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22 Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2020 P h a r mTe c h . c o m submission of information and reference standard materials from multiple sources; increased effort and reduced success in influencing the outcome, resulting in greater likelihood of the need to adopt different methods and limits from what is contained in product registrations as a result of comments received during monograph development; and complexities due to different impurity profiles, formulations, and degrada- tion pathways for multi-source products. As mentioned previ- ously, there is one potential benefit in later submission of a new monograph, which is the delayed deployment of resources for monograph development. However, the subsequent process to evaluate and address monograph requirements, including additional laboratory effort needed to investigate proposed methods and limits—which are likely based on information from another company—poses potentially greater demands on available resources within a company. The US Pharmacopeial Convention (USP) has recognized that some manufacturers may not wish to submit a monograph until a product approaches multi-source status, although its policy is to first seek to work exclusively with an approved manufacturer (typically the relevant patent holder) until approximately five years prior to potential generic entry (18). If the manufacturer re- mains unwilling or unable to provide the necessary information, USP may work with another manufacturer willing to sponsor a submission or begin monograph development internally. This timeframe is intended to give due regard to applicable intellectual property and patent considerations, while advancing its public policy goal of ensuring that a monograph is available for review and approval of follow-on or multi-source versions of the prod- uct. There is an additional downside associated specifically with USP monograph development; the potential impact on product labeling that may result from the USP flexible monograph ap- proach, if a company's methods or acceptance criteria are not listed as "Test 1" in the monograph (19). This means that in practical terms, the time between five years post-approval to five years pre-patent expiry may be "just right" for establishing monographs for drug substances and products. This timeframe represents a fairly broad range that must be further refined for a specific product situation, but there are several benefits to targeting this period for monograph de- velopment. These include input from a single source, simplify- ing the process for the pharmacopoeias, resulting in the inno- vator company criteria being included in the monograph. The monograph would not block market entry of other companies, following existing legal and regulatory systems, but would es- tablish the quality standard that all subsequent companies must meet to gain approval for the product. Additionally, the USP flexible monograph approach will not impact the innovator's Prospective/informal harmonization of pharmacopoeia monographs (Cont.) Further development of harmonized monographs for drug products was undertaken by companies in collaboration with USP and BP. The first monographs achieved by this informal harmonization approach were published in USP and BP in 2012 (6). Subsequent collaboration has resulted in the development of dozens of new monographs for drug substances and products that are harmonized between USP, Ph. Eur., and BP, with submissions for individual monographs coming from several different companies. Some of these harmonized monographs have also been adopted by other pharmacopoeias, including JP and IP. The authors' current perspective on the process is provided in Figure 1, showing the primary, initial harmonization work consisting of a bio/pharmaceutical company submitting the necessary information to USP, Ph. Eur., and BP to develop the harmonized monograph. Subsequent or secondary effort would include additional pharmacopoeias in partnership with the submitting company and the initial pharmacopoeias through an "adopt/adapt" approach that is enabled by Good Pharmacopoeia Practices (7). This primary and secondary sequence for monograph elaboration is not intended to suggest that the other pharmacopoeias are less important than USP, Ph. Eur., or BP in the development process, but rather reflects the current situation that the timing for monograph development occurs later for the other pharmacopoeias. This is depicted in Figure 1 of the main article (see Page 18), which displays the preferred timing for monograph development by USP (seven to eight years before generic market entry), Ph. Eur. (five years post-approval for the innovator), and BP for the drug product (following development of the drug substance monograph in the Ph. Eur.) The timing for the other pharmacopoeias is not as well understood, but typically correlates to the availability of multiple drug products on the market in the particular country, leading to the goal of establishing a common quality standard that is applicable to all manufacturers. It is hoped that the development of new monographs that are harmonized from the beginning will continue in order to establish global pharmacopoeia standards, and that more companies and more pharmacopoeias will be engaged in this collaborative process. References 1. J.M. Wiggins et al., "Ph. Eur/USP Prospective Harmonization—API Pilot Project: Industry Perspective," Stimuli Article, USP Pharmacopeial Forum 36 (6) 1792-1796 (November–December 2010). 2. J.M. Wiggins, et al., "Ph. Eur/USP Prospective Harmonization—API Pilot Project: Industry Perspective," Pharmeuropa, 22 (4) 415-418 (October 2010). 3. J.M. Wiggins, et al., "Ph. Eur/USP Prospective Harmonization—API Pilot Project: Industry Perspective," Japanese Pharmacopoeial Forum 20 (1) 49-53 (March 2011). 4. J. M. Wiggins, "Monograph Harmonization: In Search of True North," Presentation at the 3rd Global Summit of the Pharmacopoeias (Baltimore, MD, Sept. 19, 2013). 5. EDQM, "Conclusion of Prospective Harmonization Pilot Project," Press Release, April 28, 2015. 6. G. Macdonald, "USP and BPC Harmonize First Finished Product Monographs," in-pharmatechnologist.com (May 2012). 7. WHO, Good Pharmacopoeial Practices, WHO Expert Committee on Specifications for Pharmaceutical Preparations Fiftieth Report, Technical Report Series No. 996, Annex 1, 67-85 (2016). — J. Mark Wiggins and Joseph A. Albanese Pharmacopoeia Compliance Series