Observation 1
Failure to maintain complete data derived
from all laboratory tests conducted to ensure compliance with established
specifications and standards
The firm inspected
lacked accurate raw laboratory data records for batches of API that were
shipped. The inspection revealed that batch samples were retested until
acceptable results were obtained. In addition, Quality Control (QC) laboratory
failed to include complete data on QC testing sheets. Failing or otherwise
atypical results were not included in the official laboratory control records,
not reported, and not investigated.
According to
laboratory analysts interviewed by FDA during the inspection, the common
practice followed was to complete the analysis and to record the sample
preparation data only if the results were acceptable. If the results obtained
were atypical, a fresh sample was to be prepared and analyzed. The original
sample testing was not recorded.
Investigations
performed by FDA during the inspection conveyed a general lack of reliability
and accuracy of data generated by the firm's laboratory, which is a serious
cGMP deficiency that raised concern on the integrity of all data generated.
Outcome - FDA was very concerned that the firm's laboratory allowed the practice of
retesting for several methods without appropriate documentation, justification,
and investigation. Hence FDA strongly advised investigating these data
integrity issues and identify the extent these practices were followed in the
laboratory and manufacturing operations as part of a comprehensive data
integrity audit. In the response to follow, FDA asked to provide copies of the
procedures in place that set forth the requirements to review and preserve
complete data generated from these operations.
Observation 2
Failure to investigate and document
out-of-specifications results
The firm had failed
to investigate unknown peaks found during HPLC testing for related compounds of
API. A reviewer of the raw data had reported on the “finished product report
review data” worksheet that unknown peaks were observed due to vial
contamination. The electronic records indicate that the first analysis
performed failed the specification limit for both any single unknown impurity.
These OOS results were not reported or adequately investigated, and the raw
data was discarded. The sample was reanalyzed at which time it met
specifications and the results were recorded. According to a laboratory
analyst, the sample preparation printout corresponding to the initial testing
was destroyed.
Investigation of
the data from one of the firm's software (LIMS) identified instances where
additional testing was performed but not properly documented in laboratory
records. This investigation was limited in scope to only a short timeframe and to
only one type of laboratory instrumentation, HPLC. During FDA’s inspection, the
QC manager explained that the scope of the risk assessment was limited only to
that particular month because he was busy with other laboratory
responsibilities. According to the firm's response to the Form FDA 483, some of
the corrective actions implemented as a result of this investigation include:
retraining of QC analysts, revision of the laboratory incident investigations
SOP, and enhancements to the documentation and sample handling practices. As
failures to investigate and document OOS results have persisted, it is clear
that the corrective actions were not sufficient.
The firm's
management had failed to prevent the practices of product sample retesting
without investigation, and rewriting and/or omission of original CGMP records
persisted without the implementation of controls to prevent data manipulation.
The firm’s response to the Form FDA 483 acknowledged the deficiencies regarding
data integrity observed during this inspection. Nevertheless, the firm’s health
hazard evaluation “Drug Safety Analysis” conducted in response to the Form FDA
483 concluded that there was no effect on product quality or patient safety.
However, this evaluation was based on unreliable and incomplete data, as
undesired records appear to be excluded.
Outcome - In response to the warning letter, the firm was asked to provide
documentation of all corrective actions taken to address these failures to
initiate investigations as required by the firm's procedures and determine root
cause(s) of OOS results. The failure to perform adequate investigations was
awarded as a repeat observation reported to the facility.
OBSERVATION 3
Failure to include adequate documentation
during compliant investigation
The firm had failed
to investigate failing assay results. The original investigation, approved on
29 March 2013 indicated that the complaint was received on February 26, 2013.
During the review of that investigation, the investigators found a test record
from January 8, 2013 (prior to the date of documented receiving the complaint)
that reported failing HPLC assay results of the retain sample of batch (X).
This record was not included in the investigation report.
