[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





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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.

-----------------------------------------------------------------------

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:
    <bullet> Identification tests.
    <bullet> Quantitative tests for impurities' content.
    <bullet> Limit tests for the control of impurities.
    <bullet> 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.
    <bullet> 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.
    <bullet> 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.
    <bullet> 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:
    <bullet> Changes in the synthesis of the drug substance;
    <bullet> Changes in the composition of the finished product;
    <bullet> 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<SUP>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