FDA Guidance on Method Validation – Part One

In July of 2015, the Food and Drug Administration issued an updated Guidance for Industry titled “Analytical Procedures and Methods Validation for Drugs and Biologics”. This document replaces the draft of the same name published on February 19, 2014 and also the 2000 draft guidance for industry on Analytical Procedures and Methods Validation and the 1987 Guidelines for Submitting Samples and Analytical Data for Methods Validation. The plethora of data routinely published by organizations inclusive of the FDA, USP, and EU, as well as internal guidelines and interpretations generated by individual companies, it can be difficult to keep track of current trends and expectations. As Method Validation is a key area that effects the development and subsequent quality control testing of virtually every product that comes to market, it is worthwhile to take a moment and review the key highlights of the FDA’s most recent directive on this topic.

Some of the key points outlined in this guidance document are as follows:

This guidance provides recommendations on how the applicant can submit analytical procedures and method validation data to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products. It aims to assist a company in assembling information and present data to support analytical methodologies. The recommendations apply to drug substances and drug products covered in new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), and supplements to these applications. The principles in this guidance also apply to drug substances and drug products covered in Type II drug master files (DMFs). This guidance complements the International Conference on Harmonisation (ICH) guidance Q2(R1) Validation of Analytical Procedures: Text and Methodology (Q2(R1)) for developing and validating analytical methods.

Each NDA and ANDA must include the analytical procedures necessary to ensure the identity, strength, quality, purity, and potency of the drug substance and drug product. Each BLA must include a full description of the manufacturing process, including analytical procedures that demonstrate the manufactured product meets prescribed standards of identity, quality, safety, purity, and potency. Data must be available to establish that the analytical procedures used in testing meet proper standards of accuracy, sensitivity, specificity, and reproducibility and are suitable for their intended purpose.

When an analytical procedure is approved/licensed as part of the NDA, ANDA, or BLA, it becomes the FDA-approved analytical procedure for the approved product. This analytical procedure may originate from FDA recognized sources (e.g., a compendial procedure from the United States Pharmacopeia/National Formulary (USP/NF)) or a unique, developed and validated procedure determined to be acceptable by FDA. To apply an analytical method to a different drug product, appropriate validation or verification studies for compendial procedures with the matrix of the new product should be considered.

An analytical procedure is developed to test a defined characteristic of the drug substance or drug product against established acceptance criteria for that characteristic. Early in the development of a new analytical procedure, the choice of analytical instrumentation and methodology should be selected based on the intended purpose and scope of the analytical method. Parameters that may be evaluated during method development are specificity, linearity, limits of detection (LOD) and limits of quantitation (LOQ), range, accuracy, and precision. During early stages of method development, the robustness of methods should be evaluated, as this characteristic helps decide which method should be submitted for approval. Analytical procedures in the early stages of development are initially developed based on a combination of mechanistic understanding of the basic methodology and prior experience. Experimental data from early procedures can be used to guide further development. You should submit development data within the method validation section if they support the validation of  the method. To fully understand the effect of changes in method parameters on an analytical procedure, one should consider a systematic approach for a method robustness study (e.g., a design of experiments with method parameters) beginning with an initial risk assessment and followed by multivariate experiments. Such approaches allow you to understand factorial parameter effects on method performance. Evaluation of a method’s performance may include analyses of samples obtained from various stages of the manufacturing process from in-process to the finished product. Knowledge gained during these studies on the sources of method variation can help you assess the method performance.

These key highlights extracted from the guidance document outline the introduction and scope of the FDA’s current thinking and expected direction for Analytical Method Development and Validation. In part two of this article series, we will begin to look at specific parameters of the validation process and what the current expectations are in terms of data submission. To read the actually FDA Guidance Document, please visit FDA.gov.

Therese Abrenica
Director, Technical Services
Direct: 908-823-4517