The firm’s response
acknowledges that the assay result for the retain sample was omitted, but also
claims additional investigations are ongoing and that preventive and corrective
actions will be implemented as appropriate. However, the response to the previous
2010 inspectional findings included a similar corrective action plan regarding
OOS, deviations, stability, product complaint and CAPA investigations. In this
plan, the firm committed “to address this omission and provide assurances that
the scope and detail related to future investigations is appropriately
documented … to ensure consistent consideration for failure investigations.
Outcome : Evidence should be provided supporting the additional investigation
conducted and the corrective actions implemented to prevent the omission of
data. Provide records of all complaints relating to the APIs, including
returned API and the disposition of each returned batch. Discuss the expansion
of your investigation to other batches and APIs that could be affected by failing
assay results. Furthermore, explain the failure of firm’s complaint system and
how it going to implement proper
management oversight to ensure adequate corrections to this deficiency.
Observation 4
Failure to record activities at the time
they performed
The firm had failed
to record the data on cGMP document at the time the activity is performed. Data
related to laboratory testing had been recorded days after the testing was
performed. The secondary reviewer of these data points had marked the listings
as corrected and this in turn implied that the data was not recorded
contemporaneously.
Though the firm had
procedures in place to control quality and despite the fact that they had
re-trained personnel on it, US FDA had expressed concern over the credibility
and capability of the document. This is because US FDA had observed instances
of data that was back-dated.
The inspection
revealed that the firm selectively omitted cGMP records directly related to
testing and manufacturing of products. The observations in this context
directly question the accuracy and completeness of the data recorded.
Outcome: US FDA
advised implementing adequate controls and systems to prevent omission,
manipulation of laboratory data as critical responsibility. They also advised
that the plan should also ensure that controls are put in place to prevent
unauthorized changes to existing data. Any changes to the data should occur
with strict accordance with approved established procedures, with date of
change and identity of the person who made the change and the explanation or
the reason for change should also recorded. Also as a corrective action,
training is imparted to all the managers, supervisors, quality unit personnel
in detecting lacunae related to doubts in integrity and/or manipulation of
data.
Observation 5
The
firm had failed to maintain written production, control, or distribution
records specifically associated with a batch of a drug product for at least one
year after the expiration date of the batch
During the
inspection, the investigators found approximately 10 waste bags in the facility
that contained torn or partially destroyed raw data CGMP records related to a
variety of manufacturing activities. Some of the records found in these waste
bags included the following:
A. A
calibration check record for balance was torn and partially destroyed.
According to associate interviewed by FDA during the inspection, wrong weights
were used for calibration. Recalibration of the balance was performed with new
documentation, and subsequently discarded the original record. Furthermore,
auditors learned that additional original calibration records of other balances
had similarly been discarded.
B. Six
corrective action and preventive action (CAPA) records) were torn. According to
Senior QA officer interviewed by FDA during the inspection, these forms were
used for extending the due date of an ongoing CAPA. Inspection team compared the discarded
records to the official records and identified corresponding official copies of
only three of the records. The three other discarded records did not have an
official corresponding copy. During the
inspection, the firm could not produce official records of the corrective
actions described in these three partially destroyed documents.
C. Five completed preventive maintenance
forms were torn. According to staff member interviewed by FDA during the
inspection he mistakenly tore and destroyed these original records.
D. Investigations performed by FDA
during the inspection conveyed a general lack of basic oversight by operations,
quality unit, and site managers, as rewriting and destruction of original CGMP
records was allowed to persist over a significant period without implementation
of systems and controls to prevent data manipulation, which is a serious CGMP
deficiency that raised concern on the integrity of all records generated.
OUTCOME: FDA was very
concerned that the firm allowed the practice of destruction of original records
without appropriate documentation, justification, and investigation. In the
response to follow, FDA asked to provide:
• Third party auditor’s report of
the investigation of the data integrity practices associated with Firm’s CGMP
records along with a list of all records that Firm’s employees rewrote,
destroyed, or altered in any way.
• The root cause of the firm’s
failure to control and detect the manipulation, alteration, or premature
destruction of CGMP records and describe systemic actions to prevent
recurrence.
• Copies of procedures to manage and retain all CGMP
records.
