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26 Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2020 P h a r mTe c h . c o m Continuing several years further in the product lifecycle, the pharmacopoeias eventually develop monographs for the drug substance and product, which can introduce additional differences in testing requirements. Compliance with requirements published by pharmacopoe- ias around the world is a legal and regulatory requirement in those countries and regions in which the pharmacopoeia is applicable (3). The situation is even more complex because a company must comply with the pharmacopoeial requirements that are applicable in a particular country, and also with their product registrations as approved in countries around the world. There are many challenges that make pharmacopoeia compli- ance difficult, including the need to address differences between the pharmacopoeia and approved registrations (4). There are reasons why a company might choose to proactively submit information to the pharmacopoeias to enable mono- graph elaboration, but different companies may make different decisions (1). One option is for the company not to participate in the process, due in part to the difficulty in resolving differences that may emerge in the pharmacopoeia monograph; the later the monograph is developed, the longer the company can defer addressing the differences. These differences in the monograph, compared to the requirements contained in the product regis- trations, occur even though the monograph is usually based on specifications that are approved by regulatory authorities, as stated in the Good Pharmacopoeial Practices (GPhP) guidance (5). Differences between the monograph requirements and the registrations must be resolved so the company remains in com- pliance. There is some flexibility in how the company complies, with a range of options to resolve the differences, but in this flexibility, there is also complexity. Another choice a company might make is to participate in monograph development, but to submit the necessary infor- mation when multiple companies are involved in the process. This may be considered an intermediate approach, based on the timing for the submission, which still may result in compli- ance challenges if the monograph differs from the company's approved registrations (1). At the other end of the range of choices is proactive par- ticipation early enough that the company is the only one involved in the initial elaboration of the monograph, re- f lecting their position as the only company with regulatory approval at that time. One of the benefits of this approach is the possibility of developing a monograph that is har- monized across multiple pharmacopoeias. Even when a company chooses to participate, there will likely be differ- ences between the resulting monograph and the approved registrations. These differences may be understood in the transition from a "private" standard applicable to that com- pany alone, to the "public" standard contained in the mono- graph. Knowing why the differences emerge, however, does not make it any easier to address them and ensure ongoing compliance. Why differences emerge In the example provided here, the impact of the publica- tion of a new monograph in the pharmacopoeia is explored, based on the experience of one of the authors (6). Although the perspective is that of an innovator company, the infor- mation helps explain the compliance challenges experienced by all companies across the broader bio/pharmaceutical in- dustry. The impact of a new monograph depends, to some degree, on the answer to the following question: which came first—the pharmacopoeia monograph or the regu- latory approval? For an innovator company, the approval comes first, typically by many years, and the resulting im- pact of the monograph is due to differences between the newly published monograph and registrations that have been approved for many years. It is important to note that the differences are in the specifications—the tests, methods, and acceptance criteria—for the drug substance and product that are the subject of the monograph. The drug substance or product do not typically change after the monograph is published, rather the quality filter, or lens, through which the material is evaluated has been changed. If differences in the monograph are significant enough, the challenge of complying with the requirements published in the pharma- copoeia may become so difficult that the company may be forced to take the product off the market. This is clearly not in the best interest of patients who may rely on the medicine. If the monograph in the pharmacopoeia is supposed to ref lect the requirements in the approved registration, why should there be any differences? The answer lies in the prac- tical basis of converting the approved registration, which is used by a single company, to the public standard in the monograph that will be used by all companies who manu- facture and market that drug substance and product. In the authors' experience, 80% or more of the compliance chal- lenges are related to differences in the control of impurities. According to the International Council for Harmonization (ICH) Q3A (7) and Q3B (8) guidance documents, an organic impurity in a drug substance or product is either specified, meaning it is individually listed and limited with a specific acceptance criterion, or unspecified, meaning it is limited instead by a general acceptance criterion. For the innova- tor company who developed and validated the analytical Pharmacopoeia Compliance Series Compliance with requirements published by pharmacopoeias around the world is a legal and regulatory requirement in those countries and regions in which the pharmacopoeia is applicable.