Issue link: https://www.e-digitaleditions.com/i/1224576
www.biopharminternational.com March 2020 BioPharm International eBook 41 Regulatory Sourcebook Pharmacopoeia Compliance Series Medicines and HealthCare (EDQM) provided important perspective on the impact of innovation, stat- ing, "By listening attentively to the needs of both regulators and indus- try and rapidly incorporating new technological advances, pharmaco- poeias can ensure that their content remains relevant and state-of-the-art and that their quality standards and methods are not only able to ensure the safety and efficacy of medicines but reflect advances in technology and science. This proactive course is matched by an ability to react swiftly to emerging challenges and with a large degree of flexibility (through alternative methods)" (23). Complex biotherapeutics: Monographs and general chapters Monograph development for com- plex biotherapeutics has been a topic of vigorous debate between compendial authorities, reg ula- tors, and the innovator and generic bio/ph a r m ac e ut ic a l i ndu st r ie s for the past several years. Today, there is no single position among all pharmacopoeias and regulators as to the need for product-specific monographs for complex biologics. The European Medicines Agency ( E M A) a nd Of f ic ia l Med ic i nes Control Laboratories (OMCL) have indicated their support for prod- uct-specific monographs, noting the benefit of having a single stan- dard to help surveillance testing rather than having to use a spe- cific manufacturer's methodology. As a result, the EDQM published t he f irst of t hese produc t-spe- cific monographs for etanercept and infliximab concentrated solu- tion in the Ph. Eur. using a flexible monograph approach (9). FDA has not expressed similar support for USP monographs for complex bio- logics (24). In fact, opposition to these monographs is so strong that legislation was introduced to the US Congress stating that biologi- cal products would no longer have to comply w ith USP standards, including monographs (25). This stark difference in health authority views is a reminder of the import- ant intersection of pharmacopoeias and regulatory agencies and why companies must monitor these sit- uations to remain compliant and to influence both parties through appropriate advocacy. The pharmacopoeias are exploring other approaches for complex biotherapeutics. Among national pharmacopoe- ias, industry association surveil- lance has revealed that the Chinese Pharmacopoeia Commission (CPC) and National Institute for Food and Drug Controls (NIFDC) intend to establish reference standards and monographs for seven mono- clonal antibodies drug substances a nd produc ts (2 6). T hese new monographs will likely be included in the 12th edition of the Chinese Pharmacopoeia (ChP), scheduled for publication in 2025. The ChP currently contains one monograph for a monoclonal anti- body, nimotuzumab injection, a single-sourced or phan product. The proposed addition of these seven multi-sourced products is an ambitious goal for the CPC. It will be important for companies who manufacture these products to participate in the ChP mono- graph elaboration process in part- nership with CPC and NIFDC. It is not known how the CPC will address the complexity that comes with the analysis of these prod- ucts from multiple manufacturers, as the "one-size-fits-all" approach will not work and could potentially block manufacturers from the mar- ket. Today it is unknown whether other national pharmacopoeias will publish monographs for com- plex biologic drug products. T h e p h a r m a c o p o e i a s a r e exploring other approaches for comple x biot he r ap e ut ic s. USP has announced a wide range of approaches that would be applica- ble to complex biologics, includ- ing performance-based standards, product class standards, and gen- eral chapters (27). They are actively requesting stakeholders to partici- pate on project teams being estab- lished to develop these standards. The BP Commission is also explor- ing alternative approaches for com- plex biologics, notwithstanding their legal obligation to include Ph. Eur. monographs for complex biotherapeutic produc ts in the BP. Recently, the BP Commission complete d a consu lt at ion a nd announced a plan to develop per- for ma nce -based sta nda rds a nd pro duc t- c l a s s - b a s e d st a nd a r d s that would provide a foundation for manufacturers to follow, while retaining flexibility for developing a complex biologic (28). Clinically relevant specifications Hea lt h aut hor it ies a re mov ing toward requiring manufacturers to set clinically relevant specifica- tions (CRS) for the registration of a new drug product. The specifi- cations account for clinical impact of variations in the critical qual- ity attributes (CQAs) and process parameters. This ensures a con- sistent safety and efficacy profile of commercial product relative to product used in clinical trials. This contrasts with the approach pre-