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One reason given for proactive participation and earlier submission of a monograph was the possibility of prospective or informal harmonization across multiple pharmacopoeias. It is instructive to take a closer look at this harmonization process. Some practical aspects of following the process to develop harmonized monographs are discussed in the companion article, which can be accessed by clicking here.
Historically, the development of a new monograph began with the submission of information by a company to one pharmacopoeia. This information would include specifications (e.g., the list of tests, reference to analytical procedures, and acceptance criteria), as well as select details contained in product development reports, method validations, and drug product registrations. Typical timing for the initiation of the monograph elaboration was driven by requests from the global pharmacopoeias, resulting in submissions going first to either the United States Pharmacopeia (USP) or the European Pharmacopoeia (Ph. Eur.). Later, perhaps several years later, the same information would be provided by the company to the other pharmacopoeia, which had not been part of the original submission. Even later, the information would potentially be provided to additional pharmacopoeias, including the British Pharmacopoeia (BP) and the Japanese Pharmacopoeia (JP). One practical outcome of this sequential approach to monograph development was that the resulting standards would often differ, sometimes in significant ways, regarding methods and limits that were listed in the monographs of the different pharmacopoeias.
Recognizing the compliance challenges resulting from divergent standards contained in the various pharmacopoeia monographs for a particular material or product, the industry partnered with the pharmacopoeial authorities in a pilot project to develop “prospectively harmonized” monographs in the USP and Ph. Eur. The approach taken was to submit the necessary information and materials (samples and reference standards) to both USP and Ph. Eur. at the same time, with collaboration among the participants throughout the monograph elaboration process. The industry perspective on the details of this prospective harmonization approach was provided in an article published in the USP and Ph. Eur. pharmacopoeia forums (1, 2). With JP as an interested observer to this new approach for monograph development, the industry article was also translated into Japanese and published in the JP forum (3). The work was also shared with the authorities of other pharmacopoeias, including BP, the Indian Pharmacopoeia (IP), the Korean Pharmacopoeia (KP), and the Chinese Pharmacopoeia (ChP), through individual discussions and presentations at the Global Summit of the Pharmacopoeias (4).
The outcome of the initial pilot project was the publication of four new monographs for drug substances that were prospectively harmonized in the USP and Ph. Eur. However, the conclusions published in a press release from the pharmacopoeias pointed to the difficulty posed by the coordination of the monograph development work between the pharmacopoeias using the formalized process that had been established (5). They determined that achieving pharmacopoeia harmonization remained an important goal, and both organizations were fully committed to continue collaboration on prospectively harmonized monographs, but this would be done using an “informal harmonization” approach.
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, 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.
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, “
” 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).