63 
 
Guidance for Industry 
 
V A P :
ALIDATION OF  NALYTICAL  ROCEDURES  
D T
  EFINITION AND  ERMINOLOGY 
 
  FINAL GUIDANCE 
(October 21, 2010, this guidance document was revised to update contact information, correct 
broken internet links and minor formatting changes) 
 
This guidance document provides guidance on characteristics for consideration during the 
validation of the analytical procedures included as part of registration applications for 
approval of veterinary medicinal products submitted to the European Union, Japan, and the 
United States.  The implementation date is set for October 1999. 
 
This guidance represents current thinking and does not create or confer any rights for or on 
any person and does not operate to bind FDA or the public.  An alternative approach may 
be used if such approach satisfies the requirements of the applicable statute, regulation, or 
both.  
 
Submit comments on this guidance at any time.  Submit written comments to the Division 
of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Room 1061, Rockville, MD 20852.  Comments may also be submitted electronically on the 
Internet at http://www.regulations.gov.   
 
 For questions regarding this document, contact Rebecca Owen, Center for Veterinary 
Medicine, (HFV-140), Food and Drug Administration, 7500 Standish Place, Rockville, MD 
20855, 240-276-9842, E-mail: Rebecca.Owen@fda.hhs.gov. 
 
Additional copies of this guidance document may be requested from the Communications 
Staff, HFV-12, Center for Veterinary Medicine, U.S. Food and Drug Administration, 7519 
Standish Place, Rockville, MD  20855, and may be viewed on the Internet at 
http://www.fda.gov/AnimalVeterinary/default.htm.  
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine 
JULY 1999 
  VICH GL1 (VALIDATION DEFINITION) 
October 1998 
For implementation at Step 7  October 1999 
 
 
 
 
 
 
V A P : 
ALIDATION OF  NALYTICAL  ROCEDURES
D T  
EFINITION AND  ERMINOLOGY
 
 
 
 
Recommended for Implementation  
at Step 7 of the VICH Process 
on 22 October 1998 
by the VICH Steering Committee 
 
 
 
 
 
 
 
 
 
 
 
 
 
THIS GUIDANCE HAS BEEN DEVELOPED BY THE APPROPRIATE VICH EXPERT WORKING GROUP ON 
THE BASIS OF THE ICH GUIDELINES ON THE SAME SUBJECT AND HAS BEEN SUBJECT TO 
CONSULTATION BY THE PARTIES, IN ACCORDANCE WITH THE VICH PROCESS.  AT STEP 7 OF THE 
PROCESS THE FINAL DRAFT IS RECOMMENDED FOR ADOPTION TO THE REGULATORY BODIES OF THE 
EUROPEAN UNION, JAPAN AND USA. 
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     VALIDATION OF ANALYTICAL PROCEDURES: 
DEFINITION AND TERMINOLOGY 
 
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 (EU), Japan and USA.  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 
EU, Japan and USA. 
 
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 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 substances, 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 behaviour, chemical reactivity, etc) to that of a reference standard. 
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      -  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. 
   
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     TABLE 
       
Type of analytical  IDENTIFICATION  TESTING  FOR  ASSAY 
procedure  IMPURITIES  - dissolution 
  (measurement only)
- content/potency 
characteristics    quantitat.   limit   
Accuracy  -  +  -  + 
Precision        
    Repeatability  -  +  -  + 
    Interm. Precision  -  + (1) -       + (1) 
Specificity (2)  +  +  +  + 
Detection Limit  -  - (3)  +  - 
Quantitation Limit  -  +  -  - 
Linearity  -  +  -  + 
Range  -  +  -  + 
  -  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 
  Page 5
     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. 
 
 
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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. 
 
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. 
 
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     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. 
 
 
 
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