Inside USP: Global Harmonization Presents Opportunities and Challenges

More than 20 years after three of the world's largest pharmacopeias joined forces to work on harmonizing standards, this effort has yielded progress but has also faced numerous challenges as inherent limitations became clear. An activity of the Pharmacopoeial Discussion Group (PDG)—which consists of the organizations responsible for the European Pharmacopoeia (EP), Japanese Pharmacopoeia (JP) and US Pharmacopeia–National Formulary (USP–NF)—harmonization offers benefits to industry, pharmacopeias, and patients worldwide. It is a pursuit that USP has remained steadfastly committed to since 1990, when it was first adopted in a resolution guiding the organization through its five-year cycle. At the time, USP's then-CEO Jerome Halperin cited "disappearing borders," a trend that has only intensified in the decades following. Since that time, harmonization has been deemed a priority for USP in all subsequent governing cycles, but it requires increased engagement from industry. While harmonization occurs through a variety of avenues, this article focuses on the formal harmonization activities of PDG.

History and goals

PDG was formed in 1989 with the three participating pharmacopeias as part of a request from the pharmaceutical industry, which was grappling with redundant testing as companies were becoming increasingly multinational. (The World Health Organization was added as an observer to PDG in 2001.) The goal was—and remains—to eliminate or minimize industry's need to perform multiple tests and procedures and to comply with different countries' acceptance criteria for the same pharmaceutical article. PDG works on harmonizing specific excipients and general chapters contained within the three pharmacopeias adopted under the group's workplan. APIs are not within the scope of PDG, although USP has been involved separately in a bilateral pilot program with the European Directorate for the Quality of Medicines & Healthcare (EDQM) for prospectively harmonizing four drug substance monographs.

Excipients and pharmacopeial general chapters were targeted for harmonization because they affect a broad range of products, thus such efforts would be the most far-reaching and have the greatest impact. Today, PDG's workplan encompasses 63 excipients and 34 chapters. Of these, 41 excipients and 27 chapters have been harmonized to date.

Benefits

The primary benefit of harmonization for industry is the elimination of redundant testing that is inherent as manufacturers comply with multiple compendia. For pharmacopeias, the benefits include stronger monographs with an international set of experts reviewing standards, and specifications that are representative of the global supply chain. Such harmonization benefits patients as well, who should expect a drug supply that is of high quality, consistent, and safe regardless of where a medication is purchased. Overall, it is a win–win situation for all parties, and offers potential for greater cooperation between regulatory bodies.

The benefit to manufacturers is best illustrated by example. For carboxymethylcellulose calcium, a suspending agent, harmonized in 2001, the total test requirements in the three pharmacopeias amounted to 37 tests: 13 in the USP monograph, 13 in the JP monograph, and 11 in the EP monograph. Following adoption of the harmonized requirements by the three participating pharmacopeias this fell from 37 tests to 10 total tests. This is the type of impact such cooperation can yield.

Harmonizing process

Harmonization is a seven-stage process, with final sign-offs at the twice yearly PDG meetings. PDG items are published at two stages, Stage 4 for Official Inquiry and Stage 6 for Adoption. Each article undergoing harmonization has a coordinating pharmacopeia that takes the lead in drafting the proposal and moving the item through each stage of the PDG process. Proposals for harmonization go through a similar public process by which USP sets all standards, with Expert Committee review and an open comment process. However, additional steps are required to achieve consensus among the three pharmacopeias, because each pharmacopeia must ultimately receive approval from its respective Expert Committee based on the public comments from that region.

An item is considered harmonized when a pharmaceutical substance or product tested by the document's harmonized procedure as published in EP, JP, and USP yields the same results, and the same accept or reject decision is reached. The harmonized text does not have to be identical; each pharmacopeia can adapt the text to local style. Individual pharmacopeias can also take into consideration local reference standards and reagents.

Challenges and industry participation

While the vision of harmonization is simple and straightforward, execution presents an array of challenges—some more easily addressed than others. Chief among these is differences in the regulatory and legal requirements of each country—which can make full harmonization difficult, or even impossible. Both JP and EP fall under ministerial bodies with a direct link to their respective regulatory agencies, while USP is an independent group separate from the FDA. To the degree possible with these constraints, PDG has managed to produce encouraging results. One approach is harmonization by attribute, which moves items forward where there is significant agreement on the main attributes (e.g., definition, assay, and identification testing), even if other portions of a standard are in dispute. This also allows PDG to avoid spending resources on topics where there are insurmountable differences, and focus on items where there is progress. Another challenge is the time required to bring harmonized monographs and chapters to public status. Although the seven-stage process will likely never be considered speedy, PDG is taking strides to move more efficiently.

Other challenges could be more easily addressed, such as by earlier and increased industry participation. Frequently, the potential for harmonization has not been realized by manufacturers and other stakeholders until late in the process. Moreover, comments to proposals published in Pharmacopeial Forum (PF), the online vehicle through which USP accepts feedback on standards, has often been received too late to be considered. Unlike the inherent challenges identified above, these are conquerable. USP has intensified educational and outreach activities to industry through free webinars, a dedicated webpage that centralizes and simplifies information (www.usp.org/USPNF/pharmacopeialHarmonization/) and activities. Moreover, USP began to offer PF free to all in January 2011, eliminating any barriers to accessing the journal (www.usp.org/USPNF/pf/).

Industry participation is crucial for harmonization to achieve its ultimate potential. Most vital is for manufacturers to take notice of harmonization proposals in PF at Stage 4 and submit comments to USP. If there are implementation problems with the methods proposed by PDG, USP must hear from industry at this stage. Given that manufacturers and users will be required to comply with the eventual standard, active engagement benefits all parties.

Hot topics and future work

PDG's workplan includes a variety of hot topics. Examples include the development of general chapters on elemental impurities, viscosity determination for excipients, and the strengthening of selected high-risk monographs to control for economically motivated adulteration. Also, PDG is looking at process and other potential improvements (e.g., accelerating harmonization). Harmonization is frequently cited as an essential activity but it desperately needs the full commitment of all parties if its promises and potential are to be realized.

Anthony DeStefano, PhD, is vice-president of general chapters, and Kevin Moore, PhD, is scientific liaison, both with the US Pharmacopeial Convention (USP).