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www.biopharminternational.com October 2020 BioPharm International eBook 19 good manufacturing practices for ensuring data integrity. However, many pharmacopeial tests therein involve classical chemical analy- sis (e.g., color, appearance, titra- t ion) a nd rely on a n a na lyst 's obser vat ion w it h lit t le, if a ny, documented evidence for review. Hence, do pharmacopoeias inad- vertently facilitate data integrity violations? In this article the authors look at the following topics: • Purpose and role of the phar- macopoeias • I nte r a c t io n o f t he mo no - graphs, general notices, and general chapters • Examination of a monograph and the inter pretation into an analytical procedure to see how the testing structure in a pharmacopeia can inadver- tently facilitate data integrity violations • Practical application of the requ irements t hat data a re at t r i b ut a ble, le g i ble, c o n - temporaneous, original, and accurate (ALCOA) as well as complete, consistent, endur- ing, and available (ALCOA+) to pharmacopeial analysis to ensure data integrity. Examples are taken from the United States Pharmacopeia (USP), but t he pr inc iples apply to a ll pharmacopoeias. UNDERSTANDING PHARMACOPOEIAS The GMP regulations define the requ i rements for t he ma nu fac- turing, testing, and distribution of APIs and finished pharmaceu- t ic a l pro duc t s. However, t here are no details about how to test; test methods are the role of the p h a r m a c o p e i a l s t a n d a r d s f o r generic materials. Pha r macop o e ia s prov ide t he monog raphs that contain stan- dards for excipients, A PIs, and, in some instances, finished phar- maceutical products that for all samples tested within shelf life have to be met for compliance with legal quality standards. P h a r m a c o p o e i a s i n v a r io u s countries are published to con- trol the quality of pharmaceutical products. Each API, excipient, or finished product is defined in a pharmacopeial monograph con- taining the standard, which pres- ents the outline of the analytical procedures used to test with the acceptance criteria. In addition, certified reference materials are ident i f ied for use as reference standards for use in testing. It must be remembered t hat the acceptance criteria relate to the sample tested, not the batch. Hence pharmacopeial acceptance criteria are not suitable or intended to be for batch release (10). The original intention of the pharma- copeial monograph was to allow the practicing pharmacist to test pharmacopeial items to assess their quality. The use of simple classical analytical procedures such as volu- metric procedures (e.g., titrations), visual appearance, color tests for identity, and gravimetric proce- dures (e.g., loss on drying [LOD] or loss on ignition), continue to be used in monographs today. Many of these tests rely on observations made by the performer of the test which, in the current data integ- rity environment, may be subject to manipulation. In the 1890 edition of USP (7th edition), the monograph for whis- key has similar simple tests for quality to that of modern ethyl alcohol USP for appearance, spe- cific gravity for strength as well as tests for impurities and common adulteration. Ethyl alcohol, in the 42nd (2020) edition of the USP, still has tests and specifications for specific gravity and non-vol- atile residue based upon classi- ca l a na ly t ica l tech n iques. T he non-volatile residue test is based on the same evaporative method of 130 years earlier, although the acceptance criterion is now 100 times smaller. STRUCTURE OF THE USP The USP primarily consists of the following sections, illustrated in Figure 1: • General notices and require- ments for analysis • Monog raphs for e xc ipient s and APIs and finished phar- maceutical products • General chapters that divide into ma ndator y (nu mbered <1000) and informational or strong g uidance (numbered >1000) • R e f e r e n c e s t a n d a r d s a n d reagents. General notices and requirements Most users of the USP will focus t heir at tent ion on t he Genera l Chapters; however, the General Not ices a nd Requ i rements sec- t i o n ( b e t t e r k n o w n a s t h e G e ne r a l Not ic e s) pr e s e nt s t he basic assu mpt ions, def init ions, a nd defau lt cond it ions for t he Regulatory Sourcebook Data Integrity Acceptance criteria relate to the sample tested, not the batch. Pharmacopeial acceptance criteria are not suitable or intended to be for batch release.