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GUIDANCE DOCUMENT

Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances December 2000

Final
Issued by:
Guidance Issuing Office
Center for Drug Evaluation and Research

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

[Notices]

[Page 83041-83063]

From the Federal Register Online via GPO Access [wais.access.gpo.gov]

[DOCID:fr29de00-84]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 97D-0448]

International Conference on Harmonisation; Guidance on Q6A

Specifications: Test Procedures and Acceptance Criteria for New Drug

Substances and New Drug Products: Chemical Substances

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing a

guidance entitled ``Q6A Specifications: Test Procedures and Acceptance

Criteria for New Drug Substances and New Drug Products: Chemical

Substances.'' The guidance was prepared under the auspices of the

International Conference on Harmonisation of Technical Requirements for

Registration of Pharmaceuticals for Human Use (ICH). The guidance

describes or provides recommendations concerning the selection of test

procedures and the setting and justification of acceptance criteria for

new chemical drug substances and new drug products produced from them.

The guidance is intended to assist in the establishment of a single set

of global specifications for new drug substances and new drug products.

DATES: Submit written comments by March 29, 2001.

ADDRESSES: Submit written comments on the guidance to the Dockets

Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers

Lane, rm. 1061, Rockville, MD 20852. Copies of the guidance are

available from the Drug Information Branch (HFD-210), Center for Drug

Evaluation and Research, Food and Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857, 301-827-4573.

FOR FURTHER INFORMATION CONTACT:

    Regarding the guidance: Eric B. Sheinin, Center for Drug Evaluation

and Research (HFD-003), Food and Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857, 301-594-2847, or Neil D. Goldman, Center for

Biologics Evaluation and Research (HFM-20), Food and Drug

Administration, 1401 Rockville Pike, Rockville, MD 20852, 301-827-0377.

    Regarding the ICH: Janet J. Showalter, Office of Health Affairs

(HFY-20), Food and Drug Administration, 5600 Fishers Lane, Rockville,

MD 20857, 301-827-0864.

SUPPLEMENTARY INFORMATION: In recent years, many important initiatives

have been undertaken by regulatory authorities and industry

associations to promote international harmonization of regulatory

requirements. FDA has participated in many meetings designed to enhance

harmonization and is committed to seeking scientifically based

harmonized technical procedures for pharmaceutical development. One of

the goals of harmonization is to identify and then reduce differences

in technical requirements for drug development among regulatory

agencies.

    ICH was organized to provide an opportunity for tripartite

harmonization initiatives to be developed with input from both

regulatory and industry representatives. FDA also seeks input from

consumer representatives and others. ICH is concerned with

harmonization of technical requirements for the registration of

pharmaceutical products among three regions: The European Union, Japan,

and the United States. The six ICH sponsors are the European

Commission, the European Federation of Pharmaceutical Industries

Associations, the Japanese Ministry of Health and Welfare, the Japanese

Pharmaceutical Manufacturers Association, the Centers for Drug

Evaluation and Research and Biologics Evaluation and Research, FDA, and

the Pharmaceutical Research and Manufacturers of America. The ICH

Secretariat, which coordinates the preparation of documentation, is

provided by the International Federation of Pharmaceutical

Manufacturers Associations (IFPMA).

    The ICH Steering Committee includes representatives from each of

the ICH sponsors and the IFPMA, as well as observers from the World

Health Organization, the Canadian Health Protection Branch, and the

European Free Trade Area.

    In the Federal Register of November 25, 1997 (62 FR 62890), FDA

published a draft tripartite guidance entitled ``Q6A Specifications:

Test Procedures and

[Page 83042]

Acceptance Criteria for New Drug Substances and New Drug Products:

Chemical Substances.'' The notice gave interested persons an

opportunity to submit comments by January 26, 1998.

    After consideration of the comments received and revisions to the

guidance, a final draft of the guidance was submitted to the ICH

Steering Committee and endorsed by the three participating regulatory

agencies on October 6, 1999.

    In accordance with FDA's good guidance practices regulation (65 FR

56468, September 19, 2000), this document has been designated a

guidance, rather than a guideline.

    The guidance provides recommendations on the selection of test

procedures and the setting and justification of acceptance criteria for

new drug substances of synthetic chemical origin, and new drug products

produced from them, that have not been registered previously in the

United States, the European Union, or Japan. This guidance is intended

to assist in the establishment of a single set of global specifications

for new drug substances and new drug products.

    This guidance represents the agency's current thinking on the

selection of tests procedures and the setting and justification of

acceptance criteria for new chemical drug substances and new drug

products. It does not create or confer any rights for or on any person

and does not operate to bind FDA or the public. An alternative approach

may be used if such approach satisfies the requirements of the

applicable statutes and regulations.

    Interested persons may submit to the Dockets Management Branch

(address above) written comments on the guidance at any time. Two

copies of any comments are to be submitted, except that individuals may

submit one copy. Comments are to be identified with the docket number

found in brackets in the heading of this document. The guidance and

received comments may be seen in the Dockets Management Branch between

9 a.m. and 4 p.m., Monday through Friday. An electronic version of this

guidance is available on the Internet.

    The text of the 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 guidance represents the Food and Drug Administration's

current thinking on this topic. It does not create or confer any

rights for or on any person and does not operate to bind FDA or the

public. An alternative approach may be used if such approach

satisfies the requirements of the applicable statutes and

regulations.

Table of Contents

1. Introduction

    1.1 Objective of the Guidance

    1.2 Background

    1.3 Scope of the Guidance

2. General Concepts

    2.1 Periodic or Skip Testing

    2.2 Release vs. Shelf-Life Acceptance Criteria

    2.3 In-Process Tests

    2.4 Design and Development Considerations

    2.5 Limited Data Available at Filing

    2.6 Parametric Release

    2.7 Alternative Procedures

    2.8 Pharmacopeial Tests and Acceptance Criteria

    2.9 Evolving Technologies

    2.10 Impact of Drug Substance on Drug Product Specifications

   2.11 Reference Standard

3. Guidance

    3.1 Specifications: Definition and Justification

    3.1.1 Definition of Specifications

    3.1.2 Justification of Specifications

    3.2 Universal Tests/Criteria

    3.2.1 New Drug Substances

    3.2.2 New Drug Products

    3.3 Specific Tests/Criteria

    3.3.1 New Drug Substances

    3.3.2 New Drug Products

4. Glossary

5. References

6. Attachments: Decision Trees #1 Through #8

1. Introduction

1.1 Objective of the Guidance

    This guidance is intended to assist, to the extent possible, in the

establishment of a single set of global specifications for new drug

substances and new drug products. It provides guidance on the setting

and justification of acceptance criteria and the selection of test

procedures for new drug substances of synthetic chemical origin, and

new drug products produced from them, that have not been registered

previously in the United States, the European Union, or Japan.

1.2 Background

    A specification is defined as a list of tests, references to

analytical procedures, and appropriate acceptance criteria that are

numerical limits, ranges, or other criteria for the tests described. It

establishes the set of criteria to which a drug substance or drug

product should conform to be considered acceptable for its intended

use. ``Conformance to specifications'' means that the drug substance

and/or drug product, when tested according to the listed analytical

procedures, will meet the listed acceptance criteria. Specifications

are critical quality standards that are proposed and justified by the

manufacturer and approved by regulatory authorities as conditions of

approval.

