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Questions and Answers on
Current Good Manufacturing Practices,
Good Guidance Practices, Level 2 Guidance
Records
and Reports
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Some
products, such as transdermal patches, are made using
manufacturing processes with higher in-process material reject
rates than for other products and processes. Is this okay?
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Do the CGMP
regulations permit the destruction of an internal quality
assurance audit report once the corrective action has been
completed?
1. Some
products, such as transdermal patches, are made using manufacturing
processes with higher in-process material reject rates than for other
products and processes. Is this okay?
Maybe. It depends on the
cause and consistency of the reject rate. Many transdermal patch
manufacturing processes produce more waste (i.e., lower yield from
theoretical) than other pharmaceutical processes. This should not of
itself be a concern. The waste is usually due to the cumulative
effect of roll splicing, line start-ups and stoppages, roll-stock
changes, and perhaps higher rates of in-process sampling. This is
most pronounced for processes involving lamination of rolls of various
component layers. Roll-stock defects detected during adhesive coating
of the roll, for example, can often only be rejected from the roll
after final fabrication/lamination of the entire patch, which
contributes to the final process waste stream.
We expect that validated
and well-controlled processes will achieve fairly consistent waste
amounts batch-to-batch. Waste in excess of the normal operating rates
may need (see 211.192) to be evaluated to determine cause (e.g., due
to increase in sampling or higher than normal component defects... or
both) and the consequences on product quality assessed. We've seen a
small number of cases where unusually high intra-batch rejects/losses
were due to excessive component quality variability and poorly
developed processes.
References:
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21 CFR
211.100: Written procedures; deviations
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21 CFR
211.103: Calculation of yield
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21 CFR
211.110: Sampling and testing of in-process materials and drug
products
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21 CFR
211.192: Production record review
Contact for further
information:
Brian Hasselbalch, CDER
hasselbalchb@cder.fda.gov
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2. Do
the CGMP
regulations permit the destruction of an internal quality
assurance audit report once the corrective action has been
completed?
The CGMP regulations (21
CFR 210 and 211) for finished pharmaceutical manufacturing do not
specifically address the requirement to conduct, or to keep records
of, internal quality assurance audits. If the report in question were
from a routine audit to verify that the firm's quality system is
operating as intended, then it would be acceptable if the firm elected
to discard the report once all corrections have been verified.
However, any documentation
of corrective action as a result of such an audit would have to be
retained (see 211.180 and 211.188). For example, if a routine
internal audit finds a problem with a mixing step and the outcome is a
change in mixing time, all affected procedures, including the master
production record, are to reflect the necessary changes, and such
records are subject to FDA inspection as usual. Any investigation
into the impact this problem had on related batches is to be retained
and also made available for inspection by FDA (see 211.192).
In addition, any reports of
investigations or evaluations prepared in response to, for example, a
product complaint (211.198), vendor qualification (211.84), periodic
review of records and data (211.180(e)), and a failure investigation
(211.192) are not internal audits as discussed above. Such records
are subject to FDA inspection and must be retained for at least the
time specified in the CGMP regulations (see 211.180).
References:
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Preamble
to the Current Good Manufacturing Practice in Manufacturing,
Processing, Packing, or Holding regulations; Federal Register,
September 29, 1978 (vol. 43, no. 190), page 45015, paragraph 4
http://www.fda.gov/cder/dmpq
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21 CFR
211.84: Testing and approval/rejection of components, drug product
containers, and closures
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21 CFR
211.180: General requirements
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21 CFR
211.192: Production record review
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21 CFR
211.198: Complaint files
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Compliance Policy Guide Sec. 130-300, (7151.02)
http://www.fda.gov/ora/compliance_ref/cpg/cpggenl/cpg130-300.html
Contact for further
information:
Rosa Motta, CDER
mottar@cder.fda.gov
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cGMP
Date created: August 4, 2004 |
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