Guideline for Industry

Text on Validation of

Analytical Procedures

ICH-Q2A

 March 1995
i

TABLE OF CONTENTS

I. INTRODUCTION ............................................... 1

II. TYPES OF ANALYTICAL PROCEDURES TO BE VALIDATED ........ 2

GLOSSARY .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APPENDIX A

1. Analytical Procedure ...................................... A-1

2. Specificity .............................................. A-1

3. Accuracy ............................................... A-1

4. Precision ............................................... A-2

a. Repeatability ....................................... A-2

b. Intermediate Precision ............................... A-2

c. Reproducibility ..................................... A-2

5. Detection Limit .......................................... A-2

6. Quantitation Limit ........................................ A-2

7. Linearity ............................................... A-3

8. Range ................................................. A-3

9. Robustness ............................................. A-3
This guideline was developed within the Expert Working Group (Quality) of the 1

International Conference on Harmonisation of Technical Requirements for Registration

of Pharmaceuticals for Human Use (ICH) and has been subject to consultation by the

regulatory parties, in accordance with the ICH process. This document has been

endorsed by the ICH Steering Committee at Step 4 of the ICH process, October 27,

1994. At Step 4 of the process, the final draft is recommended for adoption to the

regulatory bodies of the European Union, Japan and the USA. This guideline was

published in the Federal Register on March 1, 1995 (60 FR 11260) and is applicable to

drug and biological products. 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 that

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. For additional copies of this guideline contact

the Consumer Affairs Branch (formerly the Executive Secretariat Staff), HFD-210,

Center for Drug Evaluation and Research, 7500 Standish Place, Rockville, MD, 20855,

301-594-1012. An electronic version of this guideline is also available via Internet by

connecting to the CDER file transfer protocol (FTP) server (CDVS2.CDER.FDA.GOV).

GUIDELINE FOR INDUSTRY1

TEXT ON VALIDATION OF ANALYTICAL PROCEDURES

I. 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
2

this document.

II. 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).
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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-by-case 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.
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TABLE

TYPE OF IDENTIFICATIO TESTING FOR ASSAY;

ANALYTICAL N IMPURITIES dissolution

PROCEDURE; (measurement

CHARACTERISTICS only);

content/potenc

y

Quantitation Limit

Accuracy - + - +

Precision

Repeatability - + - +

Intermediate 

Precision - + - +

1 1

Specificity + + + +

2

Detection Limit - - + -

3

Quantitation Limit - + - -

Linearity - + - +

Range - + - +

NOTE: - signifies that this characteristic is not normally evaluated; + signifies that this characteristic is normally evaluated.

In cases where reproducibility (see Glossary) has been performed, intermediate precision is not needed. 1

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

May be needed in some cases. 3
A-1

Appendix A

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.
A-2

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.

a. Repeatability

Repeatability expresses the precision under the same operating

conditions over a short interval of time. Repeatability is also termed

intra-assay precision 

b. Intermediate precision

Intermediate precision expresses within laboratories variations: different

days different analysts, different equipment, etc.

c. 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
A-3

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.