    Specifications are one part of a total control strategy for the

drug substance and drug product designed to ensure product quality and

consistency. Other parts of this strategy include thorough product

characterization during development, upon which specifications are

based, and adherence to good manufacturing practices (GMP's), e.g.,

suitable facilities, a validated manufacturing process, validated test

procedures, raw materials testing, in-process testing, stability

testing.

    Specifications are chosen to confirm the quality of the drug

substance and drug product rather than to establish full

characterization, and should focus on those characteristics found to be

useful in ensuring the safety and efficacy of the drug substance and

drug product.

1.3 Scope of the Guidance

    The quality of drug substances and drug products is determined by

their design, development, in-process controls, GMP controls, process

validation, and by specifications applied to them throughout

development and manufacture. This guidance addresses specifications,

i.e., those tests, procedures, and acceptance criteria that play a

major role in assuring the quality of the new drug substance and new

drug product at release and during shelf life. Specifications are an

important component of quality assurance, but are not its only

component. All of the factors listed above are considered necessary to

ensure consistent production of drug substances and drug products of

high quality.

    This guidance addresses only the marketing approval of new drug

products (including combination products) and, where applicable, new

drug substances; it does not address drug substances or drug products

during the clinical research stages of drug development. This guidance

may be applicable to synthetic and semisynthetic antibiotics and

synthetic peptides of low molecular weight; however, it is not

sufficient to

[Page 83043]

adequately describe specifications of higher molecular weight peptides

and polypeptides, and biotechnological/biological products. The ICH

guidance on ``Q6B Specifications: Test Procedures and Acceptance

Criteria for Biotechnological/Biological Products'' addresses guidance

specifications, tests, and procedures for biotechnological/biological

products. Radiopharmaceuticals, products of fermentation,

oligonucleotides, herbal products, and crude products of animal or

plant origin are similarly not covered.

    Guidance is provided with regard to acceptance criteria that should

be established for all new drug substances and new drug products, i.e.,

universal acceptance criteria, and those that are considered specific

to individual drug substances and/or dosage forms. This guidance should

not be considered all encompassing. New analytical technologies, and

modifications to existing technology, are continually being developed.

Such technologies should be used when justified.

    Dosage forms addressed in this guidance include solid oral dosage

forms, liquid oral dosage forms, and parenterals (small and large

volume). This is not meant to be an all-inclusive list, or to limit the

number of dosage forms to which this guidance applies. The dosage forms

presented serve as models that may be applicable to other dosage forms

that have not been discussed. The extended application of the concepts

in this guidance to other dosage forms, e.g., to inhalation dosage

forms (powders, solutions, etc.), to topical formulations (creams,

ointments, gels), and to transdermal systems, is encouraged.

2. General Concepts

    The following concepts are important in the development and setting

of harmonized specifications. They are not universally applicable, but

each should be considered in particular circumstances. This guidance

presents a brief definition of each concept and an indication of the

circumstances under which it may be applicable. Generally, proposals to

implement these concepts should be justified by the applicant and

approved by the appropriate regulatory authority before being put into

effect.

2.1 Periodic or Skip Testing

    Periodic or skip testing is the performance of specified tests at

release on preselected batches and/or at predetermined intervals,

rather than on a batch-by-batch basis, with the understanding that

those batches not being tested still meet all acceptance criteria

established for that product. This represents a less than full schedule

of testing and should therefore be justified and presented to and

approved by the regulatory authority prior to implementation. This

concept may be applicable to, for example, residual solvents and

microbiological testing for solid oral dosage forms. It is recognized

that only limited data may be available at the time of submission of an

application (see section 2.5). This concept should therefore generally

be implemented postapproval. When tested, any failure to meet

acceptance criteria established for the periodic test should be handled

by proper notification of the appropriate regulatory authority(ies). If

these data demonstrate a need to restore routine testing, then batch-

by-batch release testing should be reinstated.

2.2 Release vs. Shelf-Life Acceptance Criteria

    The concept of different acceptance criteria for release vs. shelf-

life specifications applies to drug products only; it pertains to the

establishment of more restrictive criteria for the release of a drug

product than are applied to the shelf life. Examples where this may be

applicable include assay and impurity (degradation product) levels. In

Japan and the United States, this concept may only be applicable to in-

house criteria, and not to the regulatory release criteria. Thus, in

these regions, the regulatory acceptance criteria are the same from

release throughout shelf life; however, an applicant may choose to have

tighter in-house limits at the time of release to provide increased

assurance to the applicant that the product will remain within the

regulatory acceptance criteria throughout its shelf life. In the

European Union there is a regulatory requirement for distinct

specifications for release and for shelf life where different.

2.3 In-Process Tests

    In-process tests, as presented in this guidance, are tests that may

be performed during the manufacture of either the drug substance or

drug product, rather than as part of the formal battery of tests that

are conducted prior to release.

    In-process tests that are only used for the purpose of adjusting

process parameters within an operating range, e.g., hardness and

friability of tablet cores that will be coated and individual tablet

weights, are not included in the specification.

    Certain tests conducted during the manufacturing process, where the

acceptance criterion is identical to or tighter than the release

requirement, (e.g., pH (hydrogen-ion concentration) of a solution) may

be sufficient to satisfy specification requirements when the test is

included in the specification. However, this approach should be

validated to show that test results or product performance

characteristics do not change from the in-process stage to finished

product.

2.4 Design and Development Considerations

    The experience and data accumulated during the development of a new

drug substance or product should form the basis for the setting of

specifications. It may be possible to propose excluding or replacing

certain tests on this basis. Some examples are:

     Microbiological testing for drug substances and solid

dosage forms that have been shown during development not to support

microbial viability or growth (see Decision Trees #6 and #8).

     Extractables from product containers where it has been

reproducibly shown that either no extractables are found in the drug

product or the levels meet accepted standards for safety.

     Particle size testing may fall into this category, may be

performed as an in-process test, or may be performed as a release test,

depending on its relevance to product performance.

     Dissolution testing for immediate release solid oral drug

products made from highly water soluble drug substances may be replaced

by disintegration testing, if these products have been demonstrated

during development to have consistently rapid drug release

characteristics (see Decision Trees #7(1) through #7(2)).

2.5 Limited Data Available at Filing

    It is recognized that only a limited amount of data may be

available at the time of filing, which can influence the process of

setting acceptance criteria. As a result, it may be necessary to

propose revised acceptance criteria as additional experience is gained

with the manufacture of a particular drug substance or drug product

(example: acceptance limits for a specific impurity). The basis for the

acceptance criteria at the time of filing should necessarily focus on

safety and efficacy.

    When only limited data are available, the initially approved tests

and acceptance criteria should be reviewed as more information is

collected, with a view towards possible modification. This could

involve loosening, as well as tightening, acceptance criteria, as

appropriate.

[Page 83044]

2.6 Parametric Release

    Parametric release can be used as an operational alternative to

routine release testing for the drug product in certain cases, when

approved by the regulatory authority. Sterility testing for terminally

sterilized drug products is one example. In this case, the release of

each batch is based on satisfactory results from monitoring specific

parameters, e.g., temperature, pressure, and time during the terminal

sterilization phase(s) of drug product manufacturing. These parameters

can generally be more accurately controlled and measured, so they are

more reliable in predicting sterility assurance than is end-product

sterility testing. Appropriate laboratory tests (e.g., chemical or

physical indicator) may be included in the parametric release program.

