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. 
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.

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: