FDA Warning Letters, Form 483 Observations, Establishment Inspection
Reports
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FDA waning letters, 483 inspectional observations, FDA and other official
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Important: Warning letters should be interpreted in the context of full
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include good advice from the FDA not mentioned in the extract
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 cornpendial 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-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-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
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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 o