It is important to note that the sterilization process should be

adequately validated before parametric release is proposed, and

maintenance of a validated state should be demonstrated by revalidation

at established intervals. When parametric release is performed, the

attribute that is indirectly controlled (e.g., sterility), together

with a reference to the associated test procedure, still should be

included in the specifications.

2.7 Alternative Procedures

    Alternative procedures are those that may be used to measure an

attribute when such procedures control the quality of the drug

substance or drug product to an extent that is comparable or superior

to the official procedure. Example: For tablets that have been shown

not to degrade during manufacture, it may be permissible to use a

spectrophotometric procedure for release as opposed to the official

procedure, which is chromatographic. However, the chromatographic

procedure should still be used to demonstrate compliance with the

acceptance criteria during the shelf life of the product.

2.8 Pharmacopeial Tests and Acceptance Criteria

    References to certain procedures are found in pharmacopeias in each

region. Wherever they are appropriate, pharmacopeial procedures should

be used. Whereas differences in pharmacopeial procedures and/or

acceptance criteria have existed among the regions, a harmonized

specification is possible only if the procedures and acceptance

criteria defined are acceptable to regulatory authorities in all

regions.

    The full utility of this guidance is dependent on the successful

completion of harmonization of pharmacopeial procedures for several

attributes commonly considered in the specification for new drug

substances or new drug products. The Pharmacopoeial Discussion Group

(PDG) of the European Pharmacopeia, the Japanese Pharmacopoeia (JP),

and the United States Pharmacopeia has expressed a commitment to

achieving harmonization of the procedures in a timely fashion.

    Where harmonization has been achieved, an appropriate reference to

the harmonized procedure and acceptance criteria is considered

acceptable for a specification in all three regions. For example, after

harmonization, sterility data generated using the JP procedure, as well

as the JP procedure itself and its acceptance criteria, will be

considered acceptable for registration in all three regions. To signify

the harmonized status of these procedures, the pharmacopeias have

agreed to include a statement in their respective texts that indicates

that the procedures and acceptance criteria from all three

pharmacopeias are considered equivalent and are, therefore,

interchangeable.

    Since the overall value of this guidance is linked to the extent of

harmonization of the analytical procedures and acceptance criteria of

the pharmacopeias, it is agreed by the members of the Q6A expert

working group that none of the three pharmacopeias should change a

harmonized monograph unilaterally. According to the PDG procedure for

the revision of harmonized monographs and chapters, ``no pharmacopoeia

shall revise unilaterally any monograph or chapter after sign-off or

after publication.''

2.9 Evolving Technologies

    New analytical technologies, and modifications to existing

technology, are continually being developed. Such technologies should

be used when they are considered to offer additional assurance of

quality, or are otherwise justified.

2.10 Impact of Drug Substance on Drug Product Specifications

   In general, it should not be necessary to test the drug product for

quality attributes uniquely associated with the drug substance.

Example: It is normally not considered necessary to test the drug

product for synthesis impurities that are controlled in the drug

substance and are not degradation products. Refer to the ICH guidance

on ``Q3B Impurities in New Drug Products'' for detailed information.

2.11 Reference Standard

    A reference standard, or reference material, is a substance

prepared for use as the standard in an assay, identification, or purity

test. It should have a quality appropriate to its use. It is often

characterized and evaluated for its intended purpose by additional

procedures other than those used in routine testing. For new drug

substance reference standards intended for use in assays, the

impurities should be adequately identified and/or controlled, and

purity should be measured by a quantitative procedure.

3. Guidance

3.1 Specifications: Definition and Justification

3.1.1 Definition of Specifications

    A specification is defined as a list of tests, references to

analytical procedures, and appropriate acceptance criteria that are

numerical limits, ranges, or other criteria for the tests described. It

establishes the set of criteria to which a new drug substance or new

drug product should conform to be considered acceptable for its

intended use. ``Conformance to specifications'' means that the drug

substance and/or drug product, when tested according to the listed

analytical procedures, will meet the listed acceptance criteria.

Specifications are critical quality standards that are proposed and

justified by the manufacturer and approved by regulatory authorities as

conditions of approval.

    It is possible that, in addition to release tests, a specification

may list in-process tests as defined in section 2.3, periodic or skip

tests, and other tests that are not always conducted on a batch-by-

batch basis. In such cases the applicant should specify which tests are

routinely conducted batch by batch, and which tests are not, with an

indication and justification of the actual testing frequency. In this

situation, the drug substance and/or drug product should meet the

acceptance criteria if tested.

    It should be noted that changes in the specification after approval

of the application may need prior approval by the regulatory authority.

3.1.2 Justification of Specifications

    When a specification is first proposed, justification should be

presented for each procedure and each acceptance criterion included.

The justification should refer to relevant development data,

pharmacopeial standards, test data for drug substances and drug

products

[Page 83045]

used in toxicology and clinical studies, and results from accelerated

and long-term stability studies, as appropriate. Additionally, a

reasonable range of expected analytical and manufacturing variability

should be considered. It is important to consider all of this

information.

    Approaches other than those set forth in this guidance may be

applicable and acceptable. The applicant should justify alternative

approaches. Such justification should be based on data derived from the

new drug substance synthesis and/or the new drug product manufacturing

process. This justification may consider theoretical tolerances for a

given procedure or acceptance criterion, but the actual results

obtained should form the primary basis for whatever approach is taken.

    Test results from stability and scaleup/validation batches, with

emphasis on the primary stability batches, should be considered in

setting and justifying specifications. If multiple manufacturing sites

are planned, it may be valuable to consider data from these sites in

establishing the initial tests and acceptance criteria. This is

particularly true when there is limited initial experience with the

manufacture of the drug substance or drug product at any particular

site. If data from a single representative manufacturing site are used

in setting tests and acceptance criteria, product manufactured at all

sites should still comply with these criteria.

    Presentation of test results in graphic format may be helpful in

justifying individual acceptance criteria, particularly for assay

values and impurity levels. Data from development work should be

included in such a presentation, along with stability data available

for new drug substance or new drug product batches manufactured by the

proposed commercial processes. Justification for proposing exclusion of

a test from the specification should be based on development data and

on process validation data (where appropriate).

3.2 Universal Tests/Criteria

    Implementation of the recommendations in the following section

should take into account the ICH guidances ``Q2A Text on Validation of

Analytical Procedures'' and ``Q2B Validation of Analytical Procedures:

Methodology.''

3.2.1 New Drug Substances

    The following tests and acceptance criteria are considered

generally applicable to all new drug substances.

    (a) Description: A qualitative statement about the state (e.g.,

solid, liquid) and color of the new drug substance. If any of these

characteristics change during storage, this change should be

investigated and appropriate action taken.

    (b) Identification: Identification testing should optimally be able

to discriminate between compounds of closely related structure that are

likely to be present. Identification tests should be specific for the

new drug substance, e.g., infrared spectroscopy (IR). Identification

solely by a single chromatographic retention time, for example, is not

regarded as being specific. However, the use of two chromatographic

procedures, where the separation is based on different principles or a

combination of tests into a single procedure, such as HPLC (high-

pressure liquid chromatography)/UV (ultraviolet) diode array, HPLC/MS

(mass spectroscopy), or GC (gas chromatography)/MS is generally

acceptable. If the new drug substance is a salt, identification testing

should be specific for the individual ions. An identification test that

is specific for the salt itself should suffice.

