[Federal Register Volume 62, Number 227 (Tuesday, November 25, 1997)]
[Notices]
[Pages 62890-62910]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-30916]



[[Page 62889]]

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Part V





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



International Conference on Harmonisation; Draft Guidance on 
Specifications: Test Procedures and Acceptance Criteria for New Drug 
Substances and New Drug Products: Chemical Substances; Notice

  Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / 
Notices  

[[Page 62890]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 97D-0448]


International Conference on Harmonisation; Draft Guidance on 
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SUMMARY: The Food and Drug Administration (FDA) is publishing a draft 
guidance entitled ``Q6A Specifications: Test Procedures and Acceptance 
Criteria for New Drug Substances and New Drug Products: Chemical 
Substances.'' The draft guidance was prepared under the auspices of the 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH). The draft guidance 
provides guidance on 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 The draft guidance 
is intended to assist in the establishment of a single set of global 
specifications for new drug substances and new drug products.

DATES: Written comments by January 26, 1998.

ADDRESSES: Submit written comments on the draft guidance to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 12420 
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the draft 
guidance are available from the Drug Information Branch (HFD-210), 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-800), Food and Drug Administration, 5600 Fishers 
Lane, Rockville, MD 20857, 301-827-5918, or
    Neil D. Goldman, Center for Biologic Evaluation and Research (HFM-
416), Food and Drug Administration, 8800 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 July 1997, the ICH Steering Committee agreed that a draft 
guidance entitled ``Q6A Specifications: Test Procedures and Acceptance 
Criteria for New Drug Substances and New Drug Products: Chemical 
Substances'' should be made available for public comment. The draft 
guidance is the product of the Quality Expert Working Group of the ICH. 
Comments about this draft will be considered by FDA and the Quality 
Expert Working Group. A related document for biotechnology derived 
products is the subject of a separate Expert Working Group.
    In accordance with Good Guidance Practices (62 FR 8961, February 
27, 1997), this document is now being called a guidance, rather than a 
guideline.
    The draft guidance provides guidance 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. The draft guidance is 
intended to assist in the establishment of a single set of global 
specifications for new drug substances and new drug products.
    This draft guidance represents the agency's current thinking on the 
selection of test 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 statute, regulations, or both.
    Interested persons may, on or before January 26, 1998, submit to 
the Dockets Management Branch (address above) written comments on the 
draft guidance. 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 draft guidance and received comments may be seen in the 
office above 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.htm''.
    The text of the draft guidance follows:

Q6A Specifications: Test Procedures and Acceptance Criteria for New 
Drug Substances and New Drug Products: Chemical Substances\1\
---------------------------------------------------------------------------

    \1\ This draft guidance represents the agency's current thinking 
on the selection of test 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 statute, regulations, 
or both.
---------------------------------------------------------------------------

Table of Contents

1. Introduction
    1.1 Specifications
    1.2 Objective of the Guidance
    1.3 Scope of the Guidance
2. General Concepts
    2.1 Periodic/Skip Testing
    2.2 Release vs. Shelf-Life Acceptance Criteria
    2.3 In-Process Tests

[[Page 62891]]

    2.4 Design and Development Considerations
    2.5 Limited Data Available at Filing
    2.6 Parametric Release
    2.7 Alternative Procedures
    2.8 Pharmacopoeial Tests and Acceptance Criteria
    2.9 Evolving Technologies
    2.10 Impact of Drug Substance on Drug Product Specifications
    2.11 Reference Standard
3. Guidelines
    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 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 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 binding quality standards that are agreed to between the 
appropriate governmental regulatory agency and the applicant.
    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, adherence to good manufacturing practices 
(GMP's), and a validated manufacturing process, e.g., raw material 
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.

1.2 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.

