This warning letter summarizes
significant violations of current good manufacturing practice (cGMP)
regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.
Because of methods, facilities, or
controls for manufacturing, processing, packing, or holding do not conform to
CGMP, your drug products are adulterated within the meaning of section
501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21
U.S.C. 351(a)(2)(B).
We reviewed your (Mylan) October 5,
2016, response in detail and acknowledge receipt of your subsequent
correspondence.
During our inspection, our investigator
observed specific violations including, but not limited to, the following.
1. Your
firm failed to thoroughly investigate any unexplained discrepancy or failure of
a batch or any of its components to meet any of its specifications, whether or
not the batch has already been distributed (21 CFR 211.192).
From January 1 to June 30, 2016, your
firm invalidated 101 out of 139 (about 72 percent) initial out-of-specification
(OOS) assay results without sufficient investigation to determine the root
cause of the initial failure.
For example, you opened laboratory
investigation report PR 908027 for an initial OOS six-month stability assay
result of (b)(4) percent (specification (b)(4)–(b)(4) percent)
for (b)(4) mg tablets, lot (b)(4). You invalidated
the initial failing result without adequate investigation, performed
re-testing, and then reported the (b)(4) results of these
replicate re-tests ((b)(4) percent). Your investigation did not
reach an assignable cause, nor did you take appropriate corrective actions and
preventive actions to ensure that the significant “analytical bias” to which
you ultimately attributed the initial failure would not affect other analytical
work in your laboratory.
In your response, you state that
laboratory decisions are to be made on the basis of scientific evaluation, and
that they are to determine whether OOS laboratory results are the result of the
laboratory process or the manufacturing process. However, in the example above,
your investigation assumed “analytical bias” in your laboratory process but
failed to determine how this apparently significant error in your analyses
could be eliminated or mitigated in the future.
Your response is inadequate because you
failed to implement a corrective action and preventive action (CAPA) plan to
mitigate errors that you attribute to laboratory process. Further, you did not
include these improperly invalidated OOS results in your analysis of laboratory
investigation trends. According to your Laboratory Investigation Report procedure
MLLNSK-SOP-QA-GMP-0138, version 6, only “confirmed” root causes are to be
identified and trended in laboratory investigation reports. Because your
laboratory investigations frequently invalidate initial failures without cause,
your laboratory trending excludes a large proportion of data that would
otherwise alert you to problems in your laboratory system. Failure to
identify trends in OOS investigations is a repeat observation from the previous
FDA inspection, March 19 to 26, 2015.
In response to this letter, conduct and
provide the results of a trend analysis of all your OOS results that includes
both “confirmed” root causes and the initial OOS results that you have
previously excluded as invalid without assignable root causes. For each
invalidated result, indicate the product tested, date of analysis, type of
analysis, purpose of the test, original result, retest results, and your
unconfirmed assignable root cause. Revise and provide your updated Laboratory
Investigation Report procedure. Specify how your revised procedure
ensures that all OOS investigations are included in your trending.
2. Your
firm failed to establish an adequate quality control unit with the authority to
review production records to assure that no errors have occurred or, if errors
have occurred, that they have been fully investigated (21 CFR 211.22(a)).
Your quality unit failed to monitor and
investigate error signals generated by the computerized systems that you use
for high performance liquid chromatography and gas chromatography. These
signals indicated the loss or deletion of original CGMP analytical data.
However, your quality unit did not comprehensively address the error signals or
determine the scope or impact of lost or deleted data until after these
problems were reviewed during our inspection.
For example, our investigator reviewed
audit trails from August 2016 assay testing on (b)(4) batch (b)(4) and
dissolution testing for (b)(4) tablets batch (b)(4).
The audit trail for these tests included the message, “deleted result set,” but
neither of these two incidents were recorded in the analytical packages for
these batches of drug products, nor were they reviewed or investigated by the
quality unit.
In addition, during the inspection, our
investigator observed that your Empower 3 system audit trail displayed many
instances of a “Project Integrity Failed” message, which indicates that
injections were missing from the results of analytical testing. For example, in (b)(4) analysis
for (b)(4) tablets batch (b)(4) conducted on
June 20, 2016, no chromatogram was rendered for the initial run of testing. The
data package for this testing clearly shows that the initial run is missing,
but your quality unit did not investigate the incident.