    New drug substances that are optically active may also need

specific identification testing or performance of a chiral assay.

Please refer to section 3.3.1(d) in this guidance for further

discussion of this topic.

    (c) Assay: A specific, stability-indicating procedure should be

included to determine the content of the new drug substance. In many

cases it is possible to employ the same procedure (e.g., HPLC) for both

assay of the new drug substance and quantitation of impurities.

    In cases where use of a nonspecific assay is justified, other

supporting analytical procedures should be used to achieve overall

specificity. For example, where titration is adopted to assay the drug

substance, the combination of the assay and a suitable test for

impurities should be used.

    (d) Impurities: Organic and inorganic impurities and residual

solvents are included in this category. Refer to the ICH guidances on

``Q3A Impurities in New Drug Substances'' and ``Q3C Impurities:

Residual Solvents'' for detailed information.

    Decision Tree #1 addresses the extrapolation of meaningful limits

on impurities from the body of data generated during development. At

the time of filing it is unlikely that sufficient data will be

available to assess process consistency. Therefore it is considered

inappropriate to establish acceptance criteria that tightly encompass

the batch data at the time of filing (see section 2.5).

3.2.2 New Drug Products

    The following tests and acceptance criteria are considered

generally applicable to all new drug products:

    (a) Description: A qualitative description of the dosage form

should be provided (e.g., size, shape, and color). If any of these

characteristics change during manufacture or storage, this change

should be investigated and appropriate action taken. The acceptance

criteria should include the final acceptable appearance. If color

changes during storage, a quantitative procedure may be appropriate.

    (b) Identification: Identification testing should establish the

identity of the new drug substance(s) in the new drug product and

should be able to discriminate between compounds of closely related

structure that are likely to be present. Identity tests should be

specific for the new drug substance, e.g., infrared spectroscopy.

Identification solely by a single chromatographic retention time, for

example, is not regarded as being specific. However, the use of two

chromatographic procedures, where the separation is based on different

principles, or a combination of tests into a single procedure, such as

HPLC/UV diode array, HPLC/MS, or GC/MS, is generally acceptable.

    (c) Assay: A specific, stability-indicating assay to determine

strength (content) should be included for all new drug products. In

many cases it is possible to employ the same procedure (e.g., HPLC) for

both assay of the new drug substance and quantitation of impurities.

Results of content uniformity testing for new drug products can be used

for quantitation of drug product strength, if the methods used for

content uniformity are also appropriate as assays.

    In cases where use of a nonspecific assay is justified, other

supporting analytical procedures should be used to achieve overall

specificity. For example, where titration is adopted to assay the drug

substance for release, the combination of the assay and a suitable test

for impurities can be used. A specific procedure should be used when

there is evidence of excipient interference with the nonspecific assay.

    (d) Impurities: Organic and inorganic impurities (degradation

products) and residual solvents are included in this category. Refer to

the ICH guidances on ``Q3B Impurities in New Drug Products'' and ``Q3C

Impurities: Residual Solvents'' for detailed information.

    Organic impurities arising from degradation of the new drug

substance

[Page 83046]

and impurities that arise during the manufacturing process for the drug

product should be monitored in the new drug product. Acceptance limits

should be stated for individual specified degradation products, which

may include both identified and unidentified degradation products, as

appropriate, and total degradation products. Process impurities from

the new drug substance synthesis are normally controlled during drug

substance testing, and therefore are not included in the total

impurities limit. However, when a synthesis impurity is also a

degradation product, its level should be monitored and included in the

total degradation product limit. When it has been conclusively

demonstrated via appropriate analytical methodology that the drug

substance does not degrade in the specific formulation, and under the

specific storage conditions proposed in the new drug application,

degradation product testing may be reduced or eliminated upon approval

by the regulatory authorities.

    Decision Tree #2 addresses the extrapolation of meaningful limits

on degradation products from the body of data generated during

development. At the time of filing it is unlikely that sufficient data

will be available to assess process consistency. Therefore it is

considered inappropriate to establish acceptance criteria that tightly

encompass the batch data at the time of filing (see section 2.5).

3.3 Specific Tests/Criteria

    In addition to the universal tests listed above, the following

tests may be considered on a case-by-case basis for drug substances

and/or drug products. Individual tests/criteria should be included in

the specification when the tests have an impact on the quality of the

drug substance and drug product for batch control. Tests other than

those listed below may be needed in particular situations or as new

information becomes available.

3.3.1 New Drug Substances

    (a) Physicochemical properties: These are properties such as pH of

an aqueous solution, melting point/range, and refractive index. The

procedures used for the measurement of these properties are usually

unique and do not need much elaboration, e.g., capillary melting point,

Abbe refractometry. The tests performed in this category should be

determined by the physical nature of the new drug substance and by its

intended use.

    (b) Particle size: For some new drug substances intended for use in

solid or suspension drug products, particle size can have a significant

effect on dissolution rates, bioavailability, and/or stability. In such

instances, testing for particle size distribution should be carried out

using an appropriate procedure, and acceptance criteria should be

provided.

    Decision Tree #3 provides additional guidance on when particle size

testing should be considered.

    (c) Polymorphic forms: Some new drug substances exist in different

crystalline forms that differ in their physical properties.

Polymorphism may also include solvation or hydration products (also

known as pseudopolymorphs) and amorphous forms. Differences in these

forms could, in some cases, affect the quality or performance of the

new drug products. In cases where differences exist that have been

shown to affect drug product performance, bioavailability, or

stability, then the appropriate solid state should be specified.

    Physicochemical measurements and techniques are commonly used to

determine whether multiple forms exist. Examples of these procedures

are: Melting point (including hot-stage microscopy), solid state IR, X-

ray powder diffraction, thermal analysis procedures (like DSC

(differential scanning calorimetry), TGA (thermogravimetric analysis)

and DTA (differential thermal analysis)), Raman spectroscopy, optical

microscopy, and solid state NMR (nuclear magnetic resonance)

spectroscopy.

    Decision Trees #4(1) through #4(3) provide additional guidance on

when, and how, polymorphic forms should be monitored and controlled.

    Note: These decision trees should be followed sequentially. Trees

#4(1) and #4(2) consider whether polymorphism is exhibited by the drug

substance, and whether the different polymorphic forms can affect

performance of the drug product. Tree #4(3) should only be applied when

polymorphism has been demonstrated for the drug substance, and shown to

affect these properties. Tree #4(3) considers the potential for change

in polymorphic forms in the drug product and whether such a change has

any effect on product performance.

    It is generally technically very difficult to measure polymorphic

changes in drug products. A surrogate test (e.g., dissolution) (see

Decision Tree #4(3)) can generally be used to monitor product

performance, and polymorph content should only be used as a test and

acceptance criterion of last resort.

    (d) Tests for chiral new drug substances: Where a new drug

substance is predominantly one enantiomer, the opposite enantiomer is

excluded from the qualification and identification thresholds given in

the ICH guidances on ``Q3A Impurities in New Drug Substances'' and

``Q3B Impurities in New Drug Products'' because of practical

difficulties in quantifying it at those levels. However, that impurity

in the chiral new drug substance and the resulting new drug product(s)

should otherwise be treated according to the principles established in

those guidances.

