• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services

Drugs

  • Print
  • Share
  • E-mail

Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances

[Federal Register: December 29, 2000 (Volume 65, Number 251)]

[Notices]              
[Page 83041-83063]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr29de00-84]                        
 
-----------------------------------------------------------------------
 
DEPARTMENT OF HEALTH AND HUMAN SERVICES
 
Food and Drug Administration
 
[Docket No. 97D-0448]
 
International Conference on Harmonisation; Guidance on Q6A
Specifications: Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products: Chemical Substances
 
AGENCY: Food and Drug Administration, HHS.
 
ACTION: Notice.
 
-----------------------------------------------------------------------
 
SUMMARY: The Food and Drug Administration (FDA) is publishing a
guidance entitled ``Q6A Specifications: Test Procedures and Acceptance
Criteria for New Drug Substances and New Drug Products: Chemical
Substances.'' The guidance was prepared under the auspices of the
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH). The guidance
describes or provides recommendations concerning the selection of test
procedures and the setting and justification of acceptance criteria for
new chemical drug substances and new drug products produced from them.
The guidance is intended to assist in the establishment of a single set
of global specifications for new drug substances and new drug products.
 
DATES: Submit written comments by March 29, 2001.
 
ADDRESSES: Submit written comments on the guidance to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852. Copies of the guidance are
available from the Drug Information Branch (HFD-210), Center for Drug
Evaluation and Research, Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857, 301-827-4573.
 
FOR FURTHER INFORMATION CONTACT:
    Regarding the guidance: Eric B. Sheinin, Center for Drug Evaluation
and Research (HFD-003), Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857, 301-594-2847, or Neil D. Goldman, Center for
Biologics Evaluation and Research (HFM-20), Food and Drug
Administration, 1401 Rockville Pike, Rockville, MD 20852, 301-827-0377.
    Regarding the ICH: Janet J. Showalter, Office of Health Affairs
(HFY-20), Food and Drug Administration, 5600 Fishers Lane, Rockville,
MD 20857, 301-827-0864.
 
SUPPLEMENTARY INFORMATION: In recent years, many important initiatives
have been undertaken by regulatory authorities and industry
associations to promote international harmonization of regulatory
requirements. FDA has participated in many meetings designed to enhance
harmonization and is committed to seeking scientifically based
harmonized technical procedures for pharmaceutical development. One of
the goals of harmonization is to identify and then reduce differences
in technical requirements for drug development among regulatory
agencies.
    ICH was organized to provide an opportunity for tripartite
harmonization initiatives to be developed with input from both
regulatory and industry representatives. FDA also seeks input from
consumer representatives and others. ICH is concerned with
harmonization of technical requirements for the registration of
pharmaceutical products among three regions: The European Union, Japan,
and the United States. The six ICH sponsors are the European
Commission, the European Federation of Pharmaceutical Industries
Associations, the Japanese Ministry of Health and Welfare, the Japanese
Pharmaceutical Manufacturers Association, the Centers for Drug
Evaluation and Research and Biologics Evaluation and Research, FDA, and
the Pharmaceutical Research and Manufacturers of America. The ICH
Secretariat, which coordinates the preparation of documentation, is
provided by the International Federation of Pharmaceutical
Manufacturers Associations (IFPMA).
    The ICH Steering Committee includes representatives from each of
the ICH sponsors and the IFPMA, as well as observers from the World
Health Organization, the Canadian Health Protection Branch, and the
European Free Trade Area.
    In the Federal Register of November 25, 1997 (62 FR 62890), FDA
published a draft tripartite guidance entitled ``Q6A Specifications:
Test Procedures and
 
[[Page 83042]]
 
Acceptance Criteria for New Drug Substances and New Drug Products:
Chemical Substances.'' The notice gave interested persons an
opportunity to submit comments by January 26, 1998.
    After consideration of the comments received and revisions to the
guidance, a final draft of the guidance was submitted to the ICH
Steering Committee and endorsed by the three participating regulatory
agencies on October 6, 1999.
    In accordance with FDA's good guidance practices regulation (65 FR
56468, September 19, 2000), this document has been designated a
guidance, rather than a guideline.
    The guidance provides recommendations on the selection of test
procedures and the setting and justification of acceptance criteria for
new drug substances of synthetic chemical origin, and new drug products
produced from them, that have not been registered previously in the
United States, the European Union, or Japan. This guidance is intended
to assist in the establishment of a single set of global specifications
for new drug substances and new drug products.
    This guidance represents the agency's current thinking on the
selection of tests procedures and the setting and justification of
acceptance criteria for new chemical drug substances and new drug
products. It does not create or confer any rights for or on any person
and does not operate to bind FDA or the public. An alternative approach
may be used if such approach satisfies the requirements of the
applicable statutes and regulations.
    Interested persons may submit to the Dockets Management Branch
(address above) written comments on the guidance at any time. Two
copies of any comments are to be submitted, except that individuals may
submit one copy. Comments are to be identified with the docket number
found in brackets in the heading of this document. The guidance and
received comments may be seen in the Dockets Management Branch between
9 a.m. and 4 p.m., Monday through Friday. An electronic version of this
guidance is available on the Internet at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/guidance/index.htm or at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/publications.htm.
    The text of the guidance follows:
 
Q6A Specifications: Test Procedures and Acceptance Criteria for New
Drug Substances and New Drug Products: Chemical Substances \1\
---------------------------------------------------------------------------
 
    \1\ This guidance represents the Food and Drug Administration's
current thinking on this topic. It does not create or confer any
rights for or on any person and does not operate to bind FDA or the
public. An alternative approach may be used if such approach
satisfies the requirements of the applicable statutes and
regulations.
 
Table of Contents
 
1. Introduction
    1.1 Objective of the Guidance
    1.2 Background
    1.3 Scope of the Guidance
2. General Concepts
    2.1 Periodic or Skip Testing
    2.2 Release vs. Shelf-Life Acceptance Criteria
    2.3 In-Process Tests
    2.4 Design and Development Considerations
    2.5 Limited Data Available at Filing
    2.6 Parametric Release
    2.7 Alternative Procedures
    2.8 Pharmacopeial Tests and Acceptance Criteria
    2.9 Evolving Technologies
    2.10 Impact of Drug Substance on Drug Product Specifications
    2.11 Reference Standard
3. Guidance
    3.1 Specifications: Definition and Justification
    3.1.1 Definition of Specifications
    3.1.2 Justification of Specifications
    3.2 Universal Tests/Criteria
    3.2.1 New Drug Substances
    3.2.2 New Drug Products
    3.3 Specific Tests/Criteria
    3.3.1 New Drug Substances
    3.3.2 New Drug Products
4. Glossary
5. References
6. Attachments: Decision Trees #1 Through #8
 
1. Introduction
 
1.1 Objective of the Guidance
 
    This guidance is intended to assist, to the extent possible, in the
establishment of a single set of global specifications for new drug
substances and new drug products. It provides guidance on the setting
and justification of acceptance criteria and the selection of test
procedures for new drug substances of synthetic chemical origin, and
new drug products produced from them, that have not been registered
previously in the United States, the European Union, or Japan.
 
