11260 Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / Notices

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 94D–0016]

International Conference on

Harmonisation; Guideline on

Validation of Analytical Procedures:

Definitions and Terminology;

Availability

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is publishing a

final guideline entitled ‘‘Text on

Validation of Analytical Procedures.’’

This guideline was prepared under the

auspices of the International Conference

on Harmonisation of Technical

Requirements for Registration of

Pharmaceuticals for Human Use (ICH).

The guideline is intended to present

topics that should be considered during

the validation of the analytical

procedures included as part of

registration applications for

pharmaceuticals.

DATES: Effective on March 1, 1995.

Submit written comments at any time.

ADDRESSES: Submit written comments

on the guideline to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, rm. 1–23,

12420 Parklawn Dr., Rockville, MD

20857. Copies of the guideline are

available from CDER Executive

Secretariat Staff (HFD–8), Center for

Drug Evaluation and Research, Food

and Drug Administration, 7500 Standish

Pl., Rockville, MD 20855.

FOR FURTHER INFORMATION CONTACT:

Regarding the guideline: Roger L.

Williams, Center for Drug

Evaluation and Research (HFD–4),

Food and Drug Administration,

5600 Fishers Lane, Rockville, MD

20857, 301–594–6740.

Regarding ICH: Janet J. Showalter,

Office of Health Affairs (HFY–20),

Food and Drug Administration,

5600 Fishers Lane, Rockville, MD

20857, 301–443–1382.

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 Industry 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 Association (IFPMA).

The ICH Steering Committee includes

representatives from each of the ICH

sponsors and IFPMA, as well as

observers from the World Health

Organization, the Canadian Health

Protection Branch, and the European

Free Trade Area.

Harmonization of the validation of

analytical procedures for

pharmaceuticals was selected as a

priority topic during the early stages of

the ICH initiative. In the Federal

Register of March 1, 1994 (59 FR 9750),

FDA published a draft tripartite

guideline entitled ‘‘Draft Guideline on

Validation of Analytical Procedures.’’

The notice gave interested persons an

opportunity to submit comments by

May 16, 1994.

After consideration of the comments

received and revisions to the guideline,

a final draft of the guideline was

submitted to the ICH Steering

Committee and endorsed by the three

participating regulatory agencies at the

ICH meeting held in October 1994.

The guideline presents a discussion of

the characteristics that should be

considered during the validation of the

analytical procedures included as part

of registration applications submitted in

Europe, Japan, and the United States.

The guideline discusses common types

of analytical procedures and defines

basic terms, such as ‘‘analytical

procedure,’’ ‘‘specificity,’’ and

‘‘precision.’’ These terms and

definitions are meant to bridge the

differences that often exist between

various compendia and regulators of the

European Union, Japan, and the United

States.

In the past, guidelines have generally

been issued under § 10.90(b) (21 CFR

10.90(b)), which provides for the use of

guidelines to state procedures or

standards of general applicability that

are not legal requirements but are

acceptable to FDA. The agency is now

in the process of revising § 10.90(b).

Therefore, this guideline is not being

issued under the authority of § 10.90(b),

and it does not create or confer any

rights, privileges, or benefits for or on

any person, nor does it operate to bind

FDA in any way.

As with all of FDA’s guidelines, the

public is encouraged to submit written

comments with new data or other new

information pertinent to this guideline.

The comments in the docket will be

periodically reviewed, and, where

appropriate, the guideline will be

amended. The public will be notified of

any such amendments through a notice

in the Federal Register.

Interested persons may, at any time,

submit written comments on the

guideline to the Dockets Management

Branch (address above). 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 guideline and received

comments may be seen in the office

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

Monday through Friday.

The text of the guideline follows:

Text on Validation of Analytical Procedures

1. Introduction

This document presents a discussion of the

characteristics for consideration during the

validation of the analytical procedures

included as part of registration applications

submitted within the European Union, Japan,

and the United States. This document does

not necessarily seek to cover the testing that

may be required for registration in, or export

to, other areas of the world. Furthermore, this

text presentation serves as a collection of

terms, and their definitions, and is not

intended to provide direction on how to

accomplish validation. These terms and

definitions are meant to bridge the

differences that often exist between various

compendia and regulators of the European

Union, Japan, and the United States.

The objective of validation of an analytical

procedure is to demonstrate that it is suitable

for its intended purpose. A tabular

summation of the characteristics applicable

to identification, control of impurities, and

assay procedures is included. Other

analytical procedures may be considered in

future additions to this document.
Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / Notices 11261

2. Types of Analytical Procedures to be

Validated

The discussion of the validation of

analytical procedures is directed to the four

most common types of analytical procedures:

• Identification tests.

• Quantitative tests for impurities’ content.

• Limit tests for the control of impurities.

• Quantitative tests of the active moiety in

samples of drug substance or drug product or

other selected component(s) in the drug

product.

Although there are many other analytical

procedures, such as dissolution testing for

drug products or particle size determination

for drug substance, these have not been

addressed in the initial text on validation of

analytical procedures. Validation of these

additional analytical procedures is equally

important to those listed herein and may be

addressed in subsequent documents.

A brief description of the types of tests

considered in this document is provided

below.

• Identification tests are intended to ensure

the identity of an analyte in a sample. This

is normally achieved by comparison of a

property of the sample (e.g., spectrum,

chromatographic behavior, chemical

reactivity, etc.) to that of a reference

standard.