    Decision Tree #5 summarizes when and if chiral identity tests,

impurity tests, and assays may be needed for both new drug substances

and new drug products, according to the following concepts:

    Drug Substance: Impurities. For chiral drug substances that are

developed as a single enantiomer, control of the other enantiomer

should be considered in the same manner as for other impurities.

However, technical limitations may preclude the same limits of

quantification or qualification from being applied. Assurance of

control also could be given by appropriate testing of a starting

material or intermediate, with suitable justification.

    Assay. An enantioselective determination of the drug substance

should be part of the specification. It is considered acceptable for

this to be achieved either through use of a chiral assay procedure or

by the combination of an achiral assay together with appropriate

methods of controlling the enantiomeric impurity.

    Identity. For a drug substance developed as a single enantiomer,

the identity test(s) should be capable of distinguishing both

enantiomers and the racemic mixture. For a racemic drug substance,

there are generally two situations where a stereospecific identity test

is appropriate for release/acceptance testing: (1) Where there is a

significant possibility that the enantiomer might be substituted for

the racemate, or (2) when there is evidence that preferential

crystallization may lead to unintentional production of a nonracemic

mixture.

    Drug Product: Degradation products. Control of the other enantiomer

in a drug product is considered necessary unless racemization has been

shown to be insignificant during manufacture of the dosage form and on

storage.

    Assay. An achiral assay may be sufficient where racemization has

been shown to be insignificant during manufacture of the dosage form

and on storage. Otherwise a chiral assay should be used. Alternatively,

the combination of an achiral assay plus a validated

[Page 83047]

procedure to control the presence of the opposite enantiomer may be

used.

    Identity. A stereospecific identity test is not generally needed in

the drug product release specification. When racemization is

insignificant during manufacture of the dosage form and on storage,

stereospecific identity testing is more appropriately addressed as part

of the drug substance specification. When racemization in the dosage

form is a concern, chiral assay or enantiomeric impurity testing of the

drug product will serve to verify identity.

    (e) Water content: This test is important in cases where the new

drug substance is known to be hygroscopic or degraded by moisture or

when the drug substance is known to be a stoichiometric hydrate. The

acceptance criteria may be justified with data on the effects of

hydration or moisture absorption. In some cases, a loss on drying

procedure may be considered adequate; however, a detection procedure

that is specific for water (e.g., Karl Fischer titration) is preferred.

    (f) Inorganic impurities: The need for inclusion of tests and

acceptance criteria for inorganic impurities (e.g., catalysts) should

be studied during development and based on knowledge of the

manufacturing process. Procedures and acceptance criteria for sulfated

ash/residue on ignition should follow pharmacopeial precedents; other

inorganic impurities may be determined by other appropriate procedures,

e.g., atomic absorption spectroscopy.

    (g) Microbial limits: There may be a need to specify the total

count of aerobic microorganisms, the total count of yeasts and molds,

and the absence of specific objectionable bacteria (e.g.,

Staphylococcus aureus, Escherichia coli, Salmonella, Pseudomonas

aeruginosa). These should be suitably determined using pharmacopeial

procedures. The type of microbial test(s) and acceptance criteria

should be based on the nature of the drug substance, method of

manufacture, and the intended use of the drug product. For example,

sterility testing may be appropriate for drug substances manufactured

as sterile, and endotoxin testing may be appropriate for drug

substances used to formulate an injectable drug product.

    Decision Tree #6 provides additional guidance on when microbial

limits should be included.

3.3.2 New Drug Products

    Additional tests and acceptance criteria generally should be

included for particular new drug products. The following selection

presents a representative sample of both the drug products and the

types of tests and acceptance criteria that may be appropriate. The

specific dosage forms addressed include solid oral drug products,

liquid oral drug products, and parenterals (small and large volume).

Application of the concepts in this guidance to other dosage forms is

encouraged. Note that issues related to optically active drug

substances and to solid state considerations for drug products are

discussed in section 3.3.1 of this guidance.

3.3.2.1 The following tests are applicable to tablets (coated and

uncoated) and hard capsules. One or more of these tests may also be

applicable to soft capsules and granules.

    (a) Dissolution: The specification for solid oral dosage forms

normally includes a test to measure release of drug substance from the

drug product. Single-point measurements are normally considered to be

suitable for immediate-release dosage forms. For modified-release

dosage forms, appropriate test conditions and sampling procedures

should be established. For example, multiple time-point sampling should

be performed for extended-release dosage forms, and two-stage testing

(using different media in succession or in parallel, as appropriate)

may be appropriate for delayed-release dosage forms. In these cases it

is important to consider the populations of individuals who will be

taking the drug product (e.g., achlorhydric elderly) when designing the

tests and acceptance criteria. In some cases (see section 3.3.2.1(b)

Disintegration) dissolution testing may be replaced by disintegration

testing (see Decision Tree #7(1)).

    For immediate-release drug products where changes in dissolution

rate have been demonstrated to significantly affect bioavailability, it

is desirable to develop test conditions that can distinguish batches

with unacceptable bioavailability. If changes in formulation or process

variables significantly affect dissolution, and such changes are not

controlled by another aspect of the specification, it may also be

appropriate to adopt dissolution test conditions that can distinguish

these changes (see Decision Tree #7(2)).

    Where dissolution significantly affects bioavailability, the

acceptance criteria should be set to reject batches with unacceptable

bioavailability. Otherwise, test conditions and acceptance criteria

should be established that pass clinically acceptable batches (see

Decision Tree #7(2)).

    For extended-release drug products, in vitro/in vivo correlation

may be used to establish acceptance criteria when human bioavailability

data are available for formulations exhibiting different release rates.

Where such data are not available, and drug release cannot be shown to

be independent of in vitro test conditions, then acceptance criteria

should be established on the basis of available batch data. Normally,

the permitted variability in mean release rate at any given time point

should not exceed a total numerical difference of 10

percent of the labeled content of drug substance (i.e., a total

variability of 20 percent: a requirement of 5010 percent

thus means an acceptable range from 40 percent to 60 percent), unless a

wider range is supported by a bioequivalency study (see Decision Tree

#7(3)).

    (b) Disintegration: For rapidly dissolving (dissolution >80 percent

in 15 minutes at pH 1.2, 4.0, and 6.8) products containing drugs that

are highly soluble throughout the physiological range (dose/solubility

volume  250 milliliters (mL) from pH 1.2 to 6.8),

disintegration may be substituted for dissolution. Disintegration

testing is considered most appropriate when a relationship to

dissolution has been established or when disintegration is shown to be

more discriminating than dissolution. In such cases dissolution testing

may not be necessary. It is expected that development information will

be provided to support the robustness of the formulation and

manufacturing process with respect to the selection of dissolution

versus disintegration testing (see Decision Tree #7(1)).

    (c) Hardness/friability: It is normally appropriate to perform

hardness and/or friability testing as an in-process control (see

section 2.3). Under these circumstances, it is normally not necessary

to include these attributes in the specification. If the

characteristics of hardness and friability have a critical impact on

drug product quality (e.g., chewable tablets), acceptance criteria

should be included in the specification.

    (d) Uniformity of dosage units: This term includes both the mass of

the dosage form and the content of the active substance in the dosage

form; a pharmacopeial procedure should be used. In general, the

specification should include one or the other, but not both. If

appropriate, these tests may be performed in-process; the acceptance

criteria should be included in the specification. When weight variation

is applied to new drug products exceeding the threshold value to allow

testing uniformity by weight variation, applicants should verify during

drug

[Page 83048]

development that the homogeneity of the product is adequate.