1.2 Background
 
    A specification is defined as a list of tests, references to
analytical procedures, and appropriate acceptance criteria that are
numerical limits, ranges, or other criteria for the tests described. It
establishes the set of criteria to which a drug substance or drug
product should conform to be considered acceptable for its intended
use. ``Conformance to specifications'' means that the drug substance
and/or drug product, when tested according to the listed analytical
procedures, will meet the listed acceptance criteria. Specifications
are critical quality standards that are proposed and justified by the
manufacturer and approved by regulatory authorities as conditions of
approval.
    Specifications are one part of a total control strategy for the
drug substance and drug product designed to ensure product quality and
consistency. Other parts of this strategy include thorough product
characterization during development, upon which specifications are
based, and adherence to good manufacturing practices (GMP's), e.g.,
suitable facilities, a validated manufacturing process, validated test
procedures, raw materials testing, in-process testing, stability
testing.
    Specifications are chosen to confirm the quality of the drug
substance and drug product rather than to establish full
characterization, and should focus on those characteristics found to be
useful in ensuring the safety and efficacy of the drug substance and
drug product.
 
1.3 Scope of the Guidance
 
    The quality of drug substances and drug products is determined by
their design, development, in-process controls, GMP controls, process
validation, and by specifications applied to them throughout
development and manufacture. This guidance addresses specifications,
i.e., those tests, procedures, and acceptance criteria that play a
major role in assuring the quality of the new drug substance and new
drug product at release and during shelf life. Specifications are an
important component of quality assurance, but are not its only
component. All of the factors listed above are considered necessary to
ensure consistent production of drug substances and drug products of
high quality.
    This guidance addresses only the marketing approval of new drug
products (including combination products) and, where applicable, new
drug substances; it does not address drug substances or drug products
during the clinical research stages of drug development. This guidance
may be applicable to synthetic and semisynthetic antibiotics and
synthetic peptides of low molecular weight; however, it is not
sufficient to
 
[[Page 83043]]
 
adequately describe specifications of higher molecular weight peptides
and polypeptides, and biotechnological/biological products. The ICH
guidance on ``Q6B Specifications: Test Procedures and Acceptance
Criteria for Biotechnological/Biological Products'' addresses guidance
specifications, tests, and procedures for biotechnological/biological
products. Radiopharmaceuticals, products of fermentation,
oligonucleotides, herbal products, and crude products of animal or
plant origin are similarly not covered.
    Guidance is provided with regard to acceptance criteria that should
be established for all new drug substances and new drug products, i.e.,
universal acceptance criteria, and those that are considered specific
to individual drug substances and/or dosage forms. This guidance should
not be considered all encompassing. New analytical technologies, and
modifications to existing technology, are continually being developed.
Such technologies should be used when justified.
    Dosage forms addressed in this guidance include solid oral dosage
forms, liquid oral dosage forms, and parenterals (small and large
volume). This is not meant to be an all-inclusive list, or to limit the
number of dosage forms to which this guidance applies. The dosage forms
presented serve as models that may be applicable to other dosage forms
that have not been discussed. The extended application of the concepts
in this guidance to other dosage forms, e.g., to inhalation dosage
forms (powders, solutions, etc.), to topical formulations (creams,
ointments, gels), and to transdermal systems, is encouraged.
 
2. General Concepts
 
    The following concepts are important in the development and setting
of harmonized specifications. They are not universally applicable, but
each should be considered in particular circumstances. This guidance
presents a brief definition of each concept and an indication of the
circumstances under which it may be applicable. Generally, proposals to
implement these concepts should be justified by the applicant and
approved by the appropriate regulatory authority before being put into
effect.
 
2.1 Periodic or Skip Testing
 
    Periodic or skip testing is the performance of specified tests at
release on preselected batches and/or at predetermined intervals,
rather than on a batch-by-batch basis, with the understanding that
those batches not being tested still meet all acceptance criteria
established for that product. This represents a less than full schedule
of testing and should therefore be justified and presented to and
approved by the regulatory authority prior to implementation. This
concept may be applicable to, for example, residual solvents and
microbiological testing for solid oral dosage forms. It is recognized
that only limited data may be available at the time of submission of an
application (see section 2.5). This concept should therefore generally
be implemented postapproval. When tested, any failure to meet
acceptance criteria established for the periodic test should be handled
by proper notification of the appropriate regulatory authority(ies). If
these data demonstrate a need to restore routine testing, then batch-
by-batch release testing should be reinstated.
 
2.2 Release vs. Shelf-Life Acceptance Criteria
 
    The concept of different acceptance criteria for release vs. shelf-
life specifications applies to drug products only; it pertains to the
establishment of more restrictive criteria for the release of a drug
product than are applied to the shelf life. Examples where this may be
applicable include assay and impurity (degradation product) levels. In
Japan and the United States, this concept may only be applicable to in-
house criteria, and not to the regulatory release criteria. Thus, in
these regions, the regulatory acceptance criteria are the same from
release throughout shelf life; however, an applicant may choose to have
tighter in-house limits at the time of release to provide increased
assurance to the applicant that the product will remain within the
regulatory acceptance criteria throughout its shelf life. In the
European Union there is a regulatory requirement for distinct
specifications for release and for shelf life where different.
 
2.3 In-Process Tests
 
    In-process tests, as presented in this guidance, are tests that may
be performed during the manufacture of either the drug substance or
drug product, rather than as part of the formal battery of tests that
are conducted prior to release.
    In-process tests that are only used for the purpose of adjusting
process parameters within an operating range, e.g., hardness and
friability of tablet cores that will be coated and individual tablet
weights, are not included in the specification.
    Certain tests conducted during the manufacturing process, where the
acceptance criterion is identical to or tighter than the release
requirement, (e.g., pH (hydrogen-ion concentration) of a solution) may
be sufficient to satisfy specification requirements when the test is
included in the specification. However, this approach should be
validated to show that test results or product performance
characteristics do not change from the in-process stage to finished
product.
 
2.4 Design and Development Considerations
 
    The experience and data accumulated during the development of a new
drug substance or product should form the basis for the setting of
specifications. It may be possible to propose excluding or replacing
certain tests on this basis. Some examples are:
     Microbiological testing for drug substances and solid
dosage forms that have been shown during development not to support
microbial viability or growth (see Decision Trees #6 and #8).
     Extractables from product containers where it has been
reproducibly shown that either no extractables are found in the drug
product or the levels meet accepted standards for safety.
     Particle size testing may fall into this category, may be
performed as an in-process test, or may be performed as a release test,
depending on its relevance to product performance.
     Dissolution testing for immediate release solid oral drug
products made from highly water soluble drug substances may be replaced
by disintegration testing, if these products have been demonstrated
during development to have consistently rapid drug release
characteristics (see Decision Trees #7(1) through #7(2)).
 
2.5 Limited Data Available at Filing
 
    It is recognized that only a limited amount of data may be
available at the time of filing, which can influence the process of
setting acceptance criteria. As a result, it may be necessary to
propose revised acceptance criteria as additional experience is gained
with the manufacture of a particular drug substance or drug product
(example: acceptance limits for a specific impurity). The basis for the
acceptance criteria at the time of filing should necessarily focus on
safety and efficacy.
    When only limited data are available, the initially approved tests
and acceptance criteria should be reviewed as more information is
collected, with a view towards possible modification. This could
involve loosening, as well as tightening, acceptance criteria, as
appropriate.
 
[[Page 83044]]
 
2.6 Parametric Release
 
    Parametric release can be used as an operational alternative to
routine release testing for the drug product in certain cases, when
approved by the regulatory authority. Sterility testing for terminally
sterilized drug products is one example. In this case, the release of
each batch is based on satisfactory results from monitoring specific
parameters, e.g., temperature, pressure, and time during the terminal
sterilization phase(s) of drug product manufacturing. These parameters
can generally be more accurately controlled and measured, so they are
more reliable in predicting sterility assurance than is end-product
sterility testing. Appropriate laboratory tests (e.g., chemical or
physical indicator) may be included in the parametric release program.
It is important to note that the sterilization process should be
adequately validated before parametric release is proposed, and
maintenance of a validated state should be demonstrated by revalidation
at established intervals. When parametric release is performed, the
attribute that is indirectly controlled (e.g., sterility), together
with a reference to the associated test procedure, still should be
included in the specifications.
 
