Issue link: https://www.e-digitaleditions.com/i/1224576
www.biopharminternational.com March 2020 BioPharm International eBook 43 Regulatory Sourcebook Pharmacopoeia Compliance Series cal personnel in industry to gain direct insight and in-depth under- standing of CM (31). As the use of CM evolves in the bio/pharma- ceutical industry, general chapters related to the CM topic, includ- ing process analytical technologies (PAT) and statistical design con- trols, will be impacted. Still, regu- lators and pharmacopoeias are not yet in the same place on CM top- ics, including requirements when changes occur to an approved CM process. This represents another area where collaboration between reg ulators, pharmacopoeia, and industry could help deliver har- monized standards. It would pro- vide great benefit to the industry to have harmonized general chap- ters in the pharmacopoeias for CM, because CM helps to lower the cost of manufacturing and ultimately benefits patients. Multivariate statistical process controls As the concepts of QbD, PAT, and real-time release testing (RTRT) were being introduced in the pharma- ceutical industry, concerns were raised whether the pharmacopoe- ias were trying to develop stan- dards too quickly that would impair rather than enable progress in this area. This largely did not happen. Instead, both the Ph. Eur. and USP today contain language making it clear that PAT and RTRT are accept- able as alternatives to ensure compli- ance with compendial requirements. The language of these chapters was crafted by the pharmacopoeias in partnership with industry and other stakeholders. The Ph. Eur. published a draft i n f o r m a t i o n a l c h a p t e r, 5 . 2 8 Mu lt iva r iate Stat ist ica l P rocess Controls (MSPC), to provide guid- ance on good practices and require- ments (32). Ph. Eur. is the first pharmacopoeia to publish a gen- eral chapter on this topic, which will provide information comple- menting existing general chapters on chemometrics. The new Ph. Eur. chapter provides guidance on the use of MSPC being applied to CM, PAT, and RTRT (33,34). CONCERNS WITH IMPURITIES N-Nitrosamine contamination P rompted by t he d iscover y of two probable human carcinogens (N-nitrosamines) in drug products made by different manufacturers, EMA has mandated that compa- nies manufacturing sartan blood pressure medicines review their manufacturing processes to ensure N-nitrosamine impurities are not produced (17). There have been limits imposed on the maximum amount allowed for these products. It is reasonable to expect other pharmacopoeias to update their requirements for containers and packaging. M a n y g o v e r n m e n t s h a v e required that all drug substances be evaluated for the possible forma- tion of nitrosamines, with screen- ing required if they can be present in the material. Although needed to ensure patient safety, the impact to the industry is significant and could grow with additional controls being implemented by the pharma- copoeias. EDQM has begun revising Ph. Eur. monographs for the identi- fied drug substances to add controls for N-nitrosamines and published a draf t rev ision to the general monograph 2034 Substances for Pharmaceutical Use (35). The draft revision adds a section requiring a risk assessment of the drug sub- stance manufacturing process to evaluate the theoretical risk of N-nitrosamine impurities forma- tion and, if needed, implement a control strategy to detect and limit these impurities (36). A comprehen- sive list of actions taken by EDQM can be found on their website (37). Containers/packaging Impurities can be introduced from the primar y packaging systems and materials used in the bio/phar- maceutical industry. USP is revis- ing their general chapter <661> on plastic packaging systems (38) and created two new sub-chap- ters, <661.1> and <661.2>, that apply, respectively, to the resins used for manufacture of a pack- aging system and to the packag- ing systems as a whole. The new chapters become official in May 2020, with the current chapter becoming obsolete in December 2025. T his example highlights the value in companies comment- ing when new drafts are proposed by the pharmacopoeia. The orig- inal requirements and timelines proposed by USP were unrealis- tic for the industry to adopt. After many public meetings where the industry explained the difficulty to comply in the specified time- frame, USP provided this delayed implementation so that compa- nies have five years to transition to the new requirements in 2025. USP has published other chapters applying the same risk manage- ment approach to elastomeric com- ponents used in packaging and delivery systems, including <382>, <1381>, and <1382>. Additionally, USP <661.2> and <1382> require a