[Federal Register Volume 65, Number 251 (Friday, December 29, 2000)]
[Notices]
[Pages 83041-83063]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-33369]


-----------------------------------------------------------------------

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://www.fda.gov/cder/guidance/index.htm or at 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