Pharmacopeial harmonization

When using a fully harmonized pharmacopeial monograph or general chapter, an analyst will perform the same procedures and reach the same accept/reject decisions irrespective of which PDG pharmacopeia is referenced. This approach is called interchangeability, and each pharmacopeia will identify, in an appropriate manner, such a monograph or general chapter. 

Opalchenova, G.A. Comparison of the microbial limit tests in the british, european, and united states pharmacopeias and recommendation for harmonization. Pharmacopeial Forum 1994, 20 (4), 7872-7877. 

Where there are existing pharmacopeial specifications for active ingredients in the Ph Eur or the pharmacopeia of a member state, these will be expected to apply. Other pharmacopeial specifications or in-house specifications may be used in other cases. The same is true for excipients where harmonized specifications are mentioned. Particular quality requirements related to a particular application are discussed, e.g., particle size control requirements. 

Periodic discussions among the EP, JP, and USP, with the World Health Organization as observer, facilitate compendial harmonization. This association is known as the Pharmacopeial Discussion Group (PDG). The PDG has prioritized the harmonization effort for individual general test chapters based originally on those identified within ICH Q6A (1). Dissolution is prominent on the PDG work agenda. 

Any proposal for harmonization must be presented for public comment in each of the pharmacopeial journals, Phar-meuropa (EP), Japanese Pharmacopoeial Forum (JP), and Pharmacopeial Forum (USP). This was accomplished early in 2003 (21-23). Comments were collated and further PDG discussions conducted. Any agreement will be presented again, prior to implementation. The PDG harmonization process can be found as General Information Chapter < 1196 > in USP 27 (24). 

USP. <1196> Pharmacopeial harmonization. In USP27-NF22. The United States Pharmacopeial Convention, Inc., Rockville, Maryland, USA, 2003 2608-2612. 

United States Pharmacopeia 29. (2006). United States Pharmacopeial Convention, chapter <(1196), Pharmacopeial Harmonization. 

Harmonization of pharmacopeial standards as a practical matter began at the International Congresses of Pharmacy between 1865 and 1910 [2], but the first formal attempt can be traced to 1902. Both USP President Horatio C. Wood, M.D., and Frederick M. Power, Ph.D., an American chemist of the Wellcome Chemical Research Laboratories of London, were appointed by the U.S. Secretary of State as delegates to represent the United States government at the International Conference for the Unification of the Formulae for Heroic Medicines, a conference of 19 countries from Europe and North America [3]. The second conference occurred in 1918. The 3rd in 1925 was attended by 31 countries from all continents except Asia and Australia. They drafted a new International Convention, which came in force in 1929. It revised the 1902 agreements on 77 heroic medicines and introduced the concept of maximum dose. It also requested that the League of Nations create a permanent secretariat of pharmacopeias [4]. Andrew G. DuMez, Ph.D., represented the USP, and was officially appointed by the U.S. Public Health Service to represent the United States at this conference [4,5]. An expert committee of the League of Nations planned a third conference for 1938, but it was never convened because of World War II [2]. 

Two additional concepts of harmonization include prospective—to avoid conflicts among pharmacopeial standards before they occur, and retrospective—to resolve conflicts among existing pharmacopeial standards,... 

Articulating the three concepts for harmonization was particularly important. Prospective and retrospective clarify the distinction between work required to avoid conflict when establishing standards for pharmacopeial articles for which standards do not exist, or where few standards exist among the pharmacopeias, from work required to reconcile differences among well-established standards for articles that may have been in the pharmacopeias for considerable time. Prospective harmonization was inaugurated for biotechnology-derived products. Retrospective harmonization focused on pharmaceutical excipients and analytical tests and methods. Forward harmonization expresses a philosophy and environment for harmonization consistent with advances in pharmaceutical analysis. 

