Federal Register, Volume 60 Issue 40 (Wednesday, March 1, 1995)

[Federal Register Volume 60, Number 40 (Wednesday, March 1, 1995)]
[Notices]
[Pages 11260-11262]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-4956]

[[Page 11259]]

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Part VIII

Department of Health and Human Services

_______________________________________________________________________

Food and Drug Administration

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International Conference on Harmonisation; Guideline on Validation of
Analytical Procedures: Definitions and Terminology Availability; Notice

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

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.

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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
Sec. 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 Sec. 10.90(b). Therefore, this
guideline is not being issued under the authority of Sec. 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. [[Page 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-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.

TABLE
--------------------------------------------------------------------------------------------------------------------------------------------------------
Testing for impurities Assay; dissolution
Type of analytical procedure; characteristics Identification ---------------------------------------- (measurement) only;
Quantitation Limit content/potency
--------------------------------------------------------------------------------------------------------------------------------------------------------
Accuracy - + - +
Precision
Repeatab+lity - + -
Interm+\1\te Precision - +\1\ -
Specificity^{2+ + + +
Detection Li-it - -\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. [[Page 11262]]

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]
BILLING CODE 4160-01-F}