principles and practices of analytical method validation: validation of analytical methods is...

Principles and Practices of AnalyticalMethod Validation: Validation ofAnalytical Methods is Time‐consumingbut Essential

Chung Chow Chan

Editor’s Note: This article is excerpted from a chapter that appeared in Pharmaceutical ManufacturingHandbook: Regulations and Quality, which was edited by Shayne Cox Gad, PhD. The book was publishedin 2008 by John Wiley & Sons Inc.

Validation of an analytical procedure is theprocess by which it is established, by laboratorystudies, that the performance characteristics ofthe procedure meet the requirements for itsintended use. All analytical methods intendedto be used for analyzing any clinical sampleswill need to be validated. Validation of analyt-ical methods is an essential but time‐consumingactivity for most analytical development labo-ratories. It is therefore important to understandthe requirements of method validation in moredetail and the options that are available toallow for optimal utilization of analyticalresources in a development laboratory.

There are many reasons for the need tovalidate analytical procedures. Among themare regulatory requirements, good science, andquality control requirements. The Code ofFederal Regulations (CFR) 211.165e explicitly

Dr. Chung Chow Chan is employed at CCC Consulting.Reach him at [email protected]

This article was previously published in December/January2010 in Pharmaceutical Formulation & Quality.

Copyright © 2011 John Wiley & Sons, Ltd.

states that “the accuracy, sensitivity, specificity,and reproducibility of test methods employedby the firm shall be established and documen-ted.” Of course, as scientists, we would want toapply good science to demonstrate that theanalytical method used had demonstrated accu-racy, sensitivity, specificity, and reproducibility.Finally, management of the quality control unitwould definitely want to ensure that the analyt-ical methods that the department uses to releaseits products are properly validated for itsintended use so the product will be safe forhuman use.

Current Good Manufacturing Practices

The overarching philosophy in current goodmanufacturing practices of the 21st century andin robust modern quality systems is that qualityshould be built into the product, and testingalone cannot be relied on to ensure productquality. From the analytical perspective, thiswill mean that analytical methods used to test

Qual Assur J 2011; 14, 61–64DOI: 10.1002/qaj.477

C. C. Chan62

these products should have quality attributesbuilt into them.

To have quality attributes built into theanalytical method will require that fundamentalquality attributes be applied by the bench‐levelscientist. This is a paradigm shift that requiresthe bench‐level scientist to have the scientific andtechnical understanding, product knowledge,process knowledge, and/or risk assessmentabilities to appropriately execute the qualityfunctions of analytical method validation.

It will require three things:

• the appropriate training of the bench‐levelscientist to understand the principles in-volved with method validation and to beable to validate an analytical method andunderstand the principles involved with themethod validation;

• proper documentation and understandingand interpreting data; and

• cross‐functional understanding of the effectof their activities on the product and thecustomer (the patient).

It is the responsibility of management toverify that skills gained from the training areimplemented in day‐to‐day performance.

Figure 1. Life Cycle of anAnalytical Procedure


Cycle of Analytical Methods

The analytical method validation activity is not aone‐time study. This is illustrated and summarizedin the life cycle of an analytical procedure inFigure 1. An analytical method will be developedandvalidated for use to analyze samples during theearly development of an active pharmaceuticalingredient or drug product. As drug developmentprogresses from Phase 1 to commercialization, theanalyticalmethodwill followasimilarprogression.

The final method will be validated for itsintended use for the market‐image drug productand transferred to the quality control laboratoryfor the launch of the drug product. However, ifthere are any changes in themanufacturingprocessthat have the potential to change the analyticalprofile of the drug substance and drug product,this validated method may need to be revalidatedto ensure that it is still suitable to analyze theAPIordrug product for its intended purpose.

The typical process that is followed in ananalytical method validation is as follows:

1. Planning and deciding on the methodvalidation experiments.

2. Writing and approval of method valida-tion protocol.

3. Executionof themethodvalidationprotocol.4. Analysis of the method validation data.5. Reporting the analytical method validation.6. Finalizing the analytical method procedure.

Themethod validation experiments should bewell planned and laid out to ensure efficient useof time and resources during execution of themethod validation. The best way to ensure awell‐planned validation study is to write amethod validation protocol that will be reviewedand signed by the appropriate person (e.g.,laboratory management and quality assurance).

