Guideline No.
Guidance for Industry: Validation of Analytical Procedures: Definition and Terminology
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR VETERINARY MEDICINE
Guidance for Industry
VALIDATION OFANALYTICAL PROCEDURES:
DEFITION AND TERMINOLOGY
FINAL GUIDANCE
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.
Comments and suggestions regarding the document should be submitted to Carol Haley, Policy & Regulations Team, Center for Veterinary Medicine, (HFV-6), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855.
For questions regarding this draft document, contact William G. Marnane, Center for Veterinary Medicine, (HFV-140), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855,301-594-0678, E-mail: wmarnane@cvm.fda. gov.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Veterinary Medicine
JULY 1999
VALIDATION OF ANALYTICAL PROCEDURES:
DEFINITION AND TERMINOLOGY
Recommended for Implementation
|
THIS GUIDANCE HAS BEENDEVELOPEDBYTHE APPROPRIATEVICH EXPERT WORKING GROUP ON THE BASISOF THE ICH GUIDELINESON THE SAMESUBJECTAND HAS BEENSUBJECTTO CONSULTATIONBYTHE PARTIES, iN ACCORDANCEWiTH THE VICH PROCESS. AT STEP 7 OF THE PROCESS THE FINALDRAFTISRECOMMENDEDFORADOPTIONTO THE REGULATORYBODIESOF THE ELJROPEANUNION. JAPANAND USA. |
VALIDATION OF ANALYTiCAL PROCEDURES:
DEFINITIONANDTERMINOLOGY
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 ValidatedThe 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
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.
- 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:
AccuracySpecificity
Precision
Repeatability
intermediate Precision
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 cha-nges. Certain other changes may require validation as well.
TABLE
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.
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.
|
||||||
 |
||||||
|
||||||