[Federal Register Volume 61, Number 46 (Thursday, March 7, 1996)]
[Notices]
[Pages 9316-9319]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-5296]
[[Page 9315]]
_______________________________________________________________________
Part VI
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
International Conference on Harmonisation; Draft Guideline on the
Validation of Analytical Procedures: Methodology; Availability; Notice
Federal Register / Vol. 61, No. 46 / Thursday, March 7, 1996 /
Notices
[[Page 9316]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 96D-0030]
International Conference on Harmonisation; Draft Guideline on the
Validation of Analytical Procedures: Methodology; 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 entitled ``Validation of Analytical Procedures:
Methodology.'' The draft guideline was prepared under the auspices of
the International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use (ICH). The draft
guideline provides recommendations on how to consider various
validation characteristics for each analytical procedure. The draft
guideline is an extension to the ICH guideline entitled ``Text on
Validation of Analytical Procedures.''
DATES: Written comments by June 5, 1996.
ADDRESSES: Submit written comments on the draft guideline to the
Dockets Management Branch (HFA-305), Food and Drug Administration,
12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the draft
guideline are available from the Division of Communications Management
(HFD-210), Center for Drug Evaluation and Research, Food and Drug
Administration, 7500 Standish Pl., Rockville, MD 20855, 301-594-1012.
An electronic version of this draft guideline is also available via
Internet by connecting to the CDER file transfer protocol (FTP) server
(CDVS2.CDER.FDA.GOV).
FOR FURTHER INFORMATION CONTACT:
Regarding the guideline: Eric B. Sheinin, Center for Drug
Evaluation and Research (HFD-830), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-2001.
Regarding 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.
At a meeting held on November 29, 1995, the ICH Steering Committee
agreed that a draft guideline entitled ``Validation of Analytical
Procedures: Methodology'' should be made available for public comment.
The draft guideline 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. Ultimately, FDA intends to adopt the ICH
Steering Committee's final guideline.
In the Federal Register of March 1, 1995 (60 FR 11260), the agency
published a final guideline entitled ``Text on Validation of Analytical
Procedures.'' 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.
This draft guideline provides guidance and recommendations on how
to consider the various validation characteristics for each analytical
procedure. In some cases (for example, the demonstration of
specificity), the overall capabilities of a number of analytical
procedures in combination may be investigated to ensure the quality of
the drug substance or drug product.
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). Although this draft
guideline does not create or confer any rights for or on any person and
does not operate to bind FDA, it does represent the agency's current
thinking on the validation of analytical procedures.
Interested persons may, on or before June 5, 1996, submit written
comments on the draft 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 draft 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 draft guideline follows:
Extension of ICH Text on Validation of Analytical Procedures:
Methodology
Introduction
This document is complementary to the ICH guideline entitled
``Text on Validation of Analytical Procedures,'' which presents a
discussion of the characteristics that should be considered during
the validation of analytical procedures. Its purpose is to provide
some guidance and recommendations on how to consider the various
validation characteristics for each analytical procedure. In some
cases, for example, demonstration of specificity, the overall
capabilities of a number of analytical procedures in combination may
be investigated in order to ensure the quality of the drug substance
or drug product. In addition, the document provides an indication of
the data that should be presented in a new drug application.
All relevant data collected during validation and formulae used
for calculating
[[Page 9317]]
validation characteristics should be submitted and discussed as
appropriate.
Approaches other than those set forth in this guideline may be
applicable and acceptable. It is the responsibility of the applicant
to choose the validation procedure and protocol most suitable for
their product. However, it is important to remember that the main
objective of validation of an analytical procedure is to demonstrate
that the procedure is suitable for its intended purpose. Due to
their complex nature, analytical procedures for biological and
biotechnological products in some cases may be approached
differently than in this document.
Well-characterized reference materials, with documented purity,
should be used throughout the validation study. The degree of purity
required depends on the intended use.
In accordance with the parent document, and for the sake of
clarity, this document considers the various validation
characteristics in distinct sections. The arrangement of these
sections reflects the process by which an analytical procedure may
be developed and evaluated.
In practice, it is usually possible to design the experimental
work such that the appropriate validation characteristics can be
considered simultaneously to provide a sound, overall knowledge of
the capabilities of the analytical procedure, for instance:
Specificity, linearity, range, accuracy, and precision.
1. Specificity
An investigation of specificity should be conducted during the
validation of identification tests, the determination of impurities,
and the assay. The procedures used to demonstrate specificity will
depend on the intended objective of the analytical procedure.