Validation Parameters

The validation parameters that will be evaluatedwill dependon the type ofmethod to be validated.Analytical methods that are commonly validated


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can be classified into three main categories:identification, testing for impurities, and assay.Table 1 lists the ICH recommendations for eachof these methods.

Execution of the method validation protocolshould be carefully planned to optimize theresources and time required to complete the fullvalidation study. For example, in the validationof an assay method, linearity and accuracy maybe validated at the same time as both experi-ments can use the same standard solutions. Anormal validation protocol should contain thefollowing minimum contents:


• objective of the protocol;• validation parameters that will be evaluated;• acceptance criteria for all the validation

parameters evaluated;• details of the experiments to beperformed; and• draft analytical procedure.

The data from the method validation datashould be analyzed as the data are obtained andprocessed to ensure a smooth information flow.If an experimental error is detected, it should beresolved as soon as possible to reduce anyimpact it may have on later experiments.Analysis of the data includes visual examina-tion of the numerical values of the data andchromatograms followed by statistical treat-ment of the data if required.

Upon completion of all the experiments, allthe data will be compiled into a detailedvalidation report that will conclude the successor failure of the validation exercise. Dependingon the company’s strategy, a summary of thevalidation data may also be generated. Success-ful execution of the validation will lead to a finalanalytical procedure that can be used by thelaboratory to support future analytical work forthe drug substance or drug product.

The minimal information that should beincluded in a final analytical procedure is:

• Rationale of the analytical procedure anddescription of the capability of the method.


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Revision of analytical procedure shouldinclude the advantages offered by the newrevision.

• Proposed analytical procedure. This sectionshould contain a complete description of theanalytical procedure in sufficient detail toenable another analytical scientist to replicateit. The write‐up should include all importantoperational parameters and specific instruc-tions, such as preparation of reagents, systemsuitability tests, precautions, and explicitformulas for calculation of the test results.

• List of permitted impurities and their levelsin an impurity assay.

• Validation data. Either a detailed set orsummary set of validation data is included.

• Revision history.• Signature of author, reviewer, manage-

ment, and quality assurance.

References

1. International Conference on Harmonisation of Tech-

nical Requirements for Registration of Pharmaceuticals

for Human Use. ICH Guideline Q2(R1): Validation of

analytical procedures: text and methodology. Geneva,

Switzerland; 1994. Available at: www.ich.org/LOB/

media/MEDIA417.pdf. Accessed December 10, 2009.

2. International Conference on Harmonisation of

Technical Requirements for Registration of Pharma-

ceuticals for Human Use. ICH Guideline Q6A: Speci-

fications: test procedures and acceptance criteria for

new drug substances and new drug products:


chemical substances. Geneva, Switzerland; 1999.

Available at: www.ich.org/LOB/media/MEDIA430.pdf.

Accessed December 10, 2009.

3. International Conference on Harmonisation of

Technical Requirements for Registration of Pharma-

ceuticals for Human Use. ICH Guideline Q7: Good

manufacturing practice guide for active pharma-

ceutical ingredients. Geneva, Switzerland; 2000.

Available at: www.ich.org/ LOB/media/MEDIA433.pdf.


4. U.S. Food and Drug Administration. Center for Drug

Evaluation andResearch. Guidance for industry: quality

systemsapproachtopharmaceutical CGMPregulations.

FDA. Available at: www.fda.gov/downloads/Drugs/

GuidanceComplianceRegulatoryInformation/Guidances/

ucm070337.pdf. Accessed December 11, 2009.

5. U.S. Food and Drug Administration. Title 21 Code

of Federal Regulations (21 CFR Part 211). Current

good manufacturing practice for finished pharma-

ceuticals. Available at: www.accessdata.fda.gov/

scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=211.194.


6. Chan CC, Lee YC, Lam H, et al., eds. Analytical

Method Validation and Instrument Performance

Verification. Hoboken, N.J.: John Wiley & Sons, Inc;

2004.

7. United States Pharmacopeial Convention. General

chapter <1225>: Validation of compendial proce-

dures. Rockville, Md.: United States Pharmacopeial

Convention.

8. U.S. Pharmacopeial Convention.GeneralChapter<1226>:

Verification of compendial procedures. Rockville, Md.:

United States Pharmacopeial Convention.


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