maintain records in accordance with 21 CFR 211 Subpart J. For example, (several examples follow)
  • Failure to establish production and process control procedures designed to assure your drug products have the required identity, strength, quality and purity. For example …(several examples follow)

 

W-004

Keywords: impurities, change control

  • Failure to establish specifications, standard, testing procedures, or other laboratory controls for impurities identified in your xxxx drug.
  • You have not implemented a ceeting program to characterize and monitor impurities, including their quantification, toxicity and clinical effects, in a timely manner (more details follow)
  • Inadequate identification of degradants of active ingredients
  • Inadequate specific test procedures for identified impurities
  • Failure of the quality control unit to appropriately justify changes to finish product release and/or stability specification of xxxx (more details follow).

 

W-003

Keywords: sterilization process, change control

  • Failure to establish appropriate procedures for the validation of a sterilization process to prevent microbiological contamination of product xxxx, in that ….
  • Failure to inform the FDA about each change in the product, process, quality controls, equipment, … (examples follow)
  • Failure to establish appropriate time limits for the completion of each phase of production to assure quality of the production to assure quality of the drug xxxx in that ….(explanation follows)

 

W-002

Keywords: X-radiation testing of monitors, worst case testing

  • The technician failed to introduce the worst case fault. Instead the technician was measuring x-radiation of a normally operating set and high voltage and beam current measurements were not made.
  • The technician failed to record the serial numbers of the radiation survey meters as well as the electrical meters.

 

W-001

Keywords: GLP, Good laboratory practice, testing facility, SOPs, contract laboratories

  • Company failed to manage the testing facility (5 examples)
  • Study director failed to fulfill requirements (7 examples)
  • Quality Assurance Unit (QAU) does not operate in conformance with regulations (3 examples)
  • Missing SOPs, for example for archiving raw data and others
  • The contracting laboratories used by … do not provide definitions for specific tests included in a study (i.e., normal limits for clinical pathology values in rodents).
  • In cases where your firm is relying on reference data (e.g. published literature, reference standards), the citations for those- references are not documented with a memorandum to the file.
  • Failed to characterize the test and control articles (4 examples).
  • Studies not conducted according to the protocol (6 examples)
  • Study data not accurately recorded (2 examples)
  • Failed to retain samples and control articles, e.g., no archive of retained samples of the test article as specified in protocols)

 

Important: Warning letters should be interpreted in the context of full content. Just looking at extracts may be misleading. And sometimes they include good advice from the FDA not mentioned in the extracts.