It is not always possible to demonstrate that an analytical
procedure is specific for a particular analyte (complete
discrimination). In this case, a combination of two or more
analytical procedures is recommended to achieve the necessary level
of discrimination.
1.1. Identification
Suitable identification tests should be able to discriminate
between compounds of closely related structures which are likely to
be present. The discrimination of a procedure may be confirmed by
obtaining positive results (perhaps by comparison with a known
reference material) from samples containing the analyte, coupled
with negative results from samples which do not contain the analyte.
In addition, the identification test may be applied to materials
structurally similar to or closely related to the analyte to confirm
that a positive response is not obtained. The choice of such
potentially interfering materials should be based on sensible
scientific judgment with a consideration of the interferences that
could occur.
1.2. Assay and Impurity Test(s)
For chromatographic procedures, representative chromatograms
should be used to demonstrate specificity, and individual components
should be appropriately labeled. Similar considerations should be
given to other separation techniques.
Critical separations in chromatography should be investigated at
an appropriate level. For critical separations, specificity can be
demonstrated by the resolution of the two components which elute
closest to each other.
In cases where a nonspecific assay is used, other supporting
analytical procedures should be used to demonstrate overall
specificity. For example, where a titration is adopted to assay the
drug substance, the combination of the assay and a suitable test for
impurities can be used.
The approach is similar for both assay and impurity tests:
1.2.1. Impurities are available
For the assay, this should involve demonstration of the
discrimination of the analyte in the presence of impurities and/or
excipients; practically, this can be done by spiking pure substances
(drug substance or drug product) with appropriate levels of
impurities and/or excipients and demonstrating that the assay result
is unaffected by the presence of these materials (by comparison with
the assay result obtained on unspiked samples).
For the impurity test, the discrimination may be
established by spiking drug substance or drug product with
appropriate levels of impurities and demonstrating the separation of
these impurities individually and/or from other components in the
sample matrix. Alternatively, for less discriminating procedures, it
may be acceptable to demonstrate that these impurities can still be
determined with appropriate accuracy and precision.
1.2.2. Impurities are not available
If impurity or degradation product standards are unavailable,
specificity may be demonstrated by comparing the test results of
samples containing impurities or degradation products to a second
well-characterized procedure, e.g., pharmacopoeial method or other
validated analytical procedure (independent procedure). As
appropriate, this should include samples stored under relevant
stress conditions: Light, heat, humidity, acid/base hydrolysis, and
oxidation.
For the assay, the two results should be compared.
For the impurity tests, the impurity profiles should be
compared.
Peak purity tests may be useful to show that the analyte
chromatographic peak is not attributable to more than one component
(e.g., diode array, mass spectrometry).
2. Linearity
Linearity should be established across the range (see section 3)
of the analytical procedure. It may be demonstrated directly on the
drug substance (by dilution of a standard stock solution) and/or
separate weighings of synthetic mixtures of the drug product
components, using the proposed procedure. The latter aspect can be
studied during investigation of the range.
Linearity should be established by visual evaluation of a plot
of signals as a function of analyte concentration or content. If
there is a linear relationship, test results should be evaluated by
appropriate statistical methods, for example, by calculation of a
regression line by the method of least squares. In some cases, to
obtain linearity between assays and sample concentrations, the test
data may have to be subjected to a mathematical transformation prior
to the regression analysis. Data from the regression line itself may
be helpful to provide mathematical estimates of the degree of
linearity. The correlation coefficient, y-intercept, slope of the
regression line, and residual sum of squares should be submitted. A
plot of the data should be included. In addition, an analysis of the
deviation of the actual data points from the regression line may
also be helpful for evaluating linearity.
Some analytical procedures such as immunoassays do not
demonstrate linearity after any transformation. In this case, the
analytical response should be described by an appropriate function
of the concentration (amount) of an analyte in a sample.
For the establishment of linearity, a minimum of 5
concentrations is recommended. Other approaches should be justified.
3. Range
The specified range is normally derived from linearity studies
and depends on the intended application of the procedure. It is
established by confirming that the analytical procedure provides an
acceptable degree of linearity, accuracy, and precision when applied
to samples containing amounts of analyte within or at the extremes
of the specified range of the analytical procedure.