2.7 Alternative Procedures
 
    Alternative procedures are those that may be used to measure an
attribute when such procedures control the quality of the drug
substance or drug product to an extent that is comparable or superior
to the official procedure. Example: For tablets that have been shown
not to degrade during manufacture, it may be permissible to use a
spectrophotometric procedure for release as opposed to the official
procedure, which is chromatographic. However, the chromatographic
procedure should still be used to demonstrate compliance with the
acceptance criteria during the shelf life of the product.
 
2.8 Pharmacopeial Tests and Acceptance Criteria
 
    References to certain procedures are found in pharmacopeias in each
region. Wherever they are appropriate, pharmacopeial procedures should
be used. Whereas differences in pharmacopeial procedures and/or
acceptance criteria have existed among the regions, a harmonized
specification is possible only if the procedures and acceptance
criteria defined are acceptable to regulatory authorities in all
regions.
    The full utility of this guidance is dependent on the successful
completion of harmonization of pharmacopeial procedures for several
attributes commonly considered in the specification for new drug
substances or new drug products. The Pharmacopoeial Discussion Group
(PDG) of the European Pharmacopeia, the Japanese Pharmacopoeia (JP),
and the United States Pharmacopeia has expressed a commitment to
achieving harmonization of the procedures in a timely fashion.
    Where harmonization has been achieved, an appropriate reference to
the harmonized procedure and acceptance criteria is considered
acceptable for a specification in all three regions. For example, after
harmonization, sterility data generated using the JP procedure, as well
as the JP procedure itself and its acceptance criteria, will be
considered acceptable for registration in all three regions. To signify
the harmonized status of these procedures, the pharmacopeias have
agreed to include a statement in their respective texts that indicates
that the procedures and acceptance criteria from all three
pharmacopeias are considered equivalent and are, therefore,
interchangeable.
    Since the overall value of this guidance is linked to the extent of
harmonization of the analytical procedures and acceptance criteria of
the pharmacopeias, it is agreed by the members of the Q6A expert
working group that none of the three pharmacopeias should change a
harmonized monograph unilaterally. According to the PDG procedure for
the revision of harmonized monographs and chapters, ``no pharmacopoeia
shall revise unilaterally any monograph or chapter after sign-off or
after publication.''
 
2.9 Evolving Technologies
 
    New analytical technologies, and modifications to existing
technology, are continually being developed. Such technologies should
be used when they are considered to offer additional assurance of
quality, or are otherwise justified.
 
2.10 Impact of Drug Substance on Drug Product Specifications
 
    In general, it should not be necessary to test the drug product for
quality attributes uniquely associated with the drug substance.
Example: It is normally not considered necessary to test the drug
product for synthesis impurities that are controlled in the drug
substance and are not degradation products. Refer to the ICH guidance
on ``Q3B Impurities in New Drug Products'' for detailed information.
 
2.11 Reference Standard
 
    A reference standard, or reference material, is a substance
prepared for use as the standard in an assay, identification, or purity
test. It should have a quality appropriate to its use. It is often
characterized and evaluated for its intended purpose by additional
procedures other than those used in routine testing. For new drug
substance reference standards intended for use in assays, the
impurities should be adequately identified and/or controlled, and
purity should be measured by a quantitative procedure.
 
3. Guidance
 
3.1 Specifications: Definition and Justification
 
3.1.1 Definition of Specifications
    A specification is defined as a list of tests, references to
analytical procedures, and appropriate acceptance criteria that are
numerical limits, ranges, or other criteria for the tests described. It
establishes the set of criteria to which a new drug substance or new
drug product should conform to be considered acceptable for its
intended use. ``Conformance to specifications'' means that the drug
substance and/or drug product, when tested according to the listed
analytical procedures, will meet the listed acceptance criteria.
Specifications are critical quality standards that are proposed and
justified by the manufacturer and approved by regulatory authorities as
conditions of approval.
    It is possible that, in addition to release tests, a specification
may list in-process tests as defined in section 2.3, periodic or skip
tests, and other tests that are not always conducted on a batch-by-
batch basis. In such cases the applicant should specify which tests are
routinely conducted batch by batch, and which tests are not, with an
indication and justification of the actual testing frequency. In this
situation, the drug substance and/or drug product should meet the
acceptance criteria if tested.
    It should be noted that changes in the specification after approval
of the application may need prior approval by the regulatory authority.
3.1.2 Justification of Specifications
    When a specification is first proposed, justification should be
presented for each procedure and each acceptance criterion included.
The justification should refer to relevant development data,
pharmacopeial standards, test data for drug substances and drug
products
 
[[Page 83045]]
 
used in toxicology and clinical studies, and results from accelerated
and long-term stability studies, as appropriate. Additionally, a
reasonable range of expected analytical and manufacturing variability
should be considered. It is important to consider all of this
information.
    Approaches other than those set forth in this guidance may be
applicable and acceptable. The applicant should justify alternative
approaches. Such justification should be based on data derived from the
new drug substance synthesis and/or the new drug product manufacturing
process. This justification may consider theoretical tolerances for a
given procedure or acceptance criterion, but the actual results
obtained should form the primary basis for whatever approach is taken.
    Test results from stability and scaleup/validation batches, with
emphasis on the primary stability batches, should be considered in
setting and justifying specifications. If multiple manufacturing sites
are planned, it may be valuable to consider data from these sites in
establishing the initial tests and acceptance criteria. This is
particularly true when there is limited initial experience with the
manufacture of the drug substance or drug product at any particular
site. If data from a single representative manufacturing site are used
in setting tests and acceptance criteria, product manufactured at all
sites should still comply with these criteria.
    Presentation of test results in graphic format may be helpful in
justifying individual acceptance criteria, particularly for assay
values and impurity levels. Data from development work should be
included in such a presentation, along with stability data available
for new drug substance or new drug product batches manufactured by the
proposed commercial processes. Justification for proposing exclusion of
a test from the specification should be based on development data and
on process validation data (where appropriate).
 