1.3 Scope of the Guidance

    The quality of drug substances and drug products is determined 
by their design, development, in-process controls, GMP controls, and 
process validation, and by specifications applied to them throughout 
development and manufacture. This guidance addresses specifications, 
i.e., those tests, procedures, and acceptance criteria used to 
assure 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 considerations listed above are 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); it does not address drug 
substances or drug products during the clinical research stages of 
drug development. Biological/biotechnological products, peptides, 
oligonucleotides, radiopharmaceuticals, fermentation and 
semisynthetic products derived therefrom, herbal products, and crude 
products of animal or plant origin are also not covered. A separate 
ICH guidance addresses specifications, tests, and procedures for 
biotechnological/biological products.
    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 reflects the current state of the art at the 
time it has been written, and should not be considered all-
encompassing. New analytical technology, and modifications to 
existing technology, are continuously being developed. Such 
technologies should be used when justifiable.
    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., inhalation dosage forms (powders, solutions, etc.), topical 
formulations (creams, ointments, gels), and 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/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-to-batch 
basis. This represents a less than full schedule of testing and 
should therefore be justified and presented to the regulatory 
authority prior to implementation. This concept may be applicable 
to, for example, dissolution (see section 2.4), residual solvents, 
and microbiological testing, e.g., 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 may 
therefore sometimes be implemented postapproval in accordance with 
GMP.
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 inhouse criteria, and not to the regulatory release 
criteria. In the European Union, there is a regulatory requirement 
for distinct specifications for release and for shelf-life.
2.3 In-Process Tests: In-process tests 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 
which are conducted prior to release. In-process tests that are used 
for the purpose of adjusting process parameters within an operating 
range, e.g., hardness and friability of tablet cores that will be 
coated, 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 of a solution), may be acceptable to satisfy specification 
requirements when the test is included in the specification.
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.
      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 very 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(4)).
2.5 Limited Data Available at Filing: It is recognized that only a 
limited amount of data

[[Page 62892]]

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 will focus necessarily on safety and efficacy.
2.6 Parametric Release: Parametric release can be used as an 
operational alternative to routine release testing for the drug 
product. Sterility testing for terminally sterilized drug products 
is one example. In this case, the release of a batch is based on 
results from monitoring specific parameters, e.g., temperature and 
pressure, during the terminal sterilization phase(s) of drug product 
manufacturing. These parameters can generally be more accurately 
controlled and measured, so that they are more reliable in 
predicting sterility assurance than is end-product sterility 
testing. It is important to note that the sterilization process 
should be adequately validated before parametric release is 
proposed. When parametric release is performed, the attribute which 
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 Pharmacopoeial Tests and Acceptance Criteria: References to 
certain methods are found in pharmacopoeias in each region. Wherever 
they are appropriate, pharmacopoeial methods should be utilized. 
Whereas differences in pharmacopoeial methods and/or acceptance 
criteria have existed among the regions, a harmonized specification 
is possible only if the methods and acceptance criteria defined are 
acceptable to regulatory authorities in all regions. This guidance 
is dependent on the successful completion of harmonization of 
pharmacopoeial methods for several attributes commonly considered in 
the specifications for new drug substances or new drug products.
    The following attributes are essentially harmonized with respect 
to analytical method and acceptance criteria, except where noted, 
across the European Pharmacopoeia (Ph. Eur.), Japanese Pharmacopoeia 
(JP), and United States Pharmacopeia (USP):
    Sterility
    Residue on Ignition/Sulfated Ash
    Bacterial Endotoxins
    Color/Clarity
    Particulate Matter
    Dissolution (apparatus)
    Disintegration (apparatus)
    To signify the harmonized status of these general methods, the 
pharmacopoeias will include a statement in the text that indicates 
that the methods and acceptance criteria from all three 
pharmacopoeias are considered equivalent and are, therefore, 
interchangeable. An appropriate reference to the harmonized method 
and acceptance criteria is considered acceptable for a specification 
in all three regions. For example, sterility data generated using 
the JP method, as well as the JP method itself and its acceptance 
criteria, are considered acceptable for registration in all three 
regions. An appropriate reference may be expressed as JP/Ph. Eur./
USP.
    Harmonization of the following attributes will be completed 
prior to approval of a step 4 guidance:
    Dissolution (media and acceptance criteria)
    Disintegration (media and acceptance criteria)
    Uniformity of Mass
    Uniformity of Content
    Extractable Volume
    Preservative Effectiveness (scope of test and acceptance 
criteria)
    Microbial Contamination
2.9 Evolving Technologies: New analytical technology and 
modifications to existing technology are continuously being 
developed. Such technologies should be used when they are considered 
to offer additional assurance of quality, or are otherwise 
justifiable.
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 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 ``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. The substance may be either 
the new drug substance or a known impurity. It has a quality 
appropriate to its use. 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. Guidelines

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 binding quality standards that are agreed to 
between the appropriate governmental regulatory agency and the 
applicant.
    It is possible that, in addition to release tests, a 
specification may list in-process tests, periodic (skip) tests, and 
other tests which 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, 
pharmacopoeial standards, test data for drug substances and drug 
products 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 primary stability and scale-up/validation 
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 exclusion of a 
test from the specification should be based on development data and 
on process validation data (where available).
    When only limited data are available, the initially approved 
tests and acceptance criteria should be reviewed as more

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information is collected, with a view towards possible modification. 
This could involve loosening, as well as tightening, acceptance 
criteria as appropriate.