    (e) Water content: A test for water content should be included when

appropriate. The acceptance criteria may be justified with data on the

effects of hydration or water absorption on the drug product. In some

cases, a loss on drying procedure may be considered adequate; however,

a detection procedure that is specific for water (e.g., Karl Fischer

titration) is preferred.

    (f) Microbial limits: Microbial limit testing is seen as an

attribute of GMP, as well as of quality assurance. In general, it is

advisable to test the drug product unless its components are tested

before manufacture and the manufacturing process is known, through

validation studies, not to carry a significant risk of microbial

contamination or proliferation. It should be noted that, whereas this

guidance does not directly address excipients, the principles discussed

here may be applicable to excipients as well as to new drug products.

Skip testing may be an appropriate approach in both cases, where

permissible (see Decision Tree #6 for microbial testing of excipients).

    Acceptance criteria should be set for the total count of aerobic

microorganisms, the total count of yeasts and molds, and the absence of

specific objectionable bacteria (e.g., Staphylococcus aureus,

Escherichia coli, Salmonella, Pseudomonas aeruginosa). These should be

determined by suitable procedures, using pharmacopeial procedures, and

at a sampling frequency or time point in manufacture that is justified

by data and experience. The type of microbial test(s) and acceptance

criteria should be based on the nature of the drug substance, method of

manufacture, and the intended use of the drug product. With acceptable

scientific justification, it should be possible to propose no microbial

limit testing for solid oral dosage forms.

    Decision Tree #8 provides additional guidance on the use of

microbial limits testing.

3.3.2.2 Oral liquids: One or more of the following specific tests will

normally be applicable to oral liquids and to powders intended for

reconstitution as oral liquids.

    (a) Uniformity of dosage units: This term includes both the mass of

the dosage form and the content of the active drug substance in the

dosage form; a pharmacopeial procedure should be used. In general, the

specification should include one or the other, but not both. When

weight variation is applied to new drug products exceeding the

threshold value to allow testing uniformity by weight variation,

applicants should verify during drug development that the homogeneity

of the product is adequate.

    If appropriate, tests may be performed in-process; however, the

acceptance criteria should be included in the specification. This

concept may be applied to both single-dose and multiple-dose packages.

    The dosage unit is considered to be the typical dose taken by the

patient. If the actual unit dose, as taken by the patient, is

controlled, it may either be measured directly or calculated, based on

the total measured weight or volume of drug divided by the total number

of doses expected. If dispensing equipment (such as medicine droppers

or dropper tips for bottles) is an integral part of the packaging, this

equipment should be used to measure the dose. Otherwise, a standard

volume measure should be used. The dispensing equipment to be used is

normally determined during development. For powders for reconstitution,

uniformity of mass testing is generally considered acceptable.

    (b) pH: Acceptance criteria for pH should be provided where

applicable and the proposed range justified.

    (c) Microbial limits: Microbial limit testing is seen as an

attribute of GMP, as well as of quality assurance. In general, it is

advisable to test the drug product unless its components are tested

before manufacture and the manufacturing process is known, through

validation studies, not to carry a significant risk of microbial

contamination or proliferation. It should be noted that, whereas this

guidance does not directly address excipients, the principles discussed

here may be applicable to excipients as well as to new drug products.

Skip testing may be an appropriate approach in both cases, where

permissible. With acceptable scientific justification, it may be

possible to propose no microbial limit testing for powders intended for

reconstitution as oral liquids.

    Acceptance criteria should be set for the total count of aerobic

microorganisms, total count of yeasts and molds, and the absence of

specific objectionable bacteria (e.g., Staphylococcus aureus,

Escherichia coli, Salmonella, Pseudomonas aeruginosa). These should be

determined by suitable procedures, using pharmacopeial procedures, and

at a sampling frequency or time point in manufacture that is justified

by data and experience.

    Decision Tree #8 provides additional guidance on the use of

microbial limits testing.

    (d) Antimicrobial preservative content: For oral liquids needing an

antimicrobial preservative, acceptance criteria for preservative

content should be established. Acceptance criteria for preservative

content should be based upon the levels of antimicrobial preservative

necessary to maintain microbiological quality of the product at all

stages throughout its proposed usage and shelf life. The lowest

specified concentration of antimicrobial preservative should be

demonstrated to be effective in controlling microorganisms by using a

pharmacopeial antimicrobial preservative effectiveness test.

    Testing for antimicrobial preservative content should normally be

performed at release. Under certain circumstances, in-process testing

may suffice in lieu of release testing. When antimicrobial preservative

content testing is performed as an in-process test, the acceptance

criteria should remain part of the specification.

    Antimicrobial preservative effectiveness should be demonstrated

during development, during scaleup, and throughout the shelf life

(e.g., in stability testing: see the ICH guidance ``Q1A Stability

Testing of New Drug Substances and Products''), although chemical

testing for preservative content is the attribute normally included in

the specification.

    (e) Antioxidant preservative content: Release testing for

antioxidant content should normally be performed. Under certain

circumstances where justified by developmental and stability data,

shelf-life testing may be unnecessary, and in-process testing may

suffice in lieu of release testing where permitted. When antioxidant

content testing is performed as an in-process test, the acceptance

criteria should remain part of the specification. If only release

testing is performed, this decision should be reinvestigated whenever

either the manufacturing procedure or the container/closure system

changes.

    (f) Extractables: Generally, where development and stability data

show evidence that extractables from the container/closure systems are

consistently below levels that are demonstrated to be acceptable and

safe, elimination of this test can normally be accepted. This should be

reinvestigated if the container/closure system or formulation changes.

    Where data demonstrate the need, tests and acceptance criteria for

extractables from the container/closure system components (e.g., rubber

[Page 83049]

stopper, cap liner, plastic bottle, etc.) are considered appropriate

for oral solutions packaged in nonglass systems, or in glass containers

with nonglass closures. The container/closure components should be

listed, and data collected for these components as early in the

development process as possible.

    (g) Alcohol content: Where it is declared quantitatively on the

label in accordance with pertinent regulations, the alcohol content

should be specified. It may be assayed or calculated.

    (h) Dissolution: In addition to the attributes recommended

immediately above, it may be appropriate (e.g., insoluble drug

substance) to include dissolution testing and acceptance criteria for

oral suspensions and dry powder products for resuspension. Dissolution

testing should be performed at release. This test may be performed as

an in-process test when justified by product development data. The

testing apparatus, media, and conditions should be pharmacopeial, if

possible, or otherwise justified. Dissolution procedures using either a

pharmacopeial or nonpharmacopeial apparatus and conditions should be

validated.

    Single-point measurements are normally considered suitable for

immediate-release dosage forms. Multiple-point sampling, at appropriate

intervals, should be performed for modified-release dosage forms.

Acceptance criteria should be set based on the observed range of

variation, and should take into account the dissolution profiles of the

batches that showed acceptable performance in vivo. Developmental data

should be considered when determining the need for either a dissolution

procedure or a particle size distribution procedure.

    (i) Particle size distribution: Quantitative acceptance criteria

and a procedure for determination of particle size distribution may be

appropriate for oral suspensions. Developmental data should be

considered when determining the need for either a dissolution procedure

or a particle size distribution procedure for these formulations.