3.2 Universal Tests/Criteria
 
    Implementation of the recommendations in the following section
should take into account the ICH guidances ``Q2A Text on Validation of
Analytical Procedures'' and ``Q2B Validation of Analytical Procedures:
Methodology.''
3.2.1 New Drug Substances
    The following tests and acceptance criteria are considered
generally applicable to all new drug substances.
    (a) Description: A qualitative statement about the state (e.g.,
solid, liquid) and color of the new drug substance. If any of these
characteristics change during storage, this change should be
investigated and appropriate action taken.
    (b) Identification: Identification testing should optimally be able
to discriminate between compounds of closely related structure that are
likely to be present. Identification tests should be specific for the
new drug substance, e.g., infrared spectroscopy (IR). Identification
solely by a single chromatographic retention time, for example, is not
regarded as being specific. However, the use of two chromatographic
procedures, where the separation is based on different principles or a
combination of tests into a single procedure, such as HPLC (high-
pressure liquid chromatography)/UV (ultraviolet) diode array, HPLC/MS
(mass spectroscopy), or GC (gas chromatography)/MS is generally
acceptable. If the new drug substance is a salt, identification testing
should be specific for the individual ions. An identification test that
is specific for the salt itself should suffice.
    New drug substances that are optically active may also need
specific identification testing or performance of a chiral assay.
Please refer to section 3.3.1(d) in this guidance for further
discussion of this topic.
    (c) Assay: A specific, stability-indicating procedure should be
included to determine the content of the new drug substance. In many
cases it is possible to employ the same procedure (e.g., HPLC) for both
assay of the new drug substance and quantitation of impurities.
    In cases where use of a nonspecific assay is justified, other
supporting analytical procedures should be used to achieve overall
specificity. For example, where titration is adopted to assay the drug
substance, the combination of the assay and a suitable test for
impurities should be used.
    (d) Impurities: Organic and inorganic impurities and residual
solvents are included in this category. Refer to the ICH guidances on
``Q3A Impurities in New Drug Substances'' and ``Q3C Impurities:
Residual Solvents'' for detailed information.
    Decision Tree #1 addresses the extrapolation of meaningful limits
on impurities from the body of data generated during development. At
the time of filing it is unlikely that sufficient data will be
available to assess process consistency. Therefore it is considered
inappropriate to establish acceptance criteria that tightly encompass
the batch data at the time of filing (see section 2.5).
3.2.2 New Drug Products
    The following tests and acceptance criteria are considered
generally applicable to all new drug products:
    (a) Description: A qualitative description of the dosage form
should be provided (e.g., size, shape, and color). If any of these
characteristics change during manufacture or storage, this change
should be investigated and appropriate action taken. The acceptance
criteria should include the final acceptable appearance. If color
changes during storage, a quantitative procedure may be appropriate.
    (b) Identification: Identification testing should establish the
identity of the new drug substance(s) in the new drug product and
should be able to discriminate between compounds of closely related
structure that are likely to be present. Identity tests should be
specific for the new drug substance, e.g., infrared spectroscopy.
Identification solely by a single chromatographic retention time, for
example, is not regarded as being specific. However, the use of two
chromatographic procedures, where the separation is based on different
principles, or a combination of tests into a single procedure, such as
HPLC/UV diode array, HPLC/MS, or GC/MS, is generally acceptable.
    (c) Assay: A specific, stability-indicating assay to determine
strength (content) should be included for all new drug products. In
many cases it is possible to employ the same procedure (e.g., HPLC) for
both assay of the new drug substance and quantitation of impurities.
Results of content uniformity testing for new drug products can be used
for quantitation of drug product strength, if the methods used for
content uniformity are also appropriate as assays.
    In cases where use of a nonspecific assay is justified, other
supporting analytical procedures should be used to achieve overall
specificity. For example, where titration is adopted to assay the drug
substance for release, the combination of the assay and a suitable test
for impurities can be used. A specific procedure should be used when
there is evidence of excipient interference with the nonspecific assay.
    (d) Impurities: Organic and inorganic impurities (degradation
products) and residual solvents are included in this category. Refer to
the ICH guidances on ``Q3B Impurities in New Drug Products'' and ``Q3C
Impurities: Residual Solvents'' for detailed information.
    Organic impurities arising from degradation of the new drug
substance
 
[[Page 83046]]
 
and impurities that arise during the manufacturing process for the drug
product should be monitored in the new drug product. Acceptance limits
should be stated for individual specified degradation products, which
may include both identified and unidentified degradation products, as
appropriate, and total degradation products. Process impurities from
the new drug substance synthesis are normally controlled during drug
substance testing, and therefore are not included in the total
impurities limit. However, when a synthesis impurity is also a
degradation product, its level should be monitored and included in the
total degradation product limit. When it has been conclusively
demonstrated via appropriate analytical methodology that the drug
substance does not degrade in the specific formulation, and under the
specific storage conditions proposed in the new drug application,
degradation product testing may be reduced or eliminated upon approval
by the regulatory authorities.
    Decision Tree #2 addresses the extrapolation of meaningful limits
on degradation products from the body of data generated during
development. At the time of filing it is unlikely that sufficient data
will be available to assess process consistency. Therefore it is
considered inappropriate to establish acceptance criteria that tightly
encompass the batch data at the time of filing (see section 2.5).
 
3.3 Specific Tests/Criteria
 
    In addition to the universal tests listed above, the following
tests may be considered on a case-by-case basis for drug substances
and/or drug products. Individual tests/criteria should be included in
the specification when the tests have an impact on the quality of the
drug substance and drug product for batch control. Tests other than
those listed below may be needed in particular situations or as new
information becomes available.
3.3.1 New Drug Substances
    (a) Physicochemical properties: These are properties such as pH of
an aqueous solution, melting point/range, and refractive index. The
procedures used for the measurement of these properties are usually
unique and do not need much elaboration, e.g., capillary melting point,
Abbe refractometry. The tests performed in this category should be
determined by the physical nature of the new drug substance and by its
intended use.
    (b) Particle size: For some new drug substances intended for use in
solid or suspension drug products, particle size can have a significant
effect on dissolution rates, bioavailability, and/or stability. In such
instances, testing for particle size distribution should be carried out
using an appropriate procedure, and acceptance criteria should be
provided.
    Decision Tree #3 provides additional guidance on when particle size
testing should be considered.
    (c) Polymorphic forms: Some new drug substances exist in different
crystalline forms that differ in their physical properties.
Polymorphism may also include solvation or hydration products (also
known as pseudopolymorphs) and amorphous forms. Differences in these
forms could, in some cases, affect the quality or performance of the
new drug products. In cases where differences exist that have been
shown to affect drug product performance, bioavailability, or
stability, then the appropriate solid state should be specified.
    Physicochemical measurements and techniques are commonly used to
determine whether multiple forms exist. Examples of these procedures
are: Melting point (including hot-stage microscopy), solid state IR, X-
ray powder diffraction, thermal analysis procedures (like DSC
(differential scanning calorimetry), TGA (thermogravimetric analysis)
and DTA (differential thermal analysis)), Raman spectroscopy, optical
microscopy, and solid state NMR (nuclear magnetic resonance)
spectroscopy.
    Decision Trees #4(1) through #4(3) provide additional guidance on
when, and how, polymorphic forms should be monitored and controlled.
    Note: These decision trees should be followed sequentially. Trees
#4(1) and #4(2) consider whether polymorphism is exhibited by the drug
substance, and whether the different polymorphic forms can affect
performance of the drug product. Tree #4(3) should only be applied when
polymorphism has been demonstrated for the drug substance, and shown to
affect these properties. Tree #4(3) considers the potential for change
in polymorphic forms in the drug product and whether such a change has
any effect on product performance.
    It is generally technically very difficult to measure polymorphic
changes in drug products. A surrogate test (e.g., dissolution) (see
Decision Tree #4(3)) can generally be used to monitor product
performance, and polymorph content should only be used as a test and
acceptance criterion of last resort.
    (d) Tests for chiral new drug substances: Where a new drug
substance is predominantly one enantiomer, the opposite enantiomer is
excluded from the qualification and identification thresholds given in
the ICH guidances on ``Q3A Impurities in New Drug Substances'' and
``Q3B Impurities in New Drug Products'' because of practical
difficulties in quantifying it at those levels. However, that impurity
in the chiral new drug substance and the resulting new drug product(s)
should otherwise be treated according to the principles established in
those guidances.
    Decision Tree #5 summarizes when and if chiral identity tests,
impurity tests, and assays may be needed for both new drug substances
and new drug products, according to the following concepts:
    Drug Substance: Impurities. For chiral drug substances that are
developed as a single enantiomer, control of the other enantiomer
should be considered in the same manner as for other impurities.
However, technical limitations may preclude the same limits of
quantification or qualification from being applied. Assurance of
control also could be given by appropriate testing of a starting
material or intermediate, with suitable justification.
    Assay. An enantioselective determination of the drug substance
should be part of the specification. It is considered acceptable for
this to be achieved either through use of a chiral assay procedure or
by the combination of an achiral assay together with appropriate
methods of controlling the enantiomeric impurity.
    Identity. For a drug substance developed as a single enantiomer,
the identity test(s) should be capable of distinguishing both
enantiomers and the racemic mixture. For a racemic drug substance,
there are generally two situations where a stereospecific identity test
is appropriate for release/acceptance testing: (1) Where there is a
significant possibility that the enantiomer might be substituted for
the racemate, or (2) when there is evidence that preferential
crystallization may lead to unintentional production of a nonracemic
mixture.
    Drug Product: Degradation products. Control of the other enantiomer
in a drug product is considered necessary unless racemization has been
shown to be insignificant during manufacture of the dosage form and on
storage.
    Assay. An achiral assay may be sufficient where racemization has
been shown to be insignificant during manufacture of the dosage form
and on storage. Otherwise a chiral assay should be used. Alternatively,
the combination of an achiral assay plus a validated
 
