[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