Although you showed our investigator
isolated examples of interrupted, missing, deleted, and lost data for which you
had opened investigations, you reached similar conclusions in many of these
investigations regarding the root cause of your loss of data integrity but
failed to take appropriate corrective action and preventive action in response.
Our investigator observed that you attributed numerous incidents to power
interruptions, connectivity problems (disconnection of the Ethernet or power
cord), and instrument malfunctions. You could not explain why these events
occurred with frequency in your laboratory, nor had you undertaken a
comprehensive investigation into the problem or sought to correct it and
prevent its recurrence.
In your written response dated February
17, 2017, you identified seven samples from a single week of testing for which
original results were lost following data acquisition interruptions at the time
of initial analysis. Instead of uniformly initiating an investigation into the
root cause of each interruption when it occurred or even documenting it for
later review and investigation by the quality unit, you explained in your
response that you retested the samples immediately after the interruptions.
Your response is inadequate because you
have not identified and investigated each instance in which data acquisition
was interrupted. While you assessed a limited number of error codes from a
seven day period, you did not evaluate the effects of other error codes
identified in your simulation exercise report on the reliability, accuracy, or
completeness of the data you use to evaluate the quality of your drugs.
Although you have submitted multiple responses, you have not yet:
·
shown exactly how widespread these problems are;
·
evaluated their full effects on the quality of your drugs;
·
explained why these events occurred with frequency in your laboratory;
·
or demonstrated how you will ensure that your quality unit reviews,
investigates, and acts upon codes that affect the reliability of your CGMP
data.
In response to this letter, provide your
validation of laboratory instrument error codes. Identify the specific codes
that may impact product quality and the reliability of CGMP data, and provide
your procedures to demonstrate how your quality unit will review, investigate,
and respond to these specific codes.
Data Integrity Remediation
Your quality system does not adequately
ensure the accuracy and integrity of data to support the safety, effectiveness,
and quality of the drugs you manufacture. We acknowledge that you are using a
consultant to audit your operation and assist in meeting FDA requirements. In
response to this letter, provide the following.
A. A
comprehensive investigation into the extent of the inaccuracies in data records
and reporting. Your investigation should include:
·
A detailed investigation protocol and methodology; a summary of all
laboratories, manufacturing operations, and systems to be covered by the
assessment; and a justification for any part of your operation that you propose
to exclude.
·
An assessment of the extent of data integrity deficiencies at your
facility. Identify omissions, alterations, deletions, record destruction,
non-contemporaneous record completion, and other deficiencies. Describe all
parts of your facility’s operations in which you discovered data integrity
lapses.
·
A comprehensive retrospective evaluation of the nature of the testing
data integrity deficiencies.
B. A current risk
assessment of the potential effects of the observed failures on the quality of
your drugs. Your assessment should include analyses of the risks to
patients caused by the release of drugs affected by a lapse of data integrity,
and risks posed by ongoing operations.
C. A management
strategy for your firm that includes the details of your global corrective
action and preventive action plan. Your strategy should include:
·
A detailed corrective action plan that describes how you intend to
ensure the reliability and completeness of all of the data you generate,
including analytical data, manufacturing records, and all data submitted to
FDA.
·
A comprehensive description of the root causes of your data integrity
lapses, including evidence that the scope and depth of the current action plan
is commensurate with the findings of the investigation and risk assessment.
Conclusion
·
Violations cited in this letter are not intended as an all-inclusive
list. You are responsible for investigating these violations, for determining
the causes, for preventing their recurrence, and for preventing other
violations. More details click here…
GMP News, GMP guidelines, GMP Violations, GMP warnings, GMP Trends. A Public Health Global News Portal. (This story has not been edited by GMP Violations staff and is auto-generated from a syndicated feed/ experts experiences sharing.) Disclaimer: The Logos/Images & content posted here are belongs to respective to Authority / owners of firm. The Article posted under public health importance news. Please ensure the guideline as per Regulatory agencies.
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