[[Page 83047]]
 
procedure to control the presence of the opposite enantiomer may be
used.
    Identity. A stereospecific identity test is not generally needed in
the drug product release specification. When racemization is
insignificant during manufacture of the dosage form and on storage,
stereospecific identity testing is more appropriately addressed as part
of the drug substance specification. When racemization in the dosage
form is a concern, chiral assay or enantiomeric impurity testing of the
drug product will serve to verify identity.
    (e) Water content: This test is important in cases where the new
drug substance is known to be hygroscopic or degraded by moisture or
when the drug substance is known to be a stoichiometric hydrate. The
acceptance criteria may be justified with data on the effects of
hydration or moisture absorption. In some cases, a loss on drying
procedure may be considered adequate; however, a detection procedure
that is specific for water (e.g., Karl Fischer titration) is preferred.
    (f) Inorganic impurities: The need for inclusion of tests and
acceptance criteria for inorganic impurities (e.g., catalysts) should
be studied during development and based on knowledge of the
manufacturing process. Procedures and acceptance criteria for sulfated
ash/residue on ignition should follow pharmacopeial precedents; other
inorganic impurities may be determined by other appropriate procedures,
e.g., atomic absorption spectroscopy.
    (g) Microbial limits: There may be a need to specify the total
count of aerobic microorganisms, the total count of yeasts and molds,
and the absence of specific objectionable bacteria (e.g.,
Staphylococcus aureus, Escherichia coli, Salmonella, Pseudomonas
aeruginosa). These should be suitably determined using pharmacopeial
procedures. The type of microbial test(s) and acceptance criteria
should be based on the nature of the drug substance, method of
manufacture, and the intended use of the drug product. For example,
sterility testing may be appropriate for drug substances manufactured
as sterile, and endotoxin testing may be appropriate for drug
substances used to formulate an injectable drug product.
    Decision Tree #6 provides additional guidance on when microbial
limits should be included.
3.3.2 New Drug Products
    Additional tests and acceptance criteria generally should be
included for particular new drug products. The following selection
presents a representative sample of both the drug products and the
types of tests and acceptance criteria that may be appropriate. The
specific dosage forms addressed include solid oral drug products,
liquid oral drug products, and parenterals (small and large volume).
Application of the concepts in this guidance to other dosage forms is
encouraged. Note that issues related to optically active drug
substances and to solid state considerations for drug products are
discussed in section 3.3.1 of this guidance.
3.3.2.1 The following tests are applicable to tablets (coated and
uncoated) and hard capsules. One or more of these tests may also be
applicable to soft capsules and granules.
    (a) Dissolution: The specification for solid oral dosage forms
normally includes a test to measure release of drug substance from the
drug product. Single-point measurements are normally considered to be
suitable for immediate-release dosage forms. For modified-release
dosage forms, appropriate test conditions and sampling procedures
should be established. For example, multiple time-point sampling should
be performed for extended-release dosage forms, and two-stage testing
(using different media in succession or in parallel, as appropriate)
may be appropriate for delayed-release dosage forms. In these cases it
is important to consider the populations of individuals who will be
taking the drug product (e.g., achlorhydric elderly) when designing the
tests and acceptance criteria. In some cases (see section 3.3.2.1(b)
Disintegration) dissolution testing may be replaced by disintegration
testing (see Decision Tree #7(1)).
    For immediate-release drug products where changes in dissolution
rate have been demonstrated to significantly affect bioavailability, it
is desirable to develop test conditions that can distinguish batches
with unacceptable bioavailability. If changes in formulation or process
variables significantly affect dissolution, and such changes are not
controlled by another aspect of the specification, it may also be
appropriate to adopt dissolution test conditions that can distinguish
these changes (see Decision Tree #7(2)).
    Where dissolution significantly affects bioavailability, the
acceptance criteria should be set to reject batches with unacceptable
bioavailability. Otherwise, test conditions and acceptance criteria
should be established that pass clinically acceptable batches (see
Decision Tree #7(2)).
    For extended-release drug products, in vitro/in vivo correlation
may be used to establish acceptance criteria when human bioavailability
data are available for formulations exhibiting different release rates.
Where such data are not available, and drug release cannot be shown to
be independent of in vitro test conditions, then acceptance criteria
should be established on the basis of available batch data. Normally,
the permitted variability in mean release rate at any given time point
should not exceed a total numerical difference of 10
percent of the labeled content of drug substance (i.e., a total
variability of 20 percent: a requirement of 5010 percent
thus means an acceptable range from 40 percent to 60 percent), unless a
wider range is supported by a bioequivalency study (see Decision Tree
#7(3)).
    (b) Disintegration: For rapidly dissolving (dissolution >80 percent
in 15 minutes at pH 1.2, 4.0, and 6.8) products containing drugs that
are highly soluble throughout the physiological range (dose/solubility
volume  250 milliliters (mL) from pH 1.2 to 6.8),
disintegration may be substituted for dissolution. Disintegration
testing is considered most appropriate when a relationship to
dissolution has been established or when disintegration is shown to be
more discriminating than dissolution. In such cases dissolution testing
may not be necessary. It is expected that development information will
be provided to support the robustness of the formulation and
manufacturing process with respect to the selection of dissolution
versus disintegration testing (see Decision Tree #7(1)).
    (c) Hardness/friability: It is normally appropriate to perform
hardness and/or friability testing as an in-process control (see
section 2.3). Under these circumstances, it is normally not necessary
to include these attributes in the specification. If the
characteristics of hardness and friability have a critical impact on
drug product quality (e.g., chewable tablets), acceptance criteria
should be included in the specification.
    (d) Uniformity of dosage units: This term includes both the mass of
the dosage form and the content of the active substance in the dosage
form; a pharmacopeial procedure should be used. In general, the
specification should include one or the other, but not both. If
appropriate, these tests may be performed in-process; the acceptance
criteria should be included in the specification. When weight variation
is applied to new drug products exceeding the threshold value to allow
testing uniformity by weight variation, applicants should verify during
drug
 
