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-058
- 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....
W-230
- 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
- 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)].
- 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
- 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
- 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
- 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)
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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 Compendia1 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
-
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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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:
- Operating parameters were maintained with the relevant xxx. However,
electronic raw data was not saved.
- According to the Director of Quality Assurance, xxx began saving
electronic raw data just recently at the beginning of February 2006.
However, that was not observed during the 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
-
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
-
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
-
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
- 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
- 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
- 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
- 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
- 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
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:
- 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
- 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
- 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
-
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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- (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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
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
- 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
- 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
- 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
- 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
- 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.