[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]]
_______________________________________________________________________
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International Conference on Harmonisation; Draft Guidance on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International Conference on Harmonisation; Draft Guidance on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.
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SUMMARY: The Food and Drug Administration (FDA) is publishing a draft
guidance entitled ``Q6A Specifications: Test Procedures and Acceptance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 The draft guidance was prepared under the auspices of the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 The draft guidance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 The draft guidance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ADDRESSES: Submit written comments on the draft guidance to the Dockets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 Copies of the draft
guidance are available from the Drug Information Branch (HFD-210),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\
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\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.
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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
[[Page 62893]]
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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