    Particle size distribution testing should be performed at release.

It may be performed as an in-process test when justified by product

development data. If these products have been demonstrated during

development to have consistently rapid drug release characteristics,

exclusion of a particle size distribution test from the specification

may be proposed.

    Particle size distribution testing may also be proposed in place of

dissolution testing; justification should be provided. The acceptance

criteria should include acceptable particle size distribution in terms

of the percent of total particles in given size ranges. The mean,

upper, and/or lower particle size limits should be well defined.

    Acceptance criteria should be set based on the observed range of

variation, and should take into account the dissolution profiles of the

batches that showed acceptable performance in vivo, as well as the

intended use of the product. The potential for particle growth should

be investigated during product development; the acceptance criteria

should take the results of these studies into account.

    (j) Redispersibility: For oral suspensions that settle on storage

(produce sediment), acceptance criteria for redispersibility may be

appropriate. Shaking may be an appropriate procedure.

    The procedure (mechanical or manual) should be indicated. Time

required to achieve resuspension by the indicated procedure should be

clearly defined. Data generated during product development may be

sufficient to justify periodic or skip testing, or elimination of this

attribute from the specification may be proposed.

    (k) Rheological properties: For relatively viscous solutions or

suspensions, it may be appropriate to include rheological properties

(viscosity/specific gravity) in the specification. The test and

acceptance criteria should be stated. Data generated during product

development may be sufficient to justify periodic or skip testing, or

elimination of this attribute from the specification may be proposed.

    (l) Reconstitution time: Acceptance criteria for reconstitution

time should be provided for dry powder products that require

reconstitution. The choice of diluent should be justified. Data

generated during product development may be sufficient to justify

periodic or skip testing, or elimination of this attribute from the

specification may be proposed.

    (m) Water content: For oral products requiring reconstitution, a

test and acceptance criterion for water content should be proposed when

appropriate. Loss on drying is generally considered sufficient if the

effect of absorbed moisture versus water of hydration has been

adequately characterized during the development of the product. In

certain cases a more specific procedure (e.g., Karl Fischer titration)

may be preferable.

3.3.2.3 Parenteral Drug Products: The following tests may be applicable

to parenteral drug products.

    (a) Uniformity of dosage units: This term includes both the mass of

the dosage form and the content of the active drug substance in the

dosage form; a pharmacopeial procedure should be used. In general, the

specification should be one or the other, but not both, and is

applicable to powders for reconstitution. When weight variation is

applied to new drug products exceeding the threshold value to allow

testing uniformity by weight variation, applicants should verify during

drug development that the homogeneity of the product is adequate.

    If appropriate (see section 2.3), these tests may be performed in-

process; the acceptance criteria should be included in the

specification. This test may be applied to both single-dose and

multiple-dose packages.

    For powders for reconstitution, uniformity of mass testing is

generally considered acceptable.

    (b) pH: Acceptance criteria for pH should be provided where

applicable, and the proposed range justified.

    (c) Sterility: All parenteral products should have a test procedure

and acceptance criterion for evaluation of sterility. Where data

generated during development and validation justify parametric release,

this approach may be proposed for terminally sterilized drug products

(see section 2.6).

    (d) Endotoxins/Pyrogens: A test procedure and acceptance criterion

for endotoxins, using a procedure such as the limulus amoebocyte lysate

test, should be included in the specification. Pyrogenicity testing may

be proposed as an alternative to endotoxin testing where justified.

    (e) Particulate matter: Parenteral products should have appropriate

acceptance criteria for particulate matter. This will normally include

acceptance criteria for visible particulates and/or clarity of

solution, as well as for subvisible particulates, as appropriate.

    (f) Water content: For nonaqueous parenterals, and for parenteral

products for reconstitution, a test procedure and acceptance criterion

for water content should be proposed when appropriate. Loss on drying

is generally considered sufficient for parenteral products, if the

effect of absorbed moisture versus water of hydration has been

adequately characterized during development. In certain cases a more

specific procedure (e.g., Karl Fischer titration) may be preferred.

    (g) Antimicrobial preservative content: For parenteral products

[Page 83050]

needing an antimicrobial preservative, acceptance criteria for

preservative content should be established. Acceptance criteria for

preservative content should be based upon the levels of antimicrobial

preservative necessary to maintain microbiological quality of the

product at all stages throughout its proposed usage and shelf life. The

lowest specified concentration of antimicrobial preservative should be

demonstrated to be effective in controlling microorganisms by using a

pharmacopeial antimicrobial preservative effectiveness test.

    Testing for antimicrobial preservative content should normally be

performed at release. Under certain circumstances, in-process testing

may suffice in lieu of release testing, where permitted. When

antimicrobial preservative content testing is performed as an in-

process test, the acceptance criteria should remain part of the

specification.

    Antimicrobial preservative effectiveness should be demonstrated

during development, during scaleup, and throughout the shelf life

(e.g., in stability testing: see the ICH guidance ``Q1A Stability

Testing of New Drug Substances and Products''), although chemical

testing for preservative content is the attribute normally included in

the specification.

    (h) Antioxidant preservative content: Release testing for

antioxidant content should normally be performed. Under certain

circumstances, where justified by developmental and stability data,

shelf-life testing may be unnecessary and in-process testing may

suffice in lieu of release testing. When antioxidant content testing is

performed as an in-process test, the acceptance criteria should remain

part of the specification. If only release testing is performed, this

decision should be reinvestigated whenever either the manufacturing

procedure or the container/closure system changes.

    (i) Extractables: Control of extractables from container/closure

systems is considered significantly more important for parenteral

products than for oral liquids. However, where development and

stability data show evidence that extractables are consistently below

the levels that are demonstrated to be acceptable and safe, elimination

of this test can normally be accepted. This should be reinvestigated if

the container/closure system or formulation changes.

    Where data demonstrate the need, acceptance criteria for

extractables from the container/closure components are considered

appropriate for parenteral products packaged in nonglass systems or in

glass containers with elastomeric closures. This testing may be

performed at release only, where justified by data obtained during

development. The container/closure system components (e.g., rubber

stopper, etc.) should be listed, and data collected for these

components as early in the development process as possible.

    (j) Functionality testing of delivery systems: Parenteral

formulations packaged in prefilled syringes, autoinjector cartridges,

or the equivalent should have test procedures and acceptance criteria

related to the functionality of the delivery system. These may include

control of syringeability, pressure, and seal integrity (leakage), and/

or parameters such as tip cap removal force, piston release force,

piston travel force, and power injector function force. Under certain

circumstances these tests may be performed in-process. Data generated

during product development may be sufficient to justify skip lot

testing or elimination of some or all attributes from the

specification.

    (k) Osmolarity: When the tonicity of a product is declared in its

labeling, appropriate control of its osmolarity should be performed.

Data generated during development and validation may be sufficient to

justify performance of this procedure as an in-process control, skip

lot testing, or direct calculation of this attribute.

    (l) Particle size distribution: Quantitative acceptance criteria

and a procedure for determination of particle size distribution may be

appropriate for injectable suspensions. Developmental data should be

considered when determining the need for either a dissolution procedure

or a particle size distribution procedure.

    Particle size distribution testing should be performed at release.