[[Page 83048]]
 
development that the homogeneity of the product is adequate.
    (e) Water content: A test for water content should be included when
appropriate. The acceptance criteria may be justified with data on the
effects of hydration or water absorption on the drug product. In some
cases, a loss on drying procedure may be considered adequate; however,
a detection procedure that is specific for water (e.g., Karl Fischer
titration) is preferred.
    (f) Microbial limits: Microbial limit testing is seen as an
attribute of GMP, as well as of quality assurance. In general, it is
advisable to test the drug product unless its components are tested
before manufacture and the manufacturing process is known, through
validation studies, not to carry a significant risk of microbial
contamination or proliferation. It should be noted that, whereas this
guidance does not directly address excipients, the principles discussed
here may be applicable to excipients as well as to new drug products.
Skip testing may be an appropriate approach in both cases, where
permissible (see Decision Tree #6 for microbial testing of excipients).
    Acceptance criteria should be set for the total count of aerobic
microorganisms, the total count of yeasts and molds, and the absence of
specific objectionable bacteria (e.g., Staphylococcus aureus,
Escherichia coli, Salmonella, Pseudomonas aeruginosa). These should be
determined by suitable procedures, using pharmacopeial procedures, and
at a sampling frequency or time point in manufacture that is justified
by data and experience. The type of microbial test(s) and acceptance
criteria should be based on the nature of the drug substance, method of
manufacture, and the intended use of the drug product. With acceptable
scientific justification, it should be possible to propose no microbial
limit testing for solid oral dosage forms.
    Decision Tree #8 provides additional guidance on the use of
microbial limits testing.
3.3.2.2 Oral liquids: One or more of the following specific tests will
normally be applicable to oral liquids and to powders intended for
reconstitution as oral liquids.
    (a) Uniformity of dosage units: This term includes both the mass of
the dosage form and the content of the active drug substance in the
dosage form; a pharmacopeial procedure should be used. In general, the
specification should include one or the other, but not both. When
weight variation is applied to new drug products exceeding the
threshold value to allow testing uniformity by weight variation,
applicants should verify during drug development that the homogeneity
of the product is adequate.
    If appropriate, tests may be performed in-process; however, the
acceptance criteria should be included in the specification. This
concept may be applied to both single-dose and multiple-dose packages.
    The dosage unit is considered to be the typical dose taken by the
patient. If the actual unit dose, as taken by the patient, is
controlled, it may either be measured directly or calculated, based on
the total measured weight or volume of drug divided by the total number
of doses expected. If dispensing equipment (such as medicine droppers
or dropper tips for bottles) is an integral part of the packaging, this
equipment should be used to measure the dose. Otherwise, a standard
volume measure should be used. The dispensing equipment to be used is
normally determined during development. For powders for reconstitution,
uniformity of mass testing is generally considered acceptable.
    (b) pH: Acceptance criteria for pH should be provided where
applicable and the proposed range justified.
    (c) Microbial limits: Microbial limit testing is seen as an
attribute of GMP, as well as of quality assurance. In general, it is
advisable to test the drug product unless its components are tested
before manufacture and the manufacturing process is known, through
validation studies, not to carry a significant risk of microbial
contamination or proliferation. It should be noted that, whereas this
guidance does not directly address excipients, the principles discussed
here may be applicable to excipients as well as to new drug products.
Skip testing may be an appropriate approach in both cases, where
permissible. With acceptable scientific justification, it may be
possible to propose no microbial limit testing for powders intended for
reconstitution as oral liquids.
    Acceptance criteria should be set for the total count of aerobic
microorganisms, total count of yeasts and molds, and the absence of
specific objectionable bacteria (e.g., Staphylococcus aureus,
Escherichia coli, Salmonella, Pseudomonas aeruginosa). These should be
determined by suitable procedures, using pharmacopeial procedures, and
at a sampling frequency or time point in manufacture that is justified
by data and experience.
    Decision Tree #8 provides additional guidance on the use of
microbial limits testing.
    (d) Antimicrobial preservative content: For oral liquids needing an
antimicrobial preservative, acceptance criteria for preservative
content should be established. Acceptance criteria for preservative
content should be based upon the levels of antimicrobial preservative
necessary to maintain microbiological quality of the product at all
stages throughout its proposed usage and shelf life. The lowest
specified concentration of antimicrobial preservative should be
demonstrated to be effective in controlling microorganisms by using a
pharmacopeial antimicrobial preservative effectiveness test.
    Testing for antimicrobial preservative content should normally be
performed at release. Under certain circumstances, in-process testing
may suffice in lieu of release testing. When antimicrobial preservative
content testing is performed as an in-process test, the acceptance
criteria should remain part of the specification.
    Antimicrobial preservative effectiveness should be demonstrated
during development, during scaleup, and throughout the shelf life
(e.g., in stability testing: see the ICH guidance ``Q1A Stability
Testing of New Drug Substances and Products''), although chemical
testing for preservative content is the attribute normally included in
the specification.
    (e) Antioxidant preservative content: Release testing for
antioxidant content should normally be performed. Under certain
circumstances where justified by developmental and stability data,
shelf-life testing may be unnecessary, and in-process testing may
suffice in lieu of release testing where permitted. When antioxidant
content testing is performed as an in-process test, the acceptance
criteria should remain part of the specification. If only release
testing is performed, this decision should be reinvestigated whenever
either the manufacturing procedure or the container/closure system
changes.
    (f) Extractables: Generally, where development and stability data
show evidence that extractables from the container/closure systems are
consistently below levels that are demonstrated to be acceptable and
safe, elimination of this test can normally be accepted. This should be
reinvestigated if the container/closure system or formulation changes.
    Where data demonstrate the need, tests and acceptance criteria for
extractables from the container/closure system components (e.g., rubber
 
[[Page 83049]]
 