• The list of all the batches of
drug products shipped to the U.S. market that relied upon missing, inaccurate,
or unreliable records.
OBSERVATION 6
Failure
to prepare batch production and control records for each batch of drug
product that include documentation of each significant step in the manufacture,
processing, packaging, or holding of the batch
A. The inspection revealed “unofficial”
visual inspection records, signed by production personnel, with data that is
different from the official batch records reviewed by the firm’s quality
unit. The unofficial record completed by
production personnel showed 200 units failing to meet specifications.
Production personnel later completed the official batch record for this batch,
showing only 18 units as having been rejected. During the inspection, the firm
was unable to demonstrate that all units with quality defects were in fact
rejected.
The firm’s response
states that, in many cases, production personnel add extra units and lower the
number of rejected units on the official paperwork to account for these extra
units. This explanation is unacceptable for several reasons, including that
this practice does not accurately represent the number of units with quality
defects present in each batch in the official batch records, it obscures the
number of rejected units in any given batch, and it misrepresents the number of
units sterilized during each batch. The firm’s response states that they have
audited a random selection of 848 batch records and found a difference between
unofficial and official records in 2.5% of instances. However, during the
inspection, investigators found discrepancies between official and unofficial
records in 76 of 156 batches reviewed. The Firm’s response does not include an
explanation as to the differences between internal audit results and FDA
inspectional findings.
B. The inspection revealed use of
scratch paper containing critical manufacturing data. The data on these scratch
paper records did not always match the data on the corresponding official batch
records, as in the case for the amount of raw materials added to Batch.
Although the firm stated that this batch was destroyed on October 18, 2013, the
investigators observed that firm’s records showed that the batch was removed
from quarantine on October 25, 2013.
The firm’s response
to this finding does not explain why production personnel used scratch paper
for documenting CGMP-relevant data. In addition, the discrepancy between
destruction records and the quarantine records provide further evidence that
the firm’s documentation is not accurate and reliable. The use of unofficial
and scratch paper records is not acceptable with CGMP.
C. Employees interviewed during the
inspection admitted that the firm recorded activities in batch records that
were not performed. Specifically, the
firm’s head of production reported to our investigator that he completes “in
process quality assurance check” fields in the batch record but does not
actually perform the listed operations.
OBSERVATION 7
Failure
to maintain adequate written records of major equipment maintenance
FDA investigators
identified two maintenance logbooks that included multiple entries describing
significant equipment malfunctions, but for which no investigation into the
potential effect on product quality was performed. In addition, the firm’s
records do not always include information on repairs following these
malfunctions. For instance, no maintenance actions or product impact
investigations were recorded for out-of-limit findings during equipment
calibration. In other cases, the firm determined that there was no product
impact without justification. In addition, auditors noted that ten serialized
entries had been torn out of the logbooks. The firm’s staff could not locate
these records during the inspection and reported to FDA investigator that the entries
had likely been destroyed.
OUTCOME : FDA requested the firm to hire a
third party auditor, with experience in detecting data integrity problems, to
assist the firm with this evaluation and assist in overall compliance with
CGMP. It is the responsibility of the firm to ensure that data generated during
operations is accurate and that the results reported are a true representation
of the quality of the firm’s drug products. In addition FDA requested,
(a) To provide an updated assessment of
the extent of the differences between unofficial and official records used at
the facility.
• To describe controls in place to
prevent data manipulation by your operators and supervisors.
• To Interview current and former
employees to identify activities, systems, procedures, and management behaviors
that may have resulted in or contributed to inaccurate data reporting in CGMP
records.
(b) To provide assurance that the use of
unofficial and scratch paper records has been discontinued and describe how the
firm will prevent this practice in the future.
• Also describe the procedure to
assure that all CGMP-related operations are documented at the time of
occurrence.
• Identify all instances in which
unofficial and scratch paper records have been used in the manufacturing and
laboratory facilities and assess the possibility of misrepresentation of data
on official records in each case.
(c) To describe firm’s investigation for
batch record entries, outlining the efforts to determine the scope of data
falsification within batch records and also the corrective and preventive
actions.
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