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18 Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2020 P h a r mTe c h . c o m specifications and supporting information are provided by a single company, usually the innovator, having regulatory ap- proval for the product in Europe. This timing also corresponds with the European Medicines Agency regulatory guidance concerning mandatory renewal of a marketing authoriza- tion within five years of its granting in Europe (13). Under the P4 procedure, the Ph. Eur. Commission works to ensure that monographs are available a few years before the patent expiry date, thus making it possible for regulators to assess dossiers on generic drugs based on existing monographs in the pharmacopoeia (14). If the monograph submission is too late to follow the P4 process, the Ph. Eur. monograph is devel- oped (or revised) using the P1 process (15), in which multiple companies with approval for the drug product in Europe may participate in developing the tests, analytical procedures, and acceptance criteria that will make up the public standard. Due to the participation of multiple companies, the development of the Ph. Eur. monograph by the P1 procedure is often more difficult for the pharmacopoeia. It may also be more difficult for individual companies to comply with the final monograph because it may contain requirements 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. mono- graph timing of five years post-approval. An additional con- sideration for monograph development timing is the possibil- ity of establishing "prospectively harmonized" or "informally harmonized" monographs in collaboration with both the Ph. Eur. and USP authorities. Details regarding development of harmonized monographs is provided in the Sidebar. In practice, many companies delay monograph submission beyond this time horizon, choosing instead to consider the appropriate timing as three to five years prior to patent expiration. Vari- ability in the patent situation for a particular company, coun- try, or product makes the actual date of submission using this approach more difficult to establish. Additionally, this delay in submission makes it more difficult to pursue a monograph that is harmonized. A corollary consideration 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 information should be provided to support monograph development of the drug substance and product at the same time. The situation regarding multiple product strengths, different dosage forms, and combination products also enters into the decision-mak- ing process. Based on experience with the prospective and in- formal harmonization of monographs, along with other prac- tical considerations, there are potential benefits in establishing the drug substance and product monographs at the same time. One of these benefits is standardizing the analytical proce- dures 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 standardization of method- ology also carries the potential risk of making it more difficult 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 Regulatory Submission/Approval Marketing Exclusivity API Monograph Patent Expiration Product Monograph C o m m e r c i a l i z a t i o n S u p p l y Ea r l y D e ve l o p m e n t USP 7-8 Years Before Generic Entry BP After Ph.Eur. API Monograph Ph.Eur. 5-Years Post-Approval IP When 2-3 Local Manufacturers ChP/KP Timing? JP Timing? Figure 1. Monograph timing considerations for pharmacopoeias. IP is Indian Pharmacopoeia. Ph.Eur. is European Pharmacopoeia. USP is United States Pharmacopeia. BP is British Pharmacopoeia. JP is Japanese Pharmacopoeia. ChP is Chinese Pharmacopoeia. KP is Korean Pharmacopoeia. ALL FIGURES COURTESY OF THE AUTHOR. Pharmacopoeia Compliance Series