stopper, cap liner, plastic bottle, etc.) are considered appropriate
for oral solutions packaged in nonglass systems, or in glass containers
with nonglass closures. The container/closure components should be
listed, and data collected for these components as early in the
development process as possible.
    (g) Alcohol content: Where it is declared quantitatively on the
label in accordance with pertinent regulations, the alcohol content
should be specified. It may be assayed or calculated.
    (h) Dissolution: In addition to the attributes recommended
immediately above, it may be appropriate (e.g., insoluble drug
substance) to include dissolution testing and acceptance criteria for
oral suspensions and dry powder products for resuspension. Dissolution
testing should be performed at release. This test may be performed as
an in-process test when justified by product development data. The
testing apparatus, media, and conditions should be pharmacopeial, if
possible, or otherwise justified. Dissolution procedures using either a
pharmacopeial or nonpharmacopeial apparatus and conditions should be
validated.
    Single-point measurements are normally considered suitable for
immediate-release dosage forms. Multiple-point sampling, at appropriate
intervals, should be performed for modified-release dosage forms.
Acceptance criteria should be set based on the observed range of
variation, and should take into account the dissolution profiles of the
batches that showed acceptable performance in vivo. Developmental data
should be considered when determining the need for either a dissolution
procedure or a particle size distribution procedure.
    (i) Particle size distribution: Quantitative acceptance criteria
and a procedure for determination of particle size distribution may be
appropriate for oral suspensions. Developmental data should be
considered when determining the need for either a dissolution procedure
or a particle size distribution procedure for these formulations.
    Particle size distribution testing should be performed at release.
It may be performed as an in-process test when justified by product
development data. If these products have been demonstrated during
development to have consistently rapid drug release characteristics,
exclusion of a particle size distribution test from the specification
may be proposed.
    Particle size distribution testing may also be proposed in place of
dissolution testing; justification should be provided. The acceptance
criteria should include acceptable particle size distribution in terms
of the percent of total particles in given size ranges. The mean,
upper, and/or lower particle size limits should be well defined.
    Acceptance criteria should be set based on the observed range of
variation, and should take into account the dissolution profiles of the
batches that showed acceptable performance in vivo, as well as the
intended use of the product. The potential for particle growth should
be investigated during product development; the acceptance criteria
should take the results of these studies into account.
    (j) Redispersibility: For oral suspensions that settle on storage
(produce sediment), acceptance criteria for redispersibility may be
appropriate. Shaking may be an appropriate procedure.
    The procedure (mechanical or manual) should be indicated. Time
required to achieve resuspension by the indicated procedure should be
clearly defined. Data generated during product development may be
sufficient to justify periodic or skip testing, or elimination of this
attribute from the specification may be proposed.
    (k) Rheological properties: For relatively viscous solutions or
suspensions, it may be appropriate to include rheological properties
(viscosity/specific gravity) in the specification. The test and
acceptance criteria should be stated. Data generated during product
development may be sufficient to justify periodic or skip testing, or
elimination of this attribute from the specification may be proposed.
    (l) Reconstitution time: Acceptance criteria for reconstitution
time should be provided for dry powder products that require
reconstitution. The choice of diluent should be justified. Data
generated during product development may be sufficient to justify
periodic or skip testing, or elimination of this attribute from the
specification may be proposed.
    (m) Water content: For oral products requiring reconstitution, a
test and acceptance criterion for water content should be proposed when
appropriate. Loss on drying is generally considered sufficient if the
effect of absorbed moisture versus water of hydration has been
adequately characterized during the development of the product. In
certain cases a more specific procedure (e.g., Karl Fischer titration)
may be preferable.
3.3.2.3 Parenteral Drug Products: The following tests may be applicable
to parenteral drug products.
    (a) Uniformity of dosage units: This term includes both the mass of
the dosage form and the content of the active drug substance in the
dosage form; a pharmacopeial procedure should be used. In general, the
specification should be one or the other, but not both, and is
applicable to powders for reconstitution. When weight variation is
applied to new drug products exceeding the threshold value to allow
testing uniformity by weight variation, applicants should verify during
drug development that the homogeneity of the product is adequate.
    If appropriate (see section 2.3), these tests may be performed in-
process; the acceptance criteria should be included in the
specification. This test may be applied to both single-dose and
multiple-dose packages.
    For powders for reconstitution, uniformity of mass testing is
generally considered acceptable.
    (b) pH: Acceptance criteria for pH should be provided where
applicable, and the proposed range justified.
    (c) Sterility: All parenteral products should have a test procedure
and acceptance criterion for evaluation of sterility. Where data
generated during development and validation justify parametric release,
this approach may be proposed for terminally sterilized drug products
(see section 2.6).
    (d) Endotoxins/Pyrogens: A test procedure and acceptance criterion
for endotoxins, using a procedure such as the limulus amoebocyte lysate
test, should be included in the specification. Pyrogenicity testing may
be proposed as an alternative to endotoxin testing where justified.
    (e) Particulate matter: Parenteral products should have appropriate
acceptance criteria for particulate matter. This will normally include
acceptance criteria for visible particulates and/or clarity of
solution, as well as for subvisible particulates, as appropriate.
    (f) Water content: For nonaqueous parenterals, and for parenteral
products for reconstitution, a test procedure and acceptance criterion
for water content should be proposed when appropriate. Loss on drying
is generally considered sufficient for parenteral products, if the
effect of absorbed moisture versus water of hydration has been
adequately characterized during development. In certain cases a more
specific procedure (e.g., Karl Fischer titration) may be preferred.
    (g) Antimicrobial preservative content: For parenteral products
 
[[Page 83050]]
 
needing an antimicrobial preservative, acceptance criteria for
preservative content should be established. Acceptance criteria for
preservative content should be based upon the levels of antimicrobial
preservative necessary to maintain microbiological quality of the
product at all stages throughout its proposed usage and shelf life. The
lowest specified concentration of antimicrobial preservative should be
demonstrated to be effective in controlling microorganisms by using a
pharmacopeial antimicrobial preservative effectiveness test.
    Testing for antimicrobial preservative content should normally be
performed at release. Under certain circumstances, in-process testing
may suffice in lieu of release testing, where permitted. When
antimicrobial preservative content testing is performed as an in-
process test, the acceptance criteria should remain part of the
specification.
    Antimicrobial preservative effectiveness should be demonstrated
during development, during scaleup, and throughout the shelf life
(e.g., in stability testing: see the ICH guidance ``Q1A Stability
Testing of New Drug Substances and Products''), although chemical
testing for preservative content is the attribute normally included in
the specification.
    (h) Antioxidant preservative content: Release testing for
antioxidant content should normally be performed. Under certain
circumstances, where justified by developmental and stability data,
shelf-life testing may be unnecessary and in-process testing may
suffice in lieu of release testing. When antioxidant content testing is
performed as an in-process test, the acceptance criteria should remain
part of the specification. If only release testing is performed, this
decision should be reinvestigated whenever either the manufacturing
procedure or the container/closure system changes.
    (i) Extractables: Control of extractables from container/closure
systems is considered significantly more important for parenteral
products than for oral liquids. However, where development and
stability data show evidence that extractables are consistently below
the levels that are demonstrated to be acceptable and safe, elimination
of this test can normally be accepted. This should be reinvestigated if
the container/closure system or formulation changes.
    Where data demonstrate the need, acceptance criteria for
extractables from the container/closure components are considered
appropriate for parenteral products packaged in nonglass systems or in
glass containers with elastomeric closures. This testing may be
performed at release only, where justified by data obtained during
development. The container/closure system components (e.g., rubber
stopper, etc.) should be listed, and data collected for these
components as early in the development process as possible.
    (j) Functionality testing of delivery systems: Parenteral
formulations packaged in prefilled syringes, autoinjector cartridges,
or the equivalent should have test procedures and acceptance criteria
related to the functionality of the delivery system. These may include
control of syringeability, pressure, and seal integrity (leakage), and/
or parameters such as tip cap removal force, piston release force,
piston travel force, and power injector function force. Under certain
circumstances these tests may be performed in-process. Data generated
during product development may be sufficient to justify skip lot
testing or elimination of some or all attributes from the
specification.
    (k) Osmolarity: When the tonicity of a product is declared in its
labeling, appropriate control of its osmolarity should be performed.
Data generated during development and validation may be sufficient to
justify performance of this procedure as an in-process control, skip
lot testing, or direct calculation of this attribute.
    (l) Particle size distribution: Quantitative acceptance criteria
and a procedure for determination of particle size distribution may be
appropriate for injectable suspensions. Developmental data should be
considered when determining the need for either a dissolution procedure
or a particle size distribution procedure.
    Particle size distribution testing should be performed at release.
It may be performed as an in-process test when justified by product
development data. If the product has been demonstrated during
development to have consistently rapid drug release characteristics,
exclusion of particle size controls from the specification may be
proposed.
    Particle size distribution testing may also be proposed in place of
dissolution testing when development studies demonstrate that particle
size is the primary factor influencing dissolution; justification
should be provided. The acceptance criteria should include acceptable
particle size distribution in terms of the percent of total particles
in given size ranges. The mean, upper, and/or lower particle size
limits should be well defined.
    Acceptance criteria should be set based on the observed range of
variation, and should take into account the dissolution profiles of the
batches that showed acceptable performance in vivo and the intended use
of the product. The potential for particle growth should be
investigated during product development; the acceptance criteria should
take the results of these studies into account.
    (m) Redispersibility: For injectable suspensions that settle on
storage (produce sediment), acceptance criteria for redispersibility
may be appropriate. Shaking may be an appropriate procedure. The
procedure (mechanical or manual) should be indicated. Time required to
achieve resuspension by the indicated procedure should be clearly
defined. Data generated during product development may be sufficient to
justify skip lot testing, or elimination of this attribute from the
specification may be proposed.
    (n) Reconstitution time: Acceptance criteria for reconstitution
time should be provided for all parenteral products that require
reconstitution. The choice of diluent should be justified. Data
generated during product development and process validation may be
sufficient to justify skip lot testing or elimination of this attribute
from the specification for rapidly dissolving products.
 
