62890 Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices

1This draft guidance represents the agency’s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.

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 97D–0448]

International Conference on

Harmonisation; Draft Guidance on

Specifications: Test Procedures and

Acceptance Criteria for New Drug

Substances and New Drug Products:

Chemical Substances

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is publishing a

draft guidance entitled ‘‘Q6A

Specifications: Test Procedures and

Acceptance Criteria for New Drug

Substances and New Drug Products:

Chemical Substances.’’ The draft

guidance was prepared under the

auspices of the International Conference

on Harmonisation of Technical

Requirements for Registration of

Pharmaceuticals for Human Use (ICH).

The draft guidance provides guidance

on the selection of test procedures and

the setting and justification of

acceptance criteria for new chemical

drug substances and new drug products

produced from them. The draft guidance

is intended to assist in the

establishment of a single set of global

specifications for new drug substances

and new drug products.

DATES: Written comments by January 26,

1998.

ADDRESSES: Submit written comments

on the draft guidance to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 12420

Parklawn Dr., rm. 1–23, Rockville, MD

20857. Copies of the draft guidance are

available from the Drug Information

Branch (HFD–210), Center for Drug

Evaluation and Research, Food and

Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857, 301–827–

4573.

FOR FURTHER INFORMATION CONTACT:

Regarding the guidance: Eric B.

Sheinin, Center for Drug Evaluation

and Research (HFD–800), Food and

Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857, 301–

827–5918, or

Neil D. Goldman, Center for Biologic

Evaluation and Research (HFM–

416), Food and Drug

Administration, 8800 Rockville

Pike, Rockville, MD 20852, 301–

827–0377.

Regarding the ICH: Janet J. Showalter,

Office of Health Affairs (HFY–20),

Food and Drug Administration,

5600 Fishers Lane, Rockville, MD

20857, 301–827–0864.

SUPPLEMENTARY INFORMATION: In recent

years, many important initiatives have

been undertaken by regulatory

authorities and industry associations to

promote international harmonization of

regulatory requirements. FDA has

participated in many meetings designed

to enhance harmonization and is

committed to seeking scientifically

based harmonized technical procedures

for pharmaceutical development. One of

the goals of harmonization is to identify

and then reduce differences in technical

requirements for drug development

among regulatory agencies.

ICH was organized to provide an

opportunity for tripartite harmonization

initiatives to be developed with input

from both regulatory and industry

representatives. FDA also seeks input

from consumer representatives and

others. ICH is concerned with

harmonization of technical

requirements for the registration of

pharmaceutical products among three

regions: The European Union, Japan,

and the United States. The six ICH

sponsors are the European Commission,

the European Federation of

Pharmaceutical Industries Associations,

the Japanese Ministry of Health and

Welfare, the Japanese Pharmaceutical

Manufacturers Association, the Centers

for Drug Evaluation and Research and

Biologics Evaluation and Research,

FDA, and the Pharmaceutical Research

and Manufacturers of America. The ICH

Secretariat, which coordinates the

preparation of documentation, is

provided by the International

Federation of Pharmaceutical

Manufacturers Associations (IFPMA).

The ICH Steering Committee includes

representatives from each of the ICH

sponsors and the IFPMA, as well as

observers from the World Health

Organization, the Canadian Health

Protection Branch, and the European

Free Trade Area.

In July 1997, the ICH Steering

Committee agreed that a draft guidance

entitled ‘‘Q6A Specifications: Test

Procedures and Acceptance Criteria for

New Drug Substances and New Drug

Products: Chemical Substances’’ should

be made available for public comment.

The draft guidance is the product of the

Quality Expert Working Group of the

ICH. Comments about this draft will be

considered by FDA and the Quality

Expert Working Group. A related

document for biotechnology derived

products is the subject of a separate

Expert Working Group.

In accordance with Good Guidance

Practices (62 FR 8961, February 27,

1997), this document is now being

called a guidance, rather than a

guideline.

The draft guidance provides guidance

on the selection of test procedures and

the setting and justification of

acceptance criteria for new drug

substances of synthetic chemical origin,

and new drug products produced from

them, that have not been registered

previously in the United States, the

European Union, or Japan. The draft

guidance is intended to assist in the

establishment of a single set of global

specifications for new drug substances

and new drug products.

This draft guidance represents the

agency’s current thinking on the

selection of test procedures and the

setting and justification of acceptance

criteria for new chemical drug

substances and new drug products. It

does not create or confer any rights for

or on any person and does not operate

to bind FDA or the public. An

alternative approach may be used if

such approach satisfies the

requirements of the applicable statute,

regulations, or both.

Interested persons may, on or before

January 26, 1998, submit to the Dockets

Management Branch (address above)

written comments on the draft guidance.

Two copies of any comments are to be

submitted, except that individuals may

submit one copy. Comments are to be

identified with the docket number

found in brackets in the heading of this

document. The draft guidance and

received comments may be seen in the

office above between 9 a.m. and 4 p.m.,

Monday through Friday. An electronic

version of this guidance is available on

the Internet at ‘‘http://www.fda.gov/

cder/guidance.htm’’.

The text of the draft guidance follows:

Q6A Specifications: Test Procedures and

Acceptance Criteria for New Drug

Substances and New Drug Products:

Chemical Substances1

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
Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices 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 allinclusive 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
62892 Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices

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 endproduct 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
Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices 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
62894 Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices

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.
Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices 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, inprocess 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.
62896 Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices

(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, inprocess 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.
Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices 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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62898 Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices
Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices 62899
62900 Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices
Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices 62901
62902 Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices
Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices 62903
62904 Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices
Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices 62905
62906 Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices
Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices 62907
62908 Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices
Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices 62909
62910 Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices

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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