[Federal Register Volume 59, Number 40 (Tuesday, March 1, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-4565]
[[Page Unknown]]
[Federal Register: March 1, 1994]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
[Docket No. 94D-0016]
International Conference on Harmonisation; Draft Guideline on
Validation of Analytical Procedures for Pharmaceuticals; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is publishing a draft
guideline on the validation of analytical procedures for
pharmaceuticals. This draft guideline was prepared by the Expert
Working Group on Quality of the International Conference on
Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH). This draft guideline is intended
to present characteristics that should be considered during the
validation of the analytical procedures included as part of
registration applications for pharmaceuticals.
DATES: Written comments by May 16, 1994.
ADDRESSES: Submit written comments on the draft guideline to the
Dockets Management Branch (HFA-305), Food and Drug Administration, rm.
1-23, 12420 Parklawn Dr., Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT:
Regarding the draft guideline: Charles S. Kumkumian, Center for
Drug Evaluation and Research (HFD-102), Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857, 301-443-4330.
Regarding ICH: Janet Showalter, Office of Health Affairs (HFY-50),
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 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.
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 other interested parties. Through notices
such as this, FDA invites public comment on ICH initiatives that have
reached the draft guideline stage. 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, FDA, and the U.S. Pharmaceutical
Manufacturers Association. 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 IFPMA, as well as observers from the World Health
Organization, the Canadian Health Protection Branch, and the European
Free Trade Area.
At a meeting held from October 27 through 29, 1993, the ICH
Steering Committee agreed that a draft tripartite guideline entitled
``Draft Guideline on Validation of Analytical Procedures'' should be
made available for public comment. The draft guideline will be made
available for comment by the European Commission and Japanese Ministry
of Health and Welfare, as well as by FDA, in accordance with their
respective consultation procedures. After analyzing the comments and
revising the guideline if appropriate, FDA will determine whether it
will adopt and issue the guideline.
The draft 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 draft 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.
Guidelines are generally issued under Secs. 10.85(d) and 10.90(b)
(21 CFR 10.85(d) and 10.90(b)), which provide for the use of guidelines
to establish 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 considering whether to revise Sec. 10.85(d) and
Sec. 10.90(b). Therefore, if the agency issues this guideline in final
form, the guideline would not be issued under the authority of
Sec. 10.85(d) and Sec. 10.90(b) and would not create or confer any
rights, privileges, or benefits for or on any person, nor would it
operate to bind FDA in any way.
Interested persons may, on or before May 16, 1994, submit to the
Dockets Management Branch (address above) written comments on the draft
guideline. 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.
Received comments may be seen in the office above between 9 a.m. and 4
p.m., Monday through Friday.
The text of the draft guideline follows:
Text on Validation of Analytical Procedures
1. Introduction
This document presents a discussion of the characteristics that
should be considered during the validation of the analytical
procedures included as part of registration applications submitted
within Europe, 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 Europe, 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.
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 measurements for impurities' content.
Limit tests for the control of impurities.
Quantitative measure 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.
Impurity tests 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 needed 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,
Reproducibility;
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.
Table
------------------------------------------------------------------------
Impurities purity test Assay;
Type of content/
analytical ------------------------ potency
procedure; Identification dissolution:
characteristics Quantitation Limit measurement
only
------------------------------------------------------------------------
Accuracy - + - +
Precision:
Repeatability - + - +
Intermediate - +\3\ - +\3\
precision
Reproducibili - -\1\ - -\1\
ty
Specificity + + + +\2\
Detection limit - + + -
Quantitation - + - -
limit
Linearity - + - +
Range - + - +
------------------------------------------------------------------------
Note:- signifies that this parameter is not normally evaluated; +
signifies that this parameter is normally evaluated.
\1\May be needed in some cases.
\2\May not be needed in some cases.
\3\In cases where reproducibility has been performed, intermediate
precision is not needed.
Annex
Glossary
1. Analytical Procedure
The analytical procedure is a detailed description of 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, and 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.
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 performed at three
levels: repeatability, intermediate precision and reproducibility.
Precision should be measured using authentic samples. However,
if it is not possible to obtain a homogeneous sample it may be
measured 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.
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).
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.
For those analytical procedures which are not linear, another
mathematical relationship (proportionality) should be demonstrated.
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, 1994.
Michael R. Taylor,
Deputy Commissioner for Policy.
[FR Doc. 94-4565 Filed 2-24-94; 1:35 pm]
BILLING CODE 4160-01-F