Questions and Answers on
Current Good Manufacturing Practices,
Good Guidance Practices, Level 2 Guidance
Laboratory Controls
-
Many leading analytical balance manufacturers provide built-in "auto
calibration" features in their balances. Are such auto-calibration
procedures acceptable instead of external performance checks? If
not, then what should the schedule for calibration be?
Answer
-
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?
Answer
-
When
performing the USP <788> Particulate Matter in Injections test for a
Large Volume Parenteral (LVP), is it acceptable to take the average
among the units tested to determine if the batch meets its
specification for this attribute?
Answer
-
Can Total Organic Carbon
(TOC) be an acceptable method for detecting residues of contaminants
in evaluating cleaning effectiveness?
Answer
-
Would a
paramagnetic or laser oxygen analyzer be able to detect all possible
contaminants or impurities in a medical gas?
Answer
-
Can up to twelve month expiration-dating be assigned to oral solid
and liquid dosage forms repackaged into unit-dose containers based
on guidance in the May 2005 draft revision of Compliance Policy
Guide, Section 480.200 (7132b.11), “Expiration Dating of Unit Dose
Repackaged Drugs”? Answer
1.
Many leading analytical balance manufacturers provide built-in "auto
calibration" features in their balances. Are such auto-calibration
procedures acceptable instead of external performance checks? If
not, then what should the schedule for calibration be?
The auto-calibration
feature of a balance may not be relied upon to the exclusion of an
external performance check (211.68). For a scale with a built-in
auto-calibrator, we recommend that external performance checks be
performed on a periodic basis, but less frequently as compared to a
scale without this feature. The frequency of performance checks
depends on the frequency of use of the scale and the criticality and
tolerance of the process or analytical step. Note that all batches
of a product manufactured between two successive verifications would
be affected should the check of the auto-calibrator reveal a
problem. Additionally, the calibration of an auto-calibrator should
be periodically verified--a common frequency is once a year--using
National Institute of Standards and Technology (NIST)-traceable
standards or NIST-accredited standards in use in other countries.
References:
-
21 CFR
211.68: Automatic, mechanical, and electronic equipment
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21 CFR
211.160(b)(4): General requirements (Lab Controls)
-
USP
Chapter <41> Weights and Balances
-
See
also: ASTM standard E 617: Standard Specification for Laboratory
Weights and Precision Mass Standards (this standard is incorporated
into the USP by reference; other widely recognized standards may be
acceptable)
Contact for further
information:
Mike
Gavini, CDER
mural.gavini@fda.hhs.gov
2. 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
-
data from
accelerated and long-term studies on drug substance
-
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
-
Compliance Policy Guide, Section 480.100 (7132a.04), Requirements
for Expiration Dating and Stability Testing
Contact for further
information:
Barry Rothman, CDER
barry.rothman@fda.hhs.gov
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3. When
performing the USP <788> Particulate Matter in Injections test for a
Large Volume Parenteral (LVP), is it acceptable to take the average
among the units tested to determine if the batch meets its
specification for this attribute?
No. It is not acceptable
to take the average among the LVP units tested in each batch/lot when
following this method because the purpose of this method is to measure
and limit intra-batch variability.
"Particulate matter" refers
to small, sub-visible particles. USP <788> provides two tests for
detecting such particulates--light obscuration and microscopic assay.
Both are generally accepted for use in testing LVPs and small volume
parenterals (SVP) for the determination of sub-visible particulate
matter. Normally, samples are first tested by the light obscuration
method; if the sample fails the specified limits, the microscopic
assay method can then be used. However, the microscopic method can be
the sole test if there is a documented technical reason or
interference from the product under test that would make the light
obscuration method unsuitable or the results invalid.
Confusion about when
averaging data is and is not acceptable is probably due to the sample
preparation method for the light obscuration test (USP <788>). At
least 2, 5-mL aliquots from each sampled unit or the pooled sample
(see below) are to be used in the particulate count determination, and
the results from these aliquots are to be averaged for comparison with
the specification. Note that the average is of the results from
examining each aliquot and not between units. (The results of the
first aliquot examined by light obscuration are to be discarded, and
the subsequent aliquots--2 or more--are retained.) Pooling units prior
to analysis is permitted only if the volume in each unit is less than
25 mL, in which case 10 or more units may be pooled. If the volume in
the SVP or LVP is 25 mL or more per unit, single units are to be
examined by this method (USP <788>).
Results among the
test units cannot be averaged because particulate matter is assumed to
be non-uniformly dispersed throughout the lot. The intent of
assessing results from each individual unit is to ensure adequate
representation of the lot and to detect potential variation within a
lot.
As to the number of
individual units to be tested for LVP and SVP units having a volume of
25mL or more, the USP states that the number of units tested depends
on "statistically sound sampling plans," and "sampling plans should be
based on consideration of product volume, numbers of particles
historically found to be present in comparison to limits, particle
size distribution of particles present, and variability of particle
counts between units." The USP also suggests that the total number of
units tested for any given batch may be less than 10 units (for LVP
and pooled SVPs) with proper justification. This is consistent with
the CGMP requirement for statistical sampling plans (see 211.165).