The following minimum specified ranges should be considered:
For the assay of a drug substance or a finished
product, from 80 to 120 percent of the test concentration;
For the determination of an impurity, from the
quantitation limit (QL) or from 50 percent of the specification of
each impurity, whichever is greater, to 120 percent of the
specification; and
For impurities known to be unusually potent or to
produce toxic or unexpected pharmacological effects, the detection/
quantitation limit should be commensurate with the level at which
the impurities must be controlled.
Note: For validation of impurity test procedures carried out
during development, it may be necessary to consider the range around
a suggested (probable) limit;
If assay and purity are performed together as one test
and only a 100 percent standard is used, linearity should cover the
range from QL or from 50 percent of the specification of each
impurity, whichever is greater, to 120 percent of the assay
specification;
For content uniformity, covering a minimum of 70 to 130
percent of the test concentration, unless a wider more appropriate
range based on the nature of the dosage form (e.g. metered dose
inhalers) is justified;
For dissolution testing, +/-20 percent over the
specified range. For example, if the specifications for a controlled
released product cover a region from 20 percent, after
[[Page 9318]]
1 hour, up to 90 percent, after 24 hours, the validated range would
be 0-110 percent of the label claim.
4. Accuracy
Accuracy should be established across the specified range of the
analytical procedure.
4.1. Assay
4.1.1. Drug substance:
Several methods of determining accuracy are available:
(a) Application of an analytical procedure to an analyte of
known purity (e.g., reference material);
(b) Comparison of the results of the proposed analytical
procedure with those of a second well-characterized procedure, the
accuracy of which is stated and/or defined (independent procedure,
see section 1.2.);
(c) Accuracy may be concurrently determined when precision,
linearity, and specificity data are acquired.
4.1.2. Drug product:
Several methods for determining accuracy are available:
(a) Application of the analytical procedure to synthetic
mixtures of the drug product components to which known quantities of
the drug substance to be analyzed have been added;
(b) In cases where it is impossible to obtain samples of all
drug product components, it may be acceptable either to add known
quantities of the analyte to the drug product or to compare the
results obtained from a second, well-characterized procedure, the
accuracy of which is stated and/or defined (independent procedure,
see section 1.2).
(c) Accuracy may be concurrently determined when precision,
linearity, and specificity data are acquired.
4.2. Impurities (Quantitation)
Accuracy should be assessed on samples (drug substance/drug
product) spiked with known amounts of impurities.
In cases where it is impossible to obtain samples of certain
impurities and/or degradation products, it is acceptable to compare
results obtained by an independent procedure (see section 1.2.). The
response factor of the drug substance can be used.
4.3. Recommended Data:
Accuracy should be assessed using a minimum of 9 determinations
over a minimum of 3 concentration levels covering the specified
range (e.g., 3 concentrations/3 replicates each).
Accuracy should be reported as percent recovery by the assay of
known added amount of analyte in the sample or as the difference
between the mean and the accepted true value together with the
confidence intervals.
5. Precision
Validation of tests for assay and for quantitative determination
of impurities includes an investigation of precision.
5.1. Repeatability
Repeatability should be assessed using:
(a) A minimum of 9 determinations covering the specified range
for the procedure (e.g., 3 concentrations/3 replicates each); or
(b) A minimum of 6 determinations at 100 percent of the test
concentration.
5.2. Intermediate Precision
The extent to which intermediate precision should be established
depends on the circumstances under which the procedure is intended
to be used. The applicant should establish the effects of random
events on the precision of the analytical procedure. Typical
variations to be studied include days, analysts, equipment, etc. It
is not necessary to study these effects individually. The use of an
experimental design (matrix) is encouraged.
5.3. Reproducibility
Reproducibility is assessed by means of an interlaboratory
trial. Reproducibility should be considered in case of the
standardization of an analytical procedure, for instance, for
inclusion of procedures in pharmacopoeias. These data are not part
of the marketing authorization dossier.
5.4. Recommended Data
The standard deviation, relative standard deviation (coefficient
of variation), and confidence interval should be reported for each
type of precision investigated.
6. Detection Limit
Several approaches for determining the detection limit are
possible, depending on whether the procedure is noninstrumental or
instrumental. Approaches other than those listed below may be
acceptable.
6.1. Based on Visual Evaluation
Visual evaluation may be used for non-instrumental methods but
may also be used with instrumental methods.
The detection limit is determined by the analysis of samples
with known concentrations of analyte and by establishing the minimum
level at which the analyte can be reliably detected.
