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www.biopharminternational.com March 2020 BioPharm International eBook 29 copoeia to establish the reference standard. Also, the company may not have a "dirty batch" of the drug substance that would include the specified impurity and enable identification for the correspond- ing chromatographic peak. In this situation, taking into account the c u r rent process- capabi l it y a nd stability data, the pharmacopoeia may determine that the specified impurity must instead become an unspecified impurity, potentially resulting in a significant tighten- ing of the limit compared to the approved registration. A related challenge that applies to the drug product is determining whether a n i mpu r it y pea k obser ved i n the chromatogram for the prod- uct corresponds to a degradation product or is instead, a process impurity from the drug substance. This issue makes it difficult for the monograph to reflect the principle in ICH Q3B that only degradation products need to be controlled in the drug product, and not drug s u b s t a nc e pr o c e s s i mp u r it ie s . Another significant difference and compliance challenge can result if the company has developed two different methods for assay and impurities in the drug product, or different methods for different product formulations or strengths, whereas the pharmacopoeia deter- mines that a single method may be used for impurities and assay across the entire product line. Other differences may emerge in the monograph, which seem to be less impactful than that expe- rienced with impurities. However, t he steps necessa r y for a com- pany to address these differences in their quality documents and reg ulatory filings can still pose significant challenges. An exam- ple is the addition of a new iden- tity test in the monograph, such as infrared (IR), to complement a chromatographic identit y test for the drug substance to ensure t hat a l l st a ke holde r s who u se the monograph can demonstrate unequivocal identification of the active ingredient. Another exam- ple is the widening of an assay limit for the dr ug substance to reflect appropriate analytical vari- abilit y. Other examples include modifications to the chromato- graphic procedure, perhaps adding an isocratic hold at the start of the run to address dwell volume, which will also impact peak reten- tion times, or the addition of new requirements to ensure acceptable system suitability for the method, such as peak resolution. As will be shown later, these changes range from minor to major impact when exploring the options of how to resolve the differences and ensure compliance with the monograph and the registration. The differ- ences will likely impact quality documents and testing performed in the laboratory, with duplicate testing of the same quality attri- bute as the worst- case outcome to comply with the registration and the monograph. Depending on t he compa ny 's compl ia nce strategy, the differences may also i mp a c t p r o d uc t r e g i s t r at ion s , requiring updates or variations in countries around the world. S o m e r e q u i r e m e nt s i n t h e monograph may be very difficult to meet (e.g., tighter impurity lim- its). If the monograph has already been published as official, another possible approach to resolve dif- ferences is communication with t he pha r macop o eia to re quest revision of the monograph to bet- ter alig n w ith the reg istration. However, the pharmacopoeia revi- sion process can be slow and is not always successful in achieving the requested changes. The proba- bility of successful revision is also reduced if the company did not provide comments and concerns to the pharmacopoeia when the monog raph was f irst proposed. This points, once again, to the benefit of proactive surveillance of pharmacopoeia updates with an appropriate response at the pro- posal stage (9). Not only does this provide the company an oppor- tunity to possibly inf luence the requirements before the mono - Regulatory Sourcebook Pharmacopoeia Compliance Series • Before Monograph Elaboration • Quality Standard (QS) reflects global product registrations (methods, limits) • ≥ 150 country-specific registrations US EU (~30) Japan China MOW #10 MOW #1 MOW #150 Registrations / QS (Updates / Renewals / Change Control) Product Life-Cycle Figure 1. Aligning product registration requirements. ALL FIGURES COURTESY OF THE AUTHORS.