3.2 Universal Tests/Criteria

    Implementation of the recommendations in the following section 
should take into account the ICH guidances ``Text on Validation of 
Analytical Procedures'' and ``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 chromatographic retention time, for 
example, is not regarded as being specific; however, a combination 
of tests into a single procedure, such as HPLC (high pressure/
performance liquid chromatography)/UV (ultraviolet)-diode array, 
HPLC/MS (mass spectroscopy), or GC (gas chromatography)/MS may be 
acceptable. If the new drug substance is a salt, identification 
testing should be performed for the individual ions.
    New drug substances which are optically active may also need 
specific identification testing. 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 can be used.
    (d) Impurities: Organic and inorganic impurities and residual 
solvents are included in this category. Refer to the ICH guidances 
``Impurities in New Drug Substances'' and ``Residual Solvents in 
Pharmaceuticals'' 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 inappropriate to establish acceptance criteria that tightly 
encompass the batch data at the time of filing. (See section 2.5, 
limited data available at filing.)

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, 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 which are likely to be present. Identity tests should be 
specific for the new drug substance, e.g., infrared spectroscopy. 
Identification solely by chromatographic retention time, for 
example, is not regarded as being specific; however, a combination 
of tests into a single procedure, such as HPLC/UV-diode array, may 
be acceptable.
    (c) Assay: A specific, stability-indicating assay to determine 
strength 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, the combination of the assay and a suitable test for 
impurities can be used.
    (d) Impurities: Organic and inorganic impurities and residual 
solvents are included in this category. Refer to the ICH guidances 
``Impurities in New Drug Products'' and ``Residual Solvents in 
Pharmaceuticals'' for detailed information.
    Organic impurities arising from degradation of the new drug 
substance 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. When it has been 
conclusively demonstrated via appropriate analytical methodology, 
with a significant body of data, 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 inappropriate to establish acceptance criteria that 
tightly encompass the batch data at the time of filing. (See section 
2.5, limited data available at filing).

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) Solid state forms: Some new drug substances exist in 
different solid state forms (polymorphs or solvates) that differ in 
their physical properties. 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.
    Physico-chemical 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, scanning electron microscopy, and 
solid state NMR (nuclear magnetic resonance spetroscopy).
    Decision trees #4(1) through #4(3) provide additional guidance 
on when, and how, solid state forms should be monitored and 
controlled.
    Note: These decision trees should be followed sequentially. 
Trees #1 and #2 consider whether polymorphism is exhibited by the 
drug substance and whether the different polymorphic forms can 
affect performance of the drug product. Tree #3 should only be 
applied when polymorphism has been demonstrated for the drug 
substance

[[Page 62894]]

and has been shown to affect these properties. Tree #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) can generally be used to monitor product performance, 
and polymorph content should only be used as a test and acceptance 
criterion of last resort.
    The decision trees focus on polymorphism, but the same decision 
process can be applied to other solid state criteria, such as 
hydration and solvation, where appropriate.
    (d) Tests for new drug substances that are optically active: 
Chiral impurities are excluded from ICH guidances on ``Impurities in 
New Drug Substances'' and ``Impurities in New Drug Products'' 
because of practical difficulties in quantifying them at the 
qualification and identification thresholds given in those 
guidances. However, chiral impurities in chiral new drug substances 
and the resulting new drug products should be treated according to 
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 
determination or qualification being applied. If it is technically 
difficult to effect control in the drug substance itself, assurance 
of control 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. The identity test(s) should be capable of 
distinguishing a single enantiomer from its opposite enantiomer. 
Where a drug substance is a racemate, the identity method should be 
capable of verifying the racemic nature and distinguishing it from 
either enantiomer.
    Drug Product: Degradation products. Control of the other 
enantiomer in a drug product is necessary if that enantiomer has 
been shown to be a degradation product.
    Assay. Where development studies have demonstrated that the 
enantiomer is not a degradation product, an achiral assay may be 
sufficient. However, a chiral assay is preferred or, alternatively, 
the combination of an achiral assay plus a procedure to control the 
presence of the opposite enantiomer.
    Identity. An identity test should be established that is capable 
of verifying the presence of the correct enantiomer or the racemate, 
as appropriate.
    (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 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 should be studied 
during development and based on knowledge of the manufacturing 
process. Where justified, procedures and acceptance criteria for 
sulfated ash/residue on ignition should follow pharmacopoeial 
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 
pharmacopoeial procedures. In special cases, sterility testing or 
endotoxin testing may be appropriate. For example, the drug 
substance is manufactured as sterile (sterility testing appropriate) 
or will be used to formulate an injectable drug product (endotoxin 
testing appropriate).
    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 which 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/disintegration: For rapidly dissolving products 
containing drugs that are highly soluble throughout the 
physiological pH range, disintegration testing may sometimes be 
sufficient. Disintegration testing is 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 always be necessary, or 
may be proposed as a skip test. 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 vs. disintegration testing.
    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.
    Where multiple-point acceptance criteria are necessary, in 
vitro/in vivo correlation may be used to establish these 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 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 50 +/-10 percent thus means an acceptable 
range from 40 to 60 percent) unless a wider range is supported by a 
bioequivalency study.
    Decision trees #7(1) through #7(4) provide additional guidance 
on the use of dissolution and disintegration testing.
    (b) 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.
    (c) Uniformity of dosage units: This term includes both 
uniformity of content and uniformity of mass; a pharmacopoeial 
procedure should be used. If appropriate, these tests may be 
performed as in-process controls; the acceptance criteria should be 
included in the specification.
    (d) 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 adequate; however, 
a detection procedure which is specific for water (e.g., Karl 
Fischer titration) is preferred.
    (e) 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. It should be noted that, whereas this guidance does 
not directly address excipients elsewhere, 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.

