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www.biopharminternational.com March 2020 BioPharm International eBook 19 Regulatory Sourcebook Pharmacopoeia Compliance Series analytical procedures, and accep- tance criteria that will make up the public standard. Due to the partic- ipation of multiple companies, the development of the Ph. Eur. mono- graph by the P1 procedure is often more difficult for the pharmaco- poeia. It may also be more diffi- cult for individual companies to comply with the final monograph because it may contain require- ments from multiple sources. For USP, the preferred timing for monograph submission is seven to eight years prior to generic drug entry to the market (16), which generally aligns with the preferred Ph. Eur. monog raph t i m i ng of five years post-approval. An addi- tional consideration for mono - graph development timing is the possibility of establishing "pro- spectively harmonized" or "infor- mally harmonized" monographs in collaboration with both the Ph. Eur. and USP authorities. Details regarding development of harmo- nized monographs is provided in the Sidebar (page 22). In practice, many companies delay monograph submission beyond this time hori- zon, choosing instead to consider the appropriate timing as three to five years prior to patent expira- tion. Variability in the patent sit- uation for a particular company, countr y, or product makes the actual date of submission using this approach more difficult to establish. Additionally, this delay in submission makes it more diffi- cult to pursue a monograph that is harmonized. A corolla r y considerat ion of monograph development is whether the submission should be first for the drug substance (shown as API in Figure 1), followed later—perhaps several years later—for the drug product, or whether the informa- tion should be provided to support monograph development of the drug substance and product at the same time. The situation regarding multiple product strengths, differ- ent dosage forms, and combina- tion products also enters into the decision-making process. Based on experience with the prospective and informal harmonization of mono- graphs, along with other practical considerations, there are potential benefits in establishing the drug substance and product monographs at the same time. One of these ben- efits is standardizing the analytical procedures across the monographs for the drug substance and drug product portfolio, particularly tests for the determination of assay and impurities, in setting consistent pubic standards for quality of the product family. This standardiza- tion of methodology also carries the potential risk of making it more dif- ficult for a company to apply the monograph methods if they are not aligned with its approved product registrations. The publication of monographs for small-molecule drug products in the Ph. Eur. is a fairly recent development, with the first such monograph adopted in 2015 (17). By contrast, the BP has long included monographs for small-molecule drug products, in addition to all the other content of the Ph. Eur. that is required for pharmacopoeia com- pliance in the United Kingdom. In the absence of an applicable Ph. Eur. monograph, compliance with BP drug product monographs is often the expectation of regulatory agen- cies throughout Europe and in many other countries around the world. For several practical and reg- ulatory reasons, the BP drug product monograph, however, cannot usu- ally be established until after the Ph. Eur. monograph has been developed for the drug substance. The pursuit of harmonized monographs has enabled concurrent development of Ph. Eur. drug substance monographs and the associated BP drug prod- uct monographs. Alternatively, the product monograph may be estab- lished in the Ph. Eur. rather than the BP, with the Ph. Eur. product mono- graph then published also in the BP. These considerations enter the determination of when and where to submit the monographs for drug substances and their associated products. Turning to the other pharmaco- poeias shown in Figure 1, the key take-away is that the appropriate time for monograph development is not consistently or precisely defined, but typically would occur after the USP, Ph. Eur., and BP mono- graphs have been established, possi- bly by several years. For the Indian Pharmacopoeia (IP), there appears to be a correlation between the approval of two to three companies in India and the development of a monograph, although this is not entirely clear in the authors' expe- rience. There seems to be a good deal of variability in the IP mono- graph timing, and in some cases, the IP monograph may be devel- oped before the USP, Ph. Eur., or BP monographs. For pharmacopoeias in other countries, including the Japanese Pharmacopoeia (JP), Korean Pharmacopoeia (KP), and ChP, there also seems to be some correlation with approval of several companies for a particular drug product and the elaboration of a monograph. While this timing for IP, JP, ChP, and KP activity seems to decrease the possibility of developing har- monized monographs across several pharmacopoeias—monographs that could truly serve as global pharma- copoeia standards—there is clear interest and commitment by the pharmacopoeia authorities to col- laborate with each other and with the industry to establish consistent public quality standards.