During its inspections, the FDA has been observing insufficient
data integrity quite often in the Far East. Now, European production sites are
not always exemplary. A Warning Letter recently published for the Czech Company
Interpharm Praha describes considerable deficiencies in the area of quality
control with regard to API and finished products testing.
Basically, the personnel of the analytical laboratory had full
access to the data processing of the HPLC- system. Accordingly, the possibility
to delete data, to integrate peak areas "by hand" and to eliminate or
add samples from sequences was used extensively.
These manipulations were
visibly clear in the audit trail: among the round 9,000 entries, more than
5,000 actions were traced as data deletion, manual integration of peaks, etc.
At the FDA inspectors' request, the employees of the laboratory indicated that
such actions are common.
One of the reasons why data had been beautified in such a way is
also due to the fact the chromatographic system was not able to execute correct
integration of peak areas. The FDA inspector identified partly incomplete or
missing integrations of peaks and concluded that the system was wholly
inadequate for the purpose. Batch release decisions were thus based on
incomplete data, which is a grave GMP-deficiency.
At the end of the Warning Letter, a list of measures is included
for the company to fulfil if it still wants to distribute its products on the
US American market.
Finished
Product Violations
1. Your
firm failed to exercise appropriate controls over computer or related systems
to assure that only authorized personnel institute changes in master production
and control records or other records (21 CFR 211.68(b)).
For
example, our investigator reviewed an audit trail for impurities testing
conducted on (b)(4) validation lot (b)(4), number (b)(4) vial
# (b)(4), Injections 1 and 2. The audit trail revealed many deleted
results and manual integrations.
As
discussed above, deleted and altered analytical test results mean that your
quality unit is presented with incomplete and inaccurate information about the
quality of your drugs.
2. Your
firm failed to establish laboratory controls that include scientifically sound
and appropriate specifications, standards, sampling plans, and test procedures
designed to assure that components, drug product containers, closures,
in-process materials, labeling, and drug products conform to appropriate
standards of identity, strength, quality, and purity (21 CFR 211.160(b)).
Your
laboratory procedures allowed analysts to modify and delete chromatographic
results without adequate justification, and to use manual integration in
uncontrolled circumstances.
For
example, our investigator found results deleted after repeated manual
integrations for (b)(4) stability lots (b)(4).
Unjustified, repeated manual integrations and deletions indicate that your
laboratory controls are not scientifically sound and appropriate to test your
products.
In your
response to this letter, describe all steps you will take to ensure that
appropriate laboratory controls have been implemented to support product
quality review and batch release decisions. Include the controls you will
implement for the modification, deletion, and manual integration of
chromatographic test results.
Data
Integrity Remediation
Your
quality system does not adequately ensure the adequacy and integrity of data to
support the safety, effectiveness, and quality of drugs you manufacture. We
strongly recommend that you retain a qualified consultant to assist in your
remediation.
In
response to this letter, provide the following.
A.
A comprehensive investigation into the extent of the inaccuracies in data,
records, and reporting. Your investigation should include:
·
A detailed investigation
protocol and methodology; a summary of all laboratories, manufacturing
operations, and systems to be covered by the assessment; and justification for
any part of your operation that you propose to exclude.
·
Interviews of current and
former employees to identify the nature, scope, and root cause of data
inaccuracies. We recommend that these interviews be conducted by a qualified
third party.
·
An assessment of the
extent of data integrity deficiencies at your facility. Identify omissions,
alterations, deletions, record destruction, non-contemporaneous record
completion, and other deficiencies. Describe all parts of your facility's
operations in which you discovered data integrity lapses.
·
A comprehensive
retrospective evaluation of the nature of your data integrity deficiencies.
·
We recommend that a
qualified third party with specific expertise in the area where potential
lapses were identified should evaluate all data integrity lapses.
B.
A current risk assessment of the potential effect 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 in data
integrity, and risks posed by ongoing operations.
C.
A management strategy that includes the details of your global corrective
action and preventive action plan. Your strategy should include:
·
The 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 the FDA.
·
A comprehensive
description of the root causes of your data integrity lapses, including
evidence that the scope and depth of the current action plan is commensurate
with the findings of the investigation and risk assessment. Indicate whether
individuals responsible for data integrity lapses remain able to influence
CGMP-related or drug application data at your firm.
·
Interim measures
describing the actions you have taken or will take to protect patients and to
ensure the quality of your drugs, such as notifying your customers, recalling
product, conducting additional testing, adding lots to your stability programs
to assure stability, drug application actions, and enhanced complaint
monitoring.
·
Long-term measures
describing any remediation efforts and enhancements to procedures, processes,
methods, controls, systems, management oversight, and human resources (e.g.,
training, staffing improvements) designed to ensure the integrity of your data.
·
A status report for any
of the above activities already underway or completed.
www.gmpviolations.com
(This story has not been edited by GMP Violations staff and is auto-generated from a syndicated feed.)
Disclaimer: The Logos/Images posted here are belongs to respective to Authority / owners of firm.
Posts
