Validation Principles

By Chung Chow Chan, PhD
Principles and Practices of Analytical Method Validation: Validation of analytical methods is time-consuming but essential

Editor’s Note: This article is excerpted from a chapter that appeared in Pharmaceutical Manufacturing Handbook: Regulations and Quality, which was edited by Shayne Cox Gad, PhD. The book was published in 2008 by John Wiley & Sons Inc., which also publishes PFQ. For more information on the book, click on the image of the book's cover to the right. To download a pdf version of this excerpted article, click here.

Validation of an analytical procedure is the process by which it is established, by laboratory studies, that the performance characteristics of the procedure meet the requirements for its intended use. All analytical methods intended to be used for analyzing any clinical samples will need to be validated. Validation of analytical methods is an essential but time-consuming activity for most analytical development laboratories. It is therefore important to understand the requirements of method validation in more detail and the options that are available to allow for optimal utilization of analytical resources in a development laboratory.

There are many reasons for the need to validate analytical procedures. Among them are regulatory requirements, good science, and quality control requirements. The Code of Federal Regulations (CFR) 211.165e explicitly states that “the accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be established and documented.” Of course, as scientists, we would want to apply good science to demonstrate that the analytical method used had demonstrated accuracy, sensitivity, specificity, and reproducibility. Finally, management of the quality control unit would definitely want to ensure that the analytical methods that the department uses to release its products are properly validated for its intended use so the product will be safe for human use.
Current Good Manufacturing Practices

The overarching philosophy in current good manufacturing practices of the 21st century and in robust modern quality systems is that quality should be built into the product, and testing alone cannot be relied on to ensure product quality. From the analytical perspective, this will mean that analytical methods used to test these products should have quality attributes built into them.
Figure 1. Life cycle of analytical method
Image courtesy of Thermo Fisher Scientific
Figure 1. Life cycle of analytical method

To have quality attributes built into the analytical method will require that fundamental quality attributes be applied by the bench-level scientist. This is a paradigm shift that requires the bench-level scientist to have the scientific and technical understanding, product knowledge, process knowledge, and/or risk assessment abilities to appropriately execute the quality functions of analytical method validation.

It will require three things:

* the appropriate training of the bench-level scientist to understand the principles involved with method validation and to be able to validate an analytical method and understand the principles involved with the method validation;
* proper documentation and understanding and interpreting data; and
* cross-functional understanding of the effect of their activities on the product and the customer (the patient).
* It is the responsibility of management to verify that skills gained from the training are implemented in day-to-day performance.

Cycle of Analytical Methods

The analytical method validation activity is not a one-time study. This is illustrated and summarized in the life cycle of an analytical procedure in Figure 1. An analytical method will be developed and validated for use to analyze samples during the early development of an active pharmaceutical ingredient or drug product. As drug development progresses from Phase 1 to commercialization, the analytical method will follow a similar progression.

The final method will be validated for its intended use for the market-image drug product and transferred to the quality control laboratory for the launch of the drug product. However, if there are any changes in the manufacturing process that have the potential to change the analytical profile of the drug substance and drug product, this validated method may need to be revalidated to ensure that it is still suitable to analyze the API or drug product for its intended purpose. (For more information, see the related article, “Perspectives on Method Validation,” in this issue.)

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

1. Planning and deciding on the method validation experiments.
2. Writing and approval of method validation protocol.
3. Execution of the method validation protocol.
4. Analysis of the method validation data.
5. Reporting the analytical method validation.
6. Finalizing the analytical method procedure.

The method validation experiments should be well planned and laid out to ensure efficient use of time and resources during execution of the method validation. The best way to ensure a well-planned validation study is to write a method validation protocol that will be reviewed and signed by the appropriate person (e.g., laboratory management and quality assurance).
Validation Parameters
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The validation parameters that will be evaluated will depend on the type of method to be validated. Analytical methods that are commonly validated can be classified into three main categories: identification, testing for impurities, and assay. Table 1 lists the ICH recommendations for each of these methods.

Execution of the method validation protocol should be carefully planned to optimize the resources and time required to complete the full validation study. For example, in the validation of an assay method, linearity and accuracy may be validated at the same time as both experiments can use the same standard solutions. A normal validation protocol should contain the following 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 be performed; and
* draft analytical procedure.

The data from the method validation data should be analyzed as the data are obtained and processed to ensure a smooth information flow. If an experimental error is detected, it should be resolved as soon as possible to reduce any impact it may have on later experiments. Analysis of the data includes visual examination of the numerical values of the data and chromatograms followed by statistical treatment of the data if required.

Upon completion of all the experiments, all the data will be compiled into a detailed validation report that will conclude the success or failure of the validation exercise. Depending on the company’s strategy, a summary of the validation data may also be generated. Successful execution of the validation will lead to a final analytical procedure that can be used by the laboratory to support future analytical work for the drug substance or drug product.

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

* Rationale of the analytical procedure and description of the capability of the method. Revision of analytical procedure should include the advantages offered by the new revision.
* Proposed analytical procedure. This section should contain a complete description of the analytical procedure in sufficient detail to enable another analytical scientist to replicate it. The write-up should include all important operational parameters and specific instructions, such as preparation of reagents, system suitability tests, precautions, and explicit formulas for calculation of the test results.
* List of permitted impurities and their levels in an impurity assay.
* Validation data. Either a detailed set or summary set of validation data is included.
* Revision history.
* Signature of author, reviewer, management, and quality assurance.

Dr. Chan is employed at CCC Consulting. Reach him at chungchow@rogers.com.
Resources
1. International Conference on Harmonisation of Technical 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 Pharmaceuticals for Human Use. ICH Guideline Q6A: Specifications: 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 Pharmaceuticals for Human Use. ICH Guideline Q7: Good manufacturing practice guide for active pharmaceutical ingredients. Geneva, Switzerland; 2000. Available at: www.ich.org/ LOB/media/MEDIA433.pdf. Accessed December 10, 2009.
4. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Guidance for industry: quality systems approach to pharmaceutical CGMP regulations. 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 pharmaceuticals. Available at: www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=211.194. Accessed December 11, 2009.
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 procedures. Rockville, Md.: United States Pharmacopeial Convention.
8. U.S. Pharmacopeial Convention. General Chapter <1226>: Verification of compendial procedures. Rockville, Md.: United States Pharmacopeial Convention.