ABSTRACT
Specifications for drug products are an integral part of overall control strategies to ensure the quality of the products. The establishment of specification limits is accomplished based on desired product performance, supporting data, application of statistical methods, and, importantly, regulatory requirements. In ICH Guidelines Q6A and Q6B (ICH 1999a,b), it is stated that “A specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges or other criteria for the tests described. It establishes the set of criteria to which a drug substance, drug product should conform to be considered acceptable for its intended use. ‘Conformance to specification’ means that the drug substance and/or drug product, when tested according to the listed analytical procedures, will meet the acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval.” Developing specifications requires the synthesis of information from various sources, including data from preclinical and clinical trials, analytical method development, stability studies, and process validation. Special consideration should be given to process capability, variability of analytical methods, drug substance and drug product stability, specific regulatory and compendial requirements of drug identity, strength, quality, and purity, as well as data from preclinical and clinical studies and process validation. In recent years, there has been a shift in both industry practice and regulatory thinking toward the use of a life cycle risk-based approach for setting specifications. Such an approach begins with the identification of critical quality attributes (CQAs) that are critical to the safety, efficacy, and quality of the product. The initial specifications for CQAs can be made based on materials used in clinical development. Knowledge from nonclinical studies and similar products can be used to justify specifications wider than the clinically qualified range. Equally useful is consideration of analytical variability, process capability, and product stability. An understanding of product degradation is particularly important in setting the product release limits. Appropriate application
of statistical methods is the key to robust specifications. It is also recommended by regulatory guidelines (ICH 1999b).
