HPLC for Pharmaceutical Scientists 2007 (Part 9)

The method validation process is to confirm that the method is suited for its intended purpose. Although the requirements of validation have been clearly documented by regulatory authorities [ICH, USP, and FDA], the approach to validation is varied and open to interpretation. Validation requirements differ during the development process of pharmaceuticals. The method validation methodologies in this chapter will focus on the method requirements for preliminary and full validation for both drug substance and drug product. Preliminary method validation is generally performed in the earlier phases of development up to Phase IIa because at this time ICH Q2A and...
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HPLC for Pharmaceutical Scientists 2007 (Part 9)9METHOD VALIDATIONRosario LoBrutto and Tarun Patel9.1 INTRODUCTIONThe method validation process is to confirm that the method is suited for itsintended purpose. Although the requirements of validation have been clearlydocumented by regulatory authorities [ICH, USP, and FDA], the approach tovalidation is varied and open to interpretation. Validation requirements differduring the development process of pharmaceuticals. The method validationmethodologies in this chapter will focus on the method requirements forpreliminary and full validation for both drug substance and drug product.Preliminary method validation is generally performed in the earlier phases ofdevelopment up to Phase IIa because at this time ICH Q2A and Q2B [1] arenot yet binding. A more extensive validation (full validation) is performedfor methods used in later stages of drug development (after Phase IIa) andfor methods that will be used to evaluate marketed products. Specific require-ments or methodologies for validation depending on the life cycle of thepotential drug candidate in each specific area in the drug development processwill be addressed in the corresponding chapter. An analytical method is a laboratory procedure that measures an attributeof a raw material, drug substance, or a drug product. Analytical method vali-dation is the process of demonstrating that an analytical method is reliableand adequate for its intended purpose. Any method that is utilized to deter-mine results during drug substance and formulation development will have tobe validated. Reliable data for release of clinical supplies, stability, and settingshelf life can only be generated with appropriate validated methods.HPLC for Pharmaceutical Scientists, Edited by Yuri Kazakevich and Rosario LoBruttoCopyright © 2007 by John Wiley & Sons, Inc. 455456 METHOD VALIDATION Validation of high-performance liquid chromatography (HPLC) methodsfocus mainly on the following: • Identification tests • Quantitative measurements of the content of related substances* • Semiquantitative and limit tests for the control of related substances* • Quantitative tests for the assay of major components (e.g., drug substance and preservatives) in samples of drug substance or drug product (assay, content uniformity, dissolution rate, etc.)Moreover, HPLC methods that are described in pharmacopeias may not haveto be validated but should be verified, if necessary. Well-characterized refer-ence materials with documented purity should be used throughout the vali-dation study, especially during full development. Validation experiments andanalyses must be carried out on fully qualified and calibrated instrumentation,and some references have been published on this subject [2–6]. Analytical method validation is established through documented evidencedemonstrating the accuracy, precision, linearity, selectivity, ruggedness, and/orrobustness of that particular test method which will be utilized to generate testresults for a drug substance or drug product. Different test methods requiredifferent validation parameters. All analytical procedures require some formof method validation, regardless of whether the test method is utilized for thetesting of Good Laboratory Practice (GLP) toxicology, shelf-life determina-tion (stability indicating), in-process controls [7], clinical release, or release ofproducts for open market [8]. As development of the project progresses andas more analytical and product-specific information is acquired, the analyticalmethods evolve and are gradually updated. The extent of validation increasesand the documentation is completed. During the early development phase, depending on the analytical labora-tory, generic validation protocols may be used because project-specific pro-tocols are not required. Sometimes an internal Standard Operating Procedure(SOP) suffices and a generic validation protocol does not need to be used.Usually, for Phase I, validation experiments may be carried out concurrentlywith the analysis of the first batch of clinical supplies or the first delivery ofdrug substance to be used for clinical supplies. However, depending on thepharmaceutical organization method validation may need to be performedprior to the analysis of material that will be used for clinical supplies. For analytical method validation during full development (after final syn-thesis has been set for drug substance and after final market formulation hasbeen set for drug product) corresponding to the definitive control procedurefor new drug application (NDA), a specific validation protocol has to bewritten. Before start of the experimental work, the protocols must b ...