[[Page 62895]]

    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). These should be 
determined by suitable procedures, using pharmacopoeial procedures, 
and at a sampling frequency or time point in manufacture that is 
justified by data and experience. With acceptable scientific 
justification, it may be possible to propose no microbial limit 
testing for solid oral dosage forms.
    Decision tree #8 provides additional guidance on the use of 
microbial limit 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 
uniformity of content and uniformity of mass. Generally, acceptance 
criteria should be set for weight variation, fill volume, and/or 
uniformity of fill. Pharmacopoeial procedures should be used.
    If appropriate, tests may be performed as in-process controls; 
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. It should be noted that, whereas this guidance does 
not directly address excipients elsewhere, 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. 
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). These should be 
determined by suitable procedures, using pharmacopoeial procedures, 
and at a sampling frequency or time point in manufacture which is 
justified by data and experience.
    Decision tree #8 provides additional guidance on the use of 
microbial limit testing.
    (d) Antimicrobial preservative content: For oral liquids needing 
an antimicrobial preservative, acceptance criteria for preservative 
content may be appropriate. These criteria should be based on the 
levels necessary to maintain microbiological product quality 
throughout the shelf-life. The lowest specified concentration of 
antimicrobial preservative should be demonstrated to be effective in 
controlling microorganisms by using a pharmacopoeial antimicrobial 
preservative effectiveness test.
    Release testing for antimicrobial preservative content should 
normally be performed. 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 ``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. 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 no significant evidence of extractables, elimination of 
this test may be proposed. This should be reinvestigated if the 
container/closure system changes.
    Where data demonstrate the need, tests and acceptance criteria 
for extractables from the container/closure system components (e.g., 
rubber stopper, cap liner, plastic bottle) 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. The 
testing apparatus, media, and conditions should be pharmacopoeial, 
if possible, or otherwise justified. Dissolution procedures using 
either pharmacopoeial or non-pharmacopoeial 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.
    Dissolution testing may be performed as an in-process test, or 
as a release test, depending on its relevance to product 
performance. The discussion of dissolution for solid oral dosage 
forms (above), and of particle size distribution (immediately 
following), should also be considered here.
    (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 may be performed as an in-
process test or as a release test, depending on its relevance to 
product performance. 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 which settle on 
storage (produce sediment), acceptance criteria for redispersibility 
may be appropriate. Shaking may be an appropriate test. 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.

[[Page 62896]]

