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20 Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2020 P h a r mTe c h . c o m At some point during the product's lifecycle, the possible de- velopment of a monograph emerges, at which point the need and value of this specific public standard is weighed against the existing regulatory approval for the product. The mono- graph will contain the specifications—tests, analytical proce- dures, and acceptance criteria—that help ensure the identity, strength, quality, and purity of the drug substance and product. It becomes necessary for all companies with regulatory approval to comply with the requirements established in the monographs for the drug substance and product. Additionally, as stated in the GPhP guidance, "Specifications that limit market access by, for example, favoring one manufacturer to the exclusion of oth- ers should be avoided" (8). This statement is intended to main- tain focus on the benefit to patients worldwide in having public standards that support access to medicines from innovator and generic-drug companies with consistent and appropriate quality. The earliest opportunity for monograph submission be- longs to the innovator company having the initial regulatory approval, during the period of patent protection and mar- keting exclusivity. Once the decision has been made whether to submit the necessary information for monograph devel- opment, consideration then turns to when to submit the information. Many product-specific points are important in this consideration, including ongoing manufacturing and analytical changes that may impact the applicable specifi- cations, as well as the timing for potential entry of generic competition. As suggested in Figure 2, there is potential benefit to the innovator company in having the monograph established to ref lect 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 companies that wish to market the product, providing ben- efit to patients through medicines with consistent quality. However, if the innovator company delays its monograph submission, or chooses not to submit at all, then any of the approved generic-drug companies have the opportunity to submit the monograph. Because monograph development by the pharmacopoe- ias generally takes about two to three years after the initial submission, more companies may begin work to develop generic versions of the product. When the draft monograph is published by the pharmacopoeia for public review, there will be more companies that may provide comments on the proposed specifications, potentially impacting the final monograph in the pharmacopoeia. Once the monograph is official in the pharmacopoeia, there is the ongoing pos- sibility of subsequent changes to the monograph to ref lect specifications approved by regulators as more generic-drug companies are authorized to market the product. The com- pliance challenges for any given company are commensu- rate with the degree of difference between the monograph 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 periods may be identified for a company 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 companies, the first of these— zero to five years post-approval—is generally too early. Among the reasons for this conclusion are the limited value of a public standard for a single-source product, with limited available data about the product, and ongoing process and analytical changes typical in the first few years of the lifecycle, as addi- tional experience is gained with the manufactured product. There is also concern about potential loss of intellectual prop- erty, especially in countries where there is less patent protec- tion. Experience has shown, however, that this threat is not significant in the larger picture, because many generic-drug companies already have products in development from an early stage, with information available in the literature and through reverse-engineering approaches. Another consid- eration for early submission is the need to provide reference standard materials to support monograph development, with available inventory 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, po- tentially extending after patents have expired and marketing exclusivity has lapsed—may be considered too late, for sev- eral reasons. These include likely generic drug entry with 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. Pharmacopoeia Compliance Series