6.2. Based on Signal-to-Noise
This approach can only be applied to analytical procedures which
exhibit baseline noise. Determination of the signal-to-noise ratio
is performed by comparing measured signals from samples with known
low concentrations of analyte with those of blank samples and
establishing the minimum concentration at which the analyte can be
reliably detected. A signal-to-noise ratio between 3 or 2:1 is
generally acceptable.
6.3 Based on the Standard Deviation of the Response and the Slope
The detection limit (DL) may be expressed as:
3.3
DL= -----------
S
where = the standard deviation of the response
S = the slope of the calibration curve
The slope S may be estimated from the calibration curve of the
analyte. The estimate of may be carried out in a variety
of ways, for example:
6.3.1. Based on the Standard Deviation of the Blank
Measurement of the magnitude of analytical background response
is performed by analyzing an appropriate number of blank samples and
calculating the standard deviation of these responses.
6.3.2. Based on the Calibration Curve
A specific calibration curve should be studied using samples
containing an analyte in the range of DL. The residual standard
deviation of a regression line or the standard deviation of y-
intercepts of regression lines may be used as the standard
deviation.
6.4. Recommended Data
The detection limit and the method used for determining the
detection limit should be presented.
In cases where an estimated value for the detection limit is
obtained by calculation or extrapolation, this estimate may
subsequently be validated by the independent analysis of a suitable
number of samples known to be near or prepared at the detection
limit.
7. Quantitation Limit
Several approaches for determining the quantitation limit are
possible, depending on whether the procedure is non-instrumental or
instrumental. Approaches other than those listed below may be
acceptable.
7.1. Based on Visual Evaluation
Visual evaluation may be used for non-instrumental methods, but
may also be used with instrumental methods.
The quantitation limit is generally determined by the analysis
of samples with known concentrations of analyte and by establishing
the minimum level at which the analyte can be quantified with
acceptable accuracy and precision.
[[Page 9319]]
7.2. Based on Signal-to-Noise
This approach can only be applied to analytical procedures which
exhibit baseline noise. Determination of the signal-to-noise ratio
is performed by comparing measured signals from samples with known
low concentrations of analyte with those of blank samples and by
establishing the minimum concentration at which the analyte can be
reliably quantified. A typical signal-to-noise ratio is 10:1.
7.3. Based on the Standard Deviation of the Response and the Slope
The quantitation limit (QL) may be expressed as:
10
QL= -----------
S
where = the standard deviation of the response
S = the slope of the calibration curve
The slope S may be estimated from the calibration curve of the
analyte. The estimate of may be carried out in a variety
of ways, for example:
7.3.1. Based on Standard Deviation of the Blank
Measurement of the magnitude of analytical background response
is performed by analyzing an appropriate number of blank samples and
calculating the standard deviation of these responses.
7.3.2. Based on the Calibration Curve
A specific calibration curve should be studied using samples,
containing an analyte in the range of QL. The residual standard
deviation of a regression line or the standard deviation of y-
intercepts of regression lines may be used as the standard
deviation.
7.4 Recommended Data
The quantitation limit and the method used for determining the
quantitation limit should be presented.
The limit should be subsequently validated by the analysis of a
suitable number of samples known to be near or prepared at the
quantitation limit.
8. Robustness
The evaluation of robustness should be considered during the
development phase and depends on the type of procedure under study.
It should show the reliability of an analysis with respect to
deliberate variations in method parameters.
If measurements are susceptible to variations in analytical
conditions, the analytical conditions should be suitably controlled
or a precautionary statement should be included in the procedure.
One consequence of the evaluation of robustness should be that a
series of system suitability parameters (e.g., resolution test) is
established to ensure that the validity of the analytical procedure
is maintained whenever used.
Typical variations are:
Stability of analytical solutions
Different equipment
Different analysts
In the case of liquid chromatography, typical variations are:
Influence of variations of pH in a mobile phase
Influence of variations in mobile phase composition
Different columns (different lots and/or suppliers)
Temperature
Flow rate
In the case of gas-chromatography, typical variations are:
Different columns (different lots and/or suppliers)
Temperature
Flow rate
9. System Suitability Testing
System suitability testing is an integral part of many
analytical procedures. The tests are based on the concept that the
equipment, electronics, analytical operations, and samples to be
analyzed constitute an integral system that can be evaluated as
such. System suitability test parameters to be established for a
particular procedure depend on the type of procedure being
validated. See Pharmacopoeias for additional information.
Dated: February 27, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-5296 Filed 3-6-96; 8:45 am]
BILLING CODE 4160-01-F