• Testing for impurities can be either a

quantitative test or a limit test for the

impurity in a sample. Either test is intended

to accurately reflect the purity characteristics

of the sample. Different validation

characteristics are required for a quantitative

test than for a limit test.

• Assay procedures are intended to

measure the analyte present in a given

sample. In the context of this document, the

assay represents a quantitative measurement

of the major component(s) in the drug

substance. For the drug product, similar

validation characteristics also apply when

assaying for the active or other selected

component(s). The same validation

characteristics may also apply to assays

associated with other analytical procedures

(e.g., dissolution).

The objective of the analytical procedure

should be clearly understood since this will

govern the validation characteristics which

need to be evaluated. Typical validation

characteristics which should be considered

are listed below:

Accuracy;

Precision:

Repeatability;

Intermediate precision;

Specificity;

Detection limit;

Quantitation limit;

Linearity;

Range.

Each of these validation characteristics is

defined in the attached Glossary. The table

lists those validation characteristics regarded

as the most important for the validation of

different types of analytical procedures. This

list should be considered typical for the

analytical procedures cited but occasional

exceptions should be dealt with on a case-bycase basis. It should be noted that robustness

is not listed in the table but should be

considered at an appropriate stage in the

development of the analytical procedure.

Furthermore revalidation may be necessary

in the following circumstances:

• Changes in the synthesis of the drug

substance;

• Changes in the composition of the

finished product;

• Changes in the analytical procedure.

The degree of revalidation required

depends on the nature of the changes. Certain

other changes may require validation as well.

TABLE

Type of analytical procedure; characteristics Identification

Testing for impurities Assay; dissolution

(measurement) only;

Quantitation Limit content/potency

Accuracy – + – +

Precision

Repeatability – + – +

Intermediate Precision – +1 – +1

Specificity2 + + + +

Detection Limit – –3 + –

Quantitation Limit – + – –

Linearity – + – +

Range – + – +

Note –signifies that this characteristic is not normally evaluated; + signifies that this characteristic is normally evaluated. 1 In cases where reproducibility (see Glossary) has been performed, intermediate precision is not needed.

2 Lack of specificity of one analytical procedure could be compensated by other supporting analytical procedure(s).

3 May be needed in some cases.

Glossary

1. Analytical Procedure

The analytical procedure refers to the way

of performing the analysis. It should describe

in detail the steps necessary to perform each

analytical test. This may include but is not

limited to: The sample, the reference

standard and the reagents preparations, use

of the apparatus, generation of the calibration

curve, use of the formulae for the calculation,

etc.

2. Specificity

Specificity is the ability to assess

unequivocally the analyte in the presence of

components which may be expected to be

present. Typically these might include

impurities, degradants, matrix, etc.

Lack of specificity of an individual

analytical procedure may be compensated by

other supporting analytical procedure(s).

This definition has the following

implications:

Identification: To ensure the identity of an

analyte.

Purity Tests: To ensure that all the

analytical procedures performed allow an

accurate statement of the content of

impurities of an analyte, i.e., related

substances test, heavy metals, residual

solvents content, etc.

Assay (content or potency): To provide an

exact result which allows an accurate

statement on the content or potency of the

analyte in a sample.

3. Accuracy

The accuracy of an analytical procedure

expresses the closeness of agreement between

the value which is accepted either as a

conventional true value or an accepted

reference value and the value found.

This is sometimes termed trueness.

4. Precision

The precision of an analytical procedure

expresses the closeness of agreement (degree

of scatter) between a series of measurements

obtained from multiple sampling of the same

homogeneous sample under the prescribed

conditions. Precision may be considered at

three levels: Repeatability, intermediate

precision and reproducibility.

Precision should be investigated using

homogeneous, authentic samples. However,

if it is not possible to obtain a homogeneous

sample it may be investigated using

artificially prepared samples or a sample

solution.

The precision of an analytical procedure is

usually expressed as the variance, standard

deviation, or coefficient of variation of a

series of measurements.

4.1. Repeatability

Repeatability expresses the precision under

the same operating conditions over a short

interval of time. Repeatability is also termed

intra-assay precision.
11262 Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / Notices

4.2. Intermediate precision

Intermediate precision expresses within

laboratories’ variations: Different days,

different analysts, different equipment, etc.

4.3. Reproducibility

Reproducibility expresses the precision

between laboratories (collaborative studies,

usually applied to standardization of

methodology).

5. Detection Limit

The detection limit of an individual

analytical procedure is the lowest amount of

analyte in a sample which can be detected

but not necessarily quantitated as an exact

value.

6. Quantitation Limit

The quantitation limit of an individual

analytical procedure is the lowest amount of

analyte in a sample which can be

quantitatively determined with suitable

precision and accuracy. The quantitation

limit is a parameter of quantitative assays for

low levels of compounds in sample matrices,

and is used particularly for the determination

of impurities and/or degradation products.

7. Linearity

The linearity of an analytical procedure is

its ability (within a given range) to obtain test

results which are directly proportional to the

concentration (amount) of analyte in the

sample.

8. Range

The range of an analytical procedure is the

interval between the upper and lower

concentration (amounts) of analyte in the

sample (including these concentrations) for

which it has been demonstrated that the

analytical procedure has a suitable level of

precision, accuracy, and linearity.

9. Robustness

The robustness of an analytical procedure

is a measure of its capacity to remain

unaffected by small, but deliberate, variations

in method parameters and provides an

indication of its reliability during normal

usage.

Dated: February 23, 1995.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 95–4956 Filed 2–28–95; 8:45 am]

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