4. Glossary (the following definitions are presented for the
purpose of this guidance)
 
    Acceptance criteria: Numerical limits, ranges, or other suitable
measures for acceptance of the results of analytical procedures.
    Chiral: Not superimposable with its mirror image, as applied to
molecules, conformations, and macroscopic objects, such as crystals.
The term has been extended to samples of substances whose molecules are
chiral, even if the macroscopic assembly of such molecules is racemic.
    Combination product: A drug product that contains more than one
drug substance.
    Degradation product: A molecule resulting from a chemical change in
the drug molecule brought about over time and/or by the action of
light, temperature, pH, water, or by reaction with an excipient and/or
the immediate container/closure system. Also called decomposition
product.
    Delayed release: Release of a drug (or drugs) at a time other than
immediately following oral administration.
    Enantiomers: Compounds with the same molecular formula as the drug
substance, which differ in the spatial arrangement of atoms within the
molecule and are nonsuperimposable mirror images.
 
[[Page 83051]]
 
    Extended release: Products that are formulated to make the drug
available over an extended period after administration.
    Highly water soluble drugs: Drugs with a dose/solubility volume of
less than or equal to 250 mL over a pH range of 1.2 to 6.8. (Example:
Compound A has as its lowest solubility at 370.5  deg.C,
1.0 milligram (mg)/milliliter (mL) at pH 6.8, and is available in 100
mg, 200 mg, and 400 mg strengths. This drug would be considered a low
solubility drug, as its dose/solubility volume is greater than 250 mL
(400 mg/1.0 mg/mL = 400 mL)).
    Immediate release: Allows the drug to dissolve in the
gastrointestinal contents, with no intention of delaying or prolonging
the dissolution or absorption of the drug.
    Impurity: (1) Any component of the new drug substance that is not
the chemical entity defined as the new drug substance. (2) Any
component of the drug product that is not the chemical entity defined
as the drug substance or an excipient in the drug product.
    Identified impurity: An impurity for which a structural
characterization has been achieved.
    In-process tests: Tests that may be performed during the
manufacture of either the drug substance or drug product, rather than
as part of the formal battery of tests that are conducted prior to
release.
    Modified release: Dosage forms whose drug release characteristics
of time course and/or location are chosen to accomplish therapeutic or
convenience objectives not offered by conventional dosage forms, such
as a solution or an immediate-release dosage form. Modified-release
solid oral dosage forms include both delayed- and extended-release drug
products.
    New drug product: A pharmaceutical product type, e.g., tablet,
capsule, solution, cream, etc., that has not previously been registered
in a region or Member State, and that contains a drug ingredient
generally, but not necessarily, in association with excipients.
    New drug substance: The designated therapeutic moiety that has not
previously been registered in a region or Member State (also referred
to as a new molecular entity or new chemical entity). It may be a
complex, simple ester, or salt of a previously approved drug substance.
    Polymorphism: The occurrence of different crystalline forms of the
same drug substance. This may include solvation or hydration products
(also known as pseudopolymorphs) and amorphous forms.
    Quality: The suitability of either a drug substance or drug product
for its intended use. This term includes such attributes as the
identity, strength, and purity.
    Racemate: A composite (solid, liquid, gaseous, or in solution) of
equimolar quantities of two enantiomeric species. It is devoid of
optical activity.
    Rapidly dissolving products: An immediate release solid oral drug
product is considered rapidly dissolving when not less than 80 percent
of the label amount of the drug substance dissolves within 15 minutes
in each of the following media: (1) pH 1.2, (2) pH 4.0, and (3) pH 6.8.
    Reagent: A substance, other than a starting material or solvent,
that is used in the manufacture of a new drug substance.
    Solvent: An inorganic or an organic liquid used as a vehicle for
the preparation of solutions or suspensions in the synthesis of a new
drug substance or the manufacture of a new drug product.
    Specification: A list of tests, references to analytical
procedures, and appropriate acceptance criteria that are numerical
limits, ranges, or other criteria for the tests described. It
establishes the set of criteria to which a drug substance or drug
product should conform to be considered acceptable for its intended
use. ``Conformance to specifications'' means that the drug substance
and/or drug product, when tested according to the listed analytical
procedures, will meet the listed acceptance criteria. Specifications
are critical quality standards that are proposed and justified by the
manufacturer and approved by regulatory authorities as conditions of
approval.
    Specific test: A test that is considered to be applicable to
particular new drug substances or particular new drug products,
depending on their specific properties and/or intended use.
    Specified impurity: An identified or unidentified impurity that is
selected for inclusion in the new drug substance or new drug product
specification and is individually listed and limited to ensure the
quality of the new drug substance or new drug product.
    Unidentified impurity: An impurity that is defined solely by
qualitative analytical properties (e.g., chromatographic retention
time).
    Universal test: A test that is considered potentially applicable to
all new drug substances, or all new drug products; e.g., appearance,
identification, assay, and impurity tests.
 
5. References
 
    International Conference on Harmonisation, ``Q3A Impurities in New
Drug Substances,'' 1996.
    International Conference on Harmonisation, ``Q3B Impurities in New
Drug Products,'' 1997.
    International Conference on Harmonisation, ``Q1A Stability Testing
of New Drug Substances and Products,'' 1994.
    International Conference on Harmonisation, ``Q2A Text on Validation
of Analytical Procedures,'' 1995.
    International Conference on Harmonisation, ``Q2B Validation of
Analytical Procedures: Methodology,'' 1996.
    International Conference on Harmonisation, ``Q3C Impurities:
Residual Solvents,'' 1997.
    International Conference on Harmonisation, ``Q6B Specifications:
Test Procedures and Acceptance Criteria for Biotechnological/Biological
Products,'' 1999.
 
6. Attachments: Decision Trees #1 through #8
 
    For the decision trees referenced in this guidance, see the
following pages.
 
BILLING CODE 4160-01-F
 
[[Page 83052]]
 
[GRAPHIC] [TIFF OMITTED] TN29DE00.037
 
 
[[Page 83053]]
 
 
[GRAPHIC] [TIFF OMITTED] TN29DE00.038
 
 
[[Page 83054]]
 
 
[GRAPHIC] [TIFF OMITTED] TN29DE00.039
 
 
[[Page 83055]]
 
 
[GRAPHIC] [TIFF OMITTED] TN29DE00.040
 
 
[[Page 83056]]
 
 
[GRAPHIC] [TIFF OMITTED] TN29DE00.041
 
 
[[Page 83057]]
 
 
[GRAPHIC] [TIFF OMITTED] TN29DE00.042
 
 
[[Page 83058]]
 
 
[GRAPHIC] [TIFF OMITTED] TN29DE00.043
 
 
[[Page 83059]]
 
 
[GRAPHIC] [TIFF OMITTED] TN29DE00.044
 
 
[[Page 83060]]
 
 
[GRAPHIC] [TIFF OMITTED] TN29DE00.045
 
 
[[Page 83061]]
 
 
[GRAPHIC] [TIFF OMITTED] TN29DE00.046
 
 
[[Page 83062]]
 
 
[GRAPHIC] [TIFF OMITTED] TN29DE00.047
 
 
 
[[Page 83063]]
 
 
    Dated: December 20, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-33369 Filed 12-28-00; 8:45 am]
BILLING CODE 4160-01-C