Reference:
-
21 CFR
211.160: General requirements (laboratory controls)
-
21 CFR
211.165(c),(d): Testing and release for distribution
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USP <788>
Particulate Matter in Injections
-
For
information only: Draft Guidance: Guidance for Industry:
Investigating Out of Specification (OOS) Test Results for
Pharmaceutical Production
Contact for further
information:
Brenda Uratani, CDER
brenda.uratani@fda.hhs.gov
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4. Can Total Organic Carbon
(TOC) be an acceptable method for detecting residues of contaminants
in evaluating cleaning effectiveness?
Yes. Since the publication
of the inspection guide on cleaning validation in 1993, a number of
studies have been published to demonstrate the adequacy of TOC in
measuring contaminant residues.
We think TOC or TC can be
an acceptable method for monitoring residues routinely and for
cleaning validation. But in order for TOC to be functionally suitable,
it should first be established that a substantial amount of the
contaminating material(s) is organic and contains carbon that can be
oxidized under TOC test conditions. This is not a trivial exercise
because we know that some organic compounds cannot be reliably
detected using TOC.
TOC use may be justified
for direct surface sample testing as well as indirect (rinse water)
sample testing. In either case, because TOC does not identify or
distinguish among different compounds containing oxidizable carbon,
any detected carbon is to be attributed to the target compound(s) for
comparing with the established limit. Thus, a firm should limit
'background' carbon (i.e., carbon from sources other than the
contaminant being removed) as much as possible. The established
limit, or the amount of residue detected for comparison to the
specification, should correct for the target material's composition of
carbon. As for any cleaning method, recovery studies are necessary
(211.160(b)). If TOC samples are being held for long periods of time
before analysis, a firm should verify the impact of sample holding
time on accuracy and limit of quantitation.
References:
-
21 CFR
211.67: Equipment cleaning and maintenance.
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21 CFR
211.160(b): General requirements (Laboratory Controls)
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USP <643>
Total Organic Carbon
-
Guide
to Inspections of Cleaning Validation, 1993
Contact for further information:
Abi
D'Sa, CDER
albinus.dsa@fda.hhs.gov
Brian
Hasselbalch, CDER
brian.hasselbalch@fda.hhs.gov
5. Would a
paramagnetic or laser oxygen analyzer be able to detect all possible
contaminants or impurities in a medical gas?
No. Although, paramagnetic
and laser oxygen analyzers are very accurate and reliable when
calibrated correctly, these types of analyzers can only detect the
identification and strength of oxygen. They are unable to detect
contaminants or impurities that may be present, such as hydrocarbons
or arsenic compounds. According to the USP General Notices, Foreign
Substances and Impurities section, "it is manifestly impossible to
include in each monograph a test for every impurity, contaminant, or
adulterant that might be present." The USP monograph test for oxygen
does not include an impurity screen and other analyzers may need to be
used. For example, assays for hydrocarbon impurities are routinely
conducted during the oxygen manufacturing process even though the USP
does not list hydrocarbons as an impurity. Also, alternative methods
may be needed to test high-pressure cylinders for cleaning solution
residues.
References:
-
21 CFR
211.160: General requirements (Laboratory Controls)
-
21 CFR
211.165: Testing and release for distribution
-
United
States Pharmacopoeia
Contact for further
information:
Duane Sylvia, CDER
duane.sylvia@fda.hhs.gov
6. Can up to twelve month
expiration-dating be assigned to oral solid and liquid dosage forms
repackaged into unit-dose containers based on guidance in the May 2005
draft revision of Compliance Policy Guide, Section 480.200 (7132b.11),
“Expiration Dating of Unit Dose Repackaged Drugs”?
No. In May 2005, a Notice of
Availability of the draft revision of FDA’s Compliance Policy Guide
Section 480.200 (CPG 7132b.11), “Expiration Dating of Unit-Dose
Repackaged Drugs,” was announced in the Federal Register. The draft
CPG specifies certain conditions when it may be possible to assign up
to twelve month expiration-dating to non-sterile solid and liquid oral
drug products repackaged into unit-dose containers without conducting
new stability studies to support the length of expiration-dating on
the repackaged products. The draft CPG was prompted by United States
Pharmacopeia (USP) standards for assigning up to a twelve month
“beyond-use date” to non-sterile solid and liquid oral dosage forms
dispensed in unit-dose containers. (“Beyond-use date” is USP’s
pharmacy dispensing term for specifying a date on a prescription
container beyond which a patient should not use the product.) If
finalized, FDA’s draft CPG would replace the current version of CPG
Section 480.200. The current version of CPG Section 480.200 was
finalized in March 1995 and provides conditions under which FDA will
not initiate action for assigning up to six month expiration dating
for drug products repackaged into unit-dose containers without
conducting new stability studies.
FDA is conducting a stability study of certain commercially repackaged
drugs to determine the suitability of the draft revision of CPG
Section 480.200. Until the stability study is complete and FDA
evaluates all comments submitted to the public docket in response to
the May 2005 Federal Register Notice of Availability, the agency does
not intend to make a final decision on the draft revision of CPG
Section 480.200. Consequently, at this time and until FDA announces a
final decision on the draft CPG, the current CPG Section.480.200,
which was finalized in March 1995, is in effect.
References:
-
Compliance Policy Guide section
480.200 (CPG 7132b.11)
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Federal Register: May 31, 2005
(Volume 70, Number 103) pages 30953-30954
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CFR 211.137 and 211.166
Contact for further information:
Barry Rothman, CDER
barry.rothman@fda.hhs.gov
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Date created: August 4, 2004, updated
September 8, 2006  |