It may be performed as an in-process test when justified by product

development data. If the product has been demonstrated during

development to have consistently rapid drug release characteristics,

exclusion of particle size controls from the specification may be

proposed.

    Particle size distribution testing may also be proposed in place of

dissolution testing when development studies demonstrate that particle

size is the primary factor influencing dissolution; justification

should be provided. The acceptance criteria should include acceptable

particle size distribution in terms of the percent of total particles

in given size ranges. The mean, upper, and/or lower particle size

limits should be well defined.

    Acceptance criteria should be set based on the observed range of

variation, and should take into account the dissolution profiles of the

batches that showed acceptable performance in vivo and the intended use

of the product. The potential for particle growth should be

investigated during product development; the acceptance criteria should

take the results of these studies into account.

    (m) Redispersibility: For injectable suspensions that settle on

storage (produce sediment), acceptance criteria for redispersibility

may be appropriate. Shaking may be an appropriate procedure. The

procedure (mechanical or manual) should be indicated. Time required to

achieve resuspension by the indicated procedure should be clearly

defined. Data generated during product development may be sufficient to

justify skip lot testing, or elimination of this attribute from the

specification may be proposed.

    (n) Reconstitution time: Acceptance criteria for reconstitution

time should be provided for all parenteral products that require

reconstitution. The choice of diluent should be justified. Data

generated during product development and process validation may be

sufficient to justify skip lot testing or elimination of this attribute

from the specification for rapidly dissolving products.

4. Glossary (the following definitions are presented for the

purpose of this guidance)

    Acceptance criteria: Numerical limits, ranges, or other suitable

measures for acceptance of the results of analytical procedures.

    Chiral: Not superimposable with its mirror image, as applied to

molecules, conformations, and macroscopic objects, such as crystals.

The term has been extended to samples of substances whose molecules are

chiral, even if the macroscopic assembly of such molecules is racemic.

    Combination product: A drug product that contains more than one

drug substance.

    Degradation product: A molecule resulting from a chemical change in

the drug molecule brought about over time and/or by the action of

light, temperature, pH, water, or by reaction with an excipient and/or

the immediate container/closure system. Also called decomposition

product.

    Delayed release: Release of a drug (or drugs) at a time other than

immediately following oral administration.

   Enantiomers: Compounds with the same molecular formula as the drug

substance, which differ in the spatial arrangement of atoms within the

molecule and are nonsuperimposable mirror images.

[Page 83051]

    Extended release: Products that are formulated to make the drug

available over an extended period after administration.

    Highly water soluble drugs: Drugs with a dose/solubility volume of

less than or equal to 250 mL over a pH range of 1.2 to 6.8. (Example:

Compound A has as its lowest solubility at 370.5  deg.C,

1.0 milligram (mg)/milliliter (mL) at pH 6.8, and is available in 100

mg, 200 mg, and 400 mg strengths. This drug would be considered a low

solubility drug, as its dose/solubility volume is greater than 250 mL

(400 mg/1.0 mg/mL = 400 mL)).

    Immediate release: Allows the drug to dissolve in the

gastrointestinal contents, with no intention of delaying or prolonging

the dissolution or absorption of the drug.

    Impurity: (1) Any component of the new drug substance that is not

the chemical entity defined as the new drug substance. (2) Any

component of the drug product that is not the chemical entity defined

as the drug substance or an excipient in the drug product.

    Identified impurity: An impurity for which a structural

characterization has been achieved.

    In-process tests: Tests that may be performed during the

manufacture of either the drug substance or drug product, rather than

as part of the formal battery of tests that are conducted prior to

release.

    Modified release: Dosage forms whose drug release characteristics

of time course and/or location are chosen to accomplish therapeutic or

convenience objectives not offered by conventional dosage forms, such

as a solution or an immediate-release dosage form. Modified-release

solid oral dosage forms include both delayed- and extended-release drug

products.

    New drug product: A pharmaceutical product type, e.g., tablet,

capsule, solution, cream, etc., that has not previously been registered

in a region or Member State, and that contains a drug ingredient

generally, but not necessarily, in association with excipients.

    New drug substance: The designated therapeutic moiety that has not

previously been registered in a region or Member State (also referred

to as a new molecular entity or new chemical entity). It may be a

complex, simple ester, or salt of a previously approved drug substance.

    Polymorphism: The occurrence of different crystalline forms of the

same drug substance. This may include solvation or hydration products

(also known as pseudopolymorphs) and amorphous forms.

    Quality: The suitability of either a drug substance or drug product

for its intended use. This term includes such attributes as the

identity, strength, and purity.

    Racemate: A composite (solid, liquid, gaseous, or in solution) of

equimolar quantities of two enantiomeric species. It is devoid of

optical activity.

    Rapidly dissolving products: An immediate release solid oral drug

product is considered rapidly dissolving when not less than 80 percent

of the label amount of the drug substance dissolves within 15 minutes

in each of the following media: (1) pH 1.2, (2) pH 4.0, and (3) pH 6.8.

    Reagent: A substance, other than a starting material or solvent,

that is used in the manufacture of a new drug substance.

    Solvent: An inorganic or an organic liquid used as a vehicle for

the preparation of solutions or suspensions in the synthesis of a new

drug substance or the manufacture of a new drug product.

    Specification: A list of tests, references to analytical

procedures, and appropriate acceptance criteria that are numerical

limits, ranges, or other criteria for the tests described. It

establishes the set of criteria to which a drug substance or drug

product should conform to be considered acceptable for its intended

use. ``Conformance to specifications'' means that the drug substance

and/or drug product, when tested according to the listed analytical

procedures, will meet the listed acceptance criteria. Specifications

are critical quality standards that are proposed and justified by the

manufacturer and approved by regulatory authorities as conditions of

approval.

    Specific test: A test that is considered to be applicable to

particular new drug substances or particular new drug products,

depending on their specific properties and/or intended use.

    Specified impurity: An identified or unidentified impurity that is

selected for inclusion in the new drug substance or new drug product

specification and is individually listed and limited to ensure the

quality of the new drug substance or new drug product.

    Unidentified impurity: An impurity that is defined solely by

qualitative analytical properties (e.g., chromatographic retention

time).

    Universal test: A test that is considered potentially applicable to

all new drug substances, or all new drug products; e.g., appearance,

identification, assay, and impurity tests.

5. References

    International Conference on Harmonisation, ``Q3A Impurities in New

Drug Substances,'' 1996.

    International Conference on Harmonisation, ``Q3B Impurities in New

Drug Products,'' 1997.

    International Conference on Harmonisation, ``Q1A Stability Testing

of New Drug Substances and Products,'' 1994.

    International Conference on Harmonisation, ``Q2A Text on Validation

of Analytical Procedures,'' 1995.

    International Conference on Harmonisation, ``Q2B Validation of

Analytical Procedures: Methodology,'' 1996.

    International Conference on Harmonisation, ``Q3C Impurities:

Residual Solvents,'' 1997.

    International Conference on Harmonisation, ``Q6B Specifications:

Test Procedures and Acceptance Criteria for Biotechnological/Biological

Products,'' 1999.

6. Attachments: Decision Trees #1 through #8

    For the decision trees referenced in this guidance, see the

following pages.

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    Dated: December 20, 2000.

Margaret M. Dotzel,

Associate Commissioner for Policy.

[FR Doc. 00-33369 Filed 12-28-00; 8:45 am]

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