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.
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.
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.