Analytical method validation regulatory requirements

It is not required to have prior FDA approval to use an alternate method to a compendial test. According to 21 CFR 314.70, Supplements and Other Changes to an Approved Application, the addition or deletion of an alternate analytical method does not require prior approval and may be filed in the Annual Product Report. However, we would need to document the equivalency of the alternate method to the regulatory or compendial test method and the validation report must be available for an FDA investigator to inspect at our manufacturing site. Where the test method is particularly novel it may be advisable to include the test in an NDA supplement so the FDA can review the new method and your company can get prior FDA approval before the new test method is implemented. 

An attempt for harmonization was made at the International Conference on Harmonization (ICH) in 1995 and 1996 by representatives from the industry and regulatory agencies from the United States, Europe, and Japan, who defined parameters, requirements, and, to some extent, also methodology, for analytical methods validation. 

As required by regulatory authorities [1-3, 6] and International Conference on Harmonisation (ICH) guidelines [7], analytical method validation is especially important in establishing the assay methods and procedures of quantitative or semi-quantitative measurement of target substances or compounds. Among the specification items for drug products, assay, content uniformity, and dissolution are typical of those which require almost full analytical validation. The purity test, related... 

Once the determinative or confirmatory method has been developed to take full advantage of the chemical properties of the analyte molecule, a study is necessary to prove that the method is valid. Criteria for method validation are outlined in guidelines from the US FDA, US EPA, and EU. A summary of the differences in regulatory requirements for method validation is provided in Table 3. The parameters addressed by all of the regulatory guidelines include accuracy, precision, sensitivity, specificity, and practicability. 

Capillary electrophoresis (CE) has become a valuable technique in the analytical toolbox for pharmaceutical analysts. CE methods have been successfully applied for identification, assay, purity determination, and chiral separation. ICH guidelines should be followed in meeting regulatory approval if CE methods are used in a registration dossier. Here, the validation parameters required for different analytical procedures are described and a comprehensive overview of CE validation studies presented in literature is given. 

The CISs are rapidly becoming more popular and reliable as their field of application broadens. This is mainly due to the production of surface images by multipoint scanning and mapping. Hyperspectral imaging has proven its potential for qualitative analysis of pharmaceutical products and can be used when spatial information becomes relevant for an analytical application. Even if online applications and regulatory method validation require further development, the power of CIS in quality control and PAT needs no further demonstration, whatever the wavelength domain or method of spectra collection. 

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) 311.165c 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. 

Method validation is the process of proving that an analytical method is acceptable for its intended purpose.3 In pharmaceutical chemistry, method validation requirements for regulatory submission include studies of method specificity, linearity, accuracy, precision, range, limit of detection, limit of quantitation, and robustness. 

Under the PBMS approach, prescriptive analytical methods of today will give way to performance-based methods that are focused on the analysis of project-specific contaminants of concern under project-specific QC requirements. These QC requirements will be selected based on the need of the regulatory program that requires data collection and will support the production of valid data of known and documented quality. 

Regulatory professionals too often assume that any analytical method can undergo the steps necessary to validate its use in marketing a pharmaceutical product. In many cases the need for validation of a particular analytical method is often revealed late in the drug development process by corporate regulatory and quality assurance (QA) professionals who are responsible for compliance with the regulatory requirements associated with product registration. Commonly these individuals view the requirements and parameters of the validation processes as independent of the actual analytical chemistry and technical objective of the method itself. 

Method validation must be performed in a regulatory-compliant environment. In particular, the organization must have a QA unit (QAU), adequate laboratory equipment and facilities, written procedures, and qualified personnel. Since a successful validation requires the cooperative efforts of each of these organizational elements, successful fulfillment of the regulatory and technical objectives of validation requires senior management support. Additionally, it is essential that the organization have a well-defined validation master plan (YMP) for analytical methods, which defines the steps necessary to effectively validate methods. 

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