Questions and Answers on
Current Good Manufacturing Practices,
Good Guidance Practices, Level 2 Guidance
Packaging and Labeling Control
-
Do
CGMPs require that forced degradation studies always be
conducted of the drug product when determining if a drug
product stability test method is stability-indicating?
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Can
containers, closures, and packaging materials be sampled for
receipt examination in the warehouse?
1. Do CGMPs
require that forced degradation studies always be conducted of the
drug product when determining if a drug product stability test method
is stability-indicating?
No. Drug product stress
testing (forced degradation) may not be necessary when the routes of
degradation and the suitability of the analytical procedures can be
determined through use of the following:
-
data from
stress testing of drug substance
-
reference
materials for process impurities and degradants
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data from
accelerated and long-term studies on drug substance
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data from
accelerated and long-term studies on drug product
Additional supportive
information on the specificity of the analytical methods and on
degradation pathways of the drug substance may be available from
literature sources.
Section 211.165(e) of the
CGMP regulations states that the accuracy, sensitivity, specificity,
and reproducibility of test methods shall be established and
documented. Further, section 211.166(a)(3) requires that stability
test methods be reliable, meaningful, and specific, which means that
the content of active ingredient, degradation products, and other
components of interest in a drug product can be accurately measured
without interference, often called "stability-indicating."
The CGMP regulations do not
specify what techniques or tests are to be used to ensure that one’s
test methods are stability-indicating. However, evaluating the
specificity of the test methods during forced degradation studies
(i.e., exposing drug to extremes of pH, temperature, oxygen, etc.) of
drug substance and drug product often is necessary to ensure that
stability test methods are stability-indicating. But in certain
circumstances conducting a forced degradation study of just the drug
substance may be sufficient to evaluate the stability-indicating
properties of a test method.
Generally, in determining
whether it is necessary to conduct forced degradation studies of the
drug product, the specificity of the test method should be evaluated
for its ability to assay drug substance, degradants, and impurities,
in the presence of each other, without interference. The evaluation
also should provide assurance that there is not a potential for
interaction between drug substance, degradants, impurities, excipients,
and container-closure system during the course of the shelf-life of
the finished drug product.
Last, the rationale for any
decision made concerning the extent of the forced degradation studies
conducted as well as the rationale for concluding that a test method
is stability-indicating should be fully documented.
References:
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21 CFR
211.137: Expiration dating
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21 CFR
211.165(e): Testing and release for distribution
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21 CFR
211.166(a)(3): Stability testing
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Compliance Policy Guide, Section 480.100 (7132a.04), Requirements
for Expiration Dating and Stability Testing
Contact for further
information:
Barry Rothman, CDER
rothmanb@cder.fda.gov
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2. Can
containers, closures, and packaging materials be sampled for receipt
examination in the warehouse?
Yes. Generally, we believe
that sampling in a typical drug manufacturing facility warehouse would
not represent a risk to the container/closure or affect the integrity
of the sample results. But whether the act of collecting a sample in
the warehouse violates the CGMPs requirement that containers "be
opened, sampled, and sealed in a manner designed to prevent
contamination of their contents..." will depend on the purported
quality characteristics of the material under sample and the warehouse
environment. For container/closures purporting to be sterile or
depyrogenated, sampling should be under conditions equivalent to the
purported quality of the material: a warehouse environment would not
suffice (see 211.94 and 211.113(b)). This is to preserve the fitness
for use of the remaining container/closures as well as ensure sample
integrity, if they are to be examined for microbial contamination. At
a minimum, any sampling should be performed in a manner to limit
exposure to the environment during and after the time samples are
removed (i.e., wiping outside surfaces, limiting time that the
original package is open, and properly resealing original package).
Well-written and followed procedures are the critical elements.
Note that the CGMPs at
211.84 permit a manufacturer to release for use a shipment of
containers/closures based on the supplier's certificate of analysis
and a visual identification of the containers/closures. Once a
supplier's reliability has been established by validation of their
test results, a manufacturer could perform the visual examination
entirely in the warehouse.
References:
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21 CFR
211.84: Testing and approval or rejection of components, drug
product containers, and closures
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21 CFR
211.94: Drug product containers and closures
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21 CFR
211.113(b): Control of microbiological contamination
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21 CFR
211.122: Materials examination and usage criteria
Contact for further
information:
Anthony Charity, CDER
charitya@cder.fda.gov
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cGMP
Date created: August 4, 2004 |