The reason a soale for harmonization is necessary is the faot that eaoh pharmacopeial monograph may contain some ten requirements, and individual monographs will be harmonized on perhaps seven or eight and perhaps even all ten of those requirements. When eight requirements out of ten are harmonized, the monograph is reported as an 80% harmonized [16]. 

Implementation of the recommendations led to a change in configuration of the membership in the pharmacopeial harmonization process. Whereas the British Pharmacopoeia had been an independent member of the Quadripartite Group from its inception, implementation of harmonization of standards and tests for excipient was... 

Joint Pharmacopeial Open Conference on International Harmonization of Excipient Standards Orlando, FL January-February 1991... 

A seeond milestone was a letter by the PDG in May 1992 asking for further candidates, beyond excipients. Responses to that inquiry focused primarily on tests and assays. Replies were ranked by order of priority. The priority of excipients was expanded to the top 25, based upon further analysis of responses. The lists of combined assignments and priorities for pharmacopeial harmonization appeared in the forum publieations of the pharmacopeias [12,13]. 

Harmonization proposals do not have official status. The work of the PDG is finished at Stage 5B. The progress of the harmonization projects can and should be verified in the most recent number of Pharmacopeial Forum, Japanese Pharmaco-poeial Forum, and Pharmeuropa. For standards in force in USP24-NF19, see also the latest Supplement or Interim Revision Annoimcement. 

Founded in 1990, the International Conference on Harmonization (ICH) is comprised of the pharmacopeial manufacturers associations in Europe (EFPIA), Japan (JPMA), the United States (PMA), and the drug regulatory agencies in Europe (EEC), Japan (MHW), and the United States (FDA), with the International Federation of Pharmaceutical Manufacturers Association (IFPMA) serving as secretariat. Pharmacopeias are not members of the ICH, where membership is reserved for three PMAs and three regulatory agencies. Invited observers include Canada, WHO, and the European Free Trade Association (EFTA). 

Jerome A. Halperin United States Pharmacopeial Convention, Ine., Roekville, Maryland Harmonization—Compendia... 

Drew, H. D., Thornton, L. K., Juhl, W. E., and Brower, J. F. (1998), An FDA/PhRMA interlaboratory study of the International Conference on Harmonization s proposed photostability testing procedures and guidelines, Pharmacopeial Forum, 24(3), 6317. 

Harmonization may be carried out retrospectively for existing monographs or chapters or prospectively for new monographs or chapters. The three pharmacopeias have a commitment to respect the agreed working procedures and the associated time deadlines as an essential part of the harmonization procedure. The PDG has defined harmonization of a pharmacopeial monograph or general chapter as follows ... 

A pharmacopeial general chapter or other pharmacopeial document is harmonized when a pharmaceutical substance or product tested by the document s harmonized procedure yields the same results, and the same accept/reject decision is reached. ... 

The last two stages of the implementation of the harmonized chapters and monographs take place independently according to the procedures established by each pharmacopeial organization. 

Currently, 29 excipient monographs have reached Stage 6 in the process and have been signed-off and accepted by the three pharmacopeias (Stage 6). To proceed to the next stage in the process, it was necessary for USP to create a new general chapter. The new chapter (1196), Pharmacopeial Harmonization, explains the role of the PDG, defines the PDG process, elaborates on the definitions of harmonized,... 

As part of the international harmonization of test methods, a proposed change to the USP <905> content uniformity test has been made [12]. This test is more restrictive than the current USP test, especially as the batch mean deviates from target. It is also more restrictive for capsules, since both the tablets and capsules are required to meet the same requirements. A number of USP Pharmacopeial Forum articles have been written by the Pharmaceutical Manufacturers Association (PhRMA) statistics expert team discussing the proposal and their characteristics. An approved version of the proposal is eventually expected. In anticipation of this happening, appropriate modifications to the CuDAL approach have been determined to evaluate the newly proposed test. 

Pharmacopeial Forum, Harmonization, General Chapter <905> Uniformity of Dosage Units. Pharm Forum 2001, May-June, 27 3) 2615—2619. 

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