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www.biopharminternational.com March 2020 BioPharm International eBook 21 Regulatory Sourcebook Pharmacopoeia Compliance Series As suggested in Figure 2, there is potential benefit to the innovator company in having the monograph established to reflect the quality standard that has been approved by the health authorities for the single-source product. This quality standard must then be met by all subsequent generic-drug compa- nies that wish to market the prod- uct, providing benefit to patients through medicines with consistent quality. However, if the innovator company delays its monograph sub- mission, or chooses not to submit at all, then any of the approved gener- ic-drug companies have the oppor- tunity to submit the monograph. Because monograph development by the pharmacopoeias generally takes about two to three years after the initial submission, more com- panies may begin work to develop generic versions of the product. When the draft monograph is pub- lished by the pharmacopoeia for public review, there will be more companies that may provide com- ments on the proposed specifica- tions, potentially impacting the final monograph in the pharma- copoeia. Once the monograph is official in the pharmacopoeia, there is the ongoing possibility of subse- quent changes to the monograph to reflect specifications approved by regulators as more generic-drug companies are authorized to mar- ket the product. The compliance challenges for any given company are commensurate with the degree of difference between the mono- graph and its own approved product specifications, so the practical goal should be to collaborate to align the pharmacopoeia requirements with the approved registration. In broad terms, three time peri- ods may be identified for a com- pany as they determine when to submit a monograph: the earliest is zero to five years post-approval, the latest is three to five years prior to patent expiration (or loss of marketing exclusivity) or even later, and the third is the period of time between these two (see Table I). In the authors' experience, from the perspective of innovator com- panies, the first of these—zero to five years post-approval—is gener- ally too early. Among the reasons for this conclusion are the limited value of a public standard for a sin- gle-source product, with limited available data about the product, and ongoing process and analyti- cal changes typical in the first few years of the lifecycle, as additional experience is gained with the man- ufactured product. There is also concern about potential loss of intellectual property, especially in countries where there is less pat- ent protection. E xperience has shown, however, that this threat is not significant in the larger pic- ture, because many generic-drug companies already have products in development from an early stage, with information available in the literature and through reverse-engi- neering approaches. Another con- sideration for early submission is the need to provide reference standard materials to support monograph development, with available inven- tory potentially limited early in the product's lifecycle. For an innovator company, the last of these time periods—three to five years prior to patent expiration or even later, potentially extending after patents have expired and mar- keting exclusivity has lapsed—may be considered too late, for several reasons. These include likely generic dr ug entr y w ith submission of information and reference standard materials from multiple sources; increased effort and reduced suc- cess in influencing the outcome, resulting in greater likelihood of the need to adopt different meth- ods and limits from what is con- tained in product registrations as a result of comments received during monograph development; and com- plexities due to different impurity profiles, formulations, and degra- dation pathways for multi-source products. As mentioned previously, there is one potential benefit in later submission of a new monograph, which is the delayed deployment of resources for monograph devel- opment. However, the subsequent process to evaluate and address The appropriate timing for monograph submissions is determined by individual companies, with particular consideration for each individual product. Timelines can be defined based on a number of different considerations (including but not limited to): • Potential opportunity to achieve prospective or informal harmonization of the new monograph across several pharmacopoeias. • New monograph development that is initiated by innovator companies to avoid conflict with content in approved regulatory filings. • New monograph development that is initiated by generic-drug companies when an innovator delays or does not submit the monograph. • Single-source vs. multi-source product availability, which determines the likely process to be used in collaboration with the pharmacopoeias; generally, more comments are received on monograph development that occurs closer to the timing when multi-source product(s) are in the market. • Timing based on an amount of time post-approval, or amount of time prior to patent expiry, loss of marketing exclusivity, or generic entry to market. • Timeline for monograph development as recommended by the pharmacopoeia(s). Table I: Considerations for appropriate timing of monograph development.