    (k) Rheological properties: For relatively viscous solutions or 
suspensions, it may be appropriate to include rheological properties 
(viscosity) in the specification. The test and acceptance criteria 
should be stated. Data generated during product development may be 
sufficient to justify skip lot testing or elimination of this 
attribute from the specification.
    (l) Specific gravity: For oral suspensions or relatively viscous 
or nonaqueous solutions, acceptance criteria for specific gravity 
may be appropriate. Testing may be performed as an in-process 
control.
    (m) Reconstitution time: Acceptance criteria for reconstitution 
time should be provided for dry powder products which require 
reconstitution. The choice of diluent should be justified. Data 
generated during product development may be sufficient to justify 
skip lot testing or elimination of this attribute from the 
specification.
    (n) 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 vs. 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 
uniformity of content and uniformity of mass; a pharmacopoeial 
procedure should be used. Generally, acceptance criteria should be 
set for weight variation, fill volume, or uniformity of fill.
    If appropriate, these tests may be performed as in-process 
controls; 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.
    (d) Endotoxins: A test procedure and acceptance criterion for 
endotoxins, using a procedure such as the limulus amoebocyte lysate 
test, should be included in the specification.
    (e) Pyrogens: Pyrogenicity testing may be proposed as an 
alternative to endotoxin testing where justified.
    (f) Particulate matter: Parenteral products should have 
appropriate acceptance criteria for particulate matter. This will 
normally include limits for visible particulates (also designated 
``foreign matter'') and/or clarity of solution, as well as for 
subvisible particulates.
    (g) 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 vs. water of 
hydration has been adequately characterized during development. In 
certain cases, a more specific procedure (e.g., Karl Fischer 
titration) may be preferred.
    (h) Antimicrobial preservative content: For parenteral products 
needing an antimicrobial preservative, acceptance criteria for 
preservative content may be appropriate. These criteria should be 
based on the levels necessary to maintain microbiological product 
quality throughout the shelf-life. The lowest specified 
concentration of antimicrobial preservative should be demonstrated 
to be effective in controlling microorganisms by using a 
pharmacopoeial antimicrobial preservative effectiveness test.
    Release testing for antimicrobial preservative content should 
normally be performed. 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 ``Stability 
Testing of New Drug Substances and Products''), although chemical 
testing for preservative content is the attribute normally included 
in the specification.
    (i) 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.
    (j) Extractables: Control of extractables is considered 
significantly more important for parenteral products than for oral 
liquids. However, where development and stability data show no 
significant evidence of extractables, elimination of this test may 
be proposed. This should be reinvestigated if the container/closure 
system 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) should be listed, and data collected for these components 
as early in the development process as possible.
    (k) 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. Data generated during product development may be 
sufficient to justify skip lot testing or elimination of some 
attributes from the specification.
    (l) Osmolality: When the tonicity of a product is declared in 
its labeling, appropriate control of its osmolality 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.
    (m) 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 may be performed as an in-
process test or as a release test, depending on its relevance to 
product performance. 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.
    (n) Redispersibility: For injectable suspensions which settle on 
storage (produce sediment), acceptance criteria for redispersibility 
may be appropriate. Shaking may be an appropriate test. 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.
    (o) Reconstitution time: Acceptance criteria for reconstitution 
time should be provided for all parenteral products which require 
reconstitution. The choice of diluent should be justified. Data 
generated during product development may be sufficient to justify 
skip lot testing or elimination of this attribute from the 
specification.

[[Page 62897]]

4. Glossary

    Acceptance criteria: Numerical limits, ranges, or other suitable 
measures for acceptance of the results of analytical procedures.
    Chiral: Not superposable 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 
e.g., light, temperature, pH, water, or by reaction with an 
excipient and/or the immediate container/closure system. Also called 
decomposition product.
    Enantiomers: Compounds with the same molecular formula as the 
drug substance, that differ in the spatial arrangement of atoms 
within the molecule and are nonsuperimposable mirror images.
    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.
    New drug product: A pharmaceutical product type, for example, 
tablet, capsule, solution, cream, that has not previously been 
registered in a region or Member State, and which 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 of the article.
    Racemate: A composite (solid, liquid, gaseous, or in solution) 
of equimolar quantities of two enantiomeric species. It is devoid of 
optical activity.
    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 binding quality standards that are agreed to between the 
appropriate governmental regulatory agency and the applicant.
    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 in 
order to assure 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 to be 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, ``Impurities in New 
Drug Substances,'' 1995.
    International Conference on Harmonisation, ``Impurities in New 
Drug Products,'' 1996.
    International Conference on Harmonisation, ``Stability Testing 
of New Drug Substances and Products,'' 1994.
    International Conference on Harmonisation, ``Text on Validation 
of Analytical Procedures,'' 1994.
    International Conference on Harmonisation, ``Validation of 
Analytical Procedures: Methodology,'' 1996.
    International Conference on Harmonisation, ``Residual Solvents 
in Pharmaceuticals,'' 1996.

6. Attachments: Decision Trees #1 through #8

    For the decision trees referenced in this guidance, see the 
following pages.

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    Dated: November 18, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-30916 Filed 11-24-97; 8:45 am]
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