Pharmacopeia harmonization

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. 

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

Alternative methods are possible the three regional pharmacopeias (United States, European, and Japanese) allow an individual laboratory able to do the official method to validate an alternative method of analysis. The latter is chosen usually for speed, eonvenience, or expense but also to incorporate an existing database when a new or revised pharmaeopeial method is adopted. Under those provisions, a laboratory ean validate a method from another pharmacopeia, thereby avoiding duplication of routine work. In all three cases, only the official method could be used in eompli-ance or contest. One point of harmonization is to avoid even the more remote in-stanees of duplieative testing in addition to international produet registration. 

Pharmaeopeial harmonization is challenging. Differences exist because of the different histories of the pharmacopoeias. There are many factors. The most obvious are content, language, legalities, speed, and the audiences for the standards. United States Pharmacopeia applies also to the practice of pharmacy, both in a com-... 

The opposite of harmony is disharmony. An example of disharmony is the need to repeat tests using rabbits for pyrogen where testing for bacterial endotoxin is otherwise prescribed. This represents the most extreme disharmony of methods. But there is even a greater disharmony, and that would be to reach different eonelusions as to pass/fail the speeimen. In this ease, the quality control professionals must make a judgment as to whether or not this material can be sold in one or more regions. Functionally equivalent to harmonization is the absence of disharmony. Because of a difference in policy, pharmacopoeias may not differ on adoption of a test at all. If certain tests are eonsidered neeessary by one pharmacopeia in order to protect the consumer, it is appropriate for that pharmacopeia to adopt the test without reference to any other region. 

One of the earliest references to USP s commitment to international harmonization may be found in the historical introduction to the 3rd revision [1] of the U.S. Pharmacopeia (1851) The new Dublin and London Pharmacopoeias were compared with our own, with a view of introducing uniformity wherever more important considerations did not seem to forbid the requisite modifications.. .. Note that uniformity for its own sake was not the sine qua non. 

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]. 

To implement the concept of forward harmonization which was agreed in Tokyo [10]. Forward harmonization has three characteristics a preference for the selection of methods that would be acceptable well into the future retaining of any standard meaningful to an individual pharmacopeia and unilateral progress not inhibited by trying to have every new advance occur simultaneously in every pharmacopeia,... 

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 conference endorsed the goals of the pharmacopeias to improve and harmonize standards for existing excipients, to focus on testing methods, and address specifications after test methods had been agreed upon, and to develop functionality tests, including particle size, siuface area, and density. 

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]. 

Limit tests have a long standing in pharmacopeias. For some, heavy metals for example, the sensitivity of the method was the basis for the standard. Modem limits in the USP-NF are toxicity based. There is divergence in harmonization because of toxicity-based rather than method-based standards. The modem basis avoids the exclusion of safe products from the marketplace, whereas the older approach could lead to lock-out specifications known as technical barriers to trade. 

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). 

Apparatuses 1, 2, and 4 are harmonized. Not all apparatuses appear in other pharmacopeias and decision rules are harmonized. Selection of media is not harmonized, and may not be a valid subject in view of population and formulation differences. 

The pharmacopeias have worked with the ICH process to facilitate the international environment of pharmaceutical research and product registration. On the other hand, the additional situation for compendia is that the standards which they have published now apply to all of the already marketed products. In that case a company has testing history and product history in their quality control departments. These are the most conservative elements within the pharmaceutical industry as is necessary to their task. Quality control departments are reluctant to change methods when they feel that their products are properly represented by the current of tests. Therefore, a tension is ereated between trying to develop harmonized standards, which facilitate one area of activity in the world of pharmaeeutieals, and not disturbing a satisfactory marketplace. A vast amount of progress has been made in the harmonization of phar-maeopeial methods. 

Shabir, G. A. Validation of high-performance liquid chromatography methods for pharmaceutical analysis. Understanding the differences and similarities between validation requirements of the U S Food and Drug Administration, the US Pharmacopeia and the International Conference on Harmonization. 

FDA, USP, and ICH U.S. Food and Drug Administration, U.S. Pharmacopeia, International Conferences on Harmonization Method validation 55,72-74... 

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 ... 

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. 

On the basis of an inquiry among its users, the PDG identifies subjects to be harmonized among PDG pharmacopeias and nominates a coordinating pharmacopeia for each subject. 

For a subject to be harmonized retrospectively, the coordinating pharmacopeia collects the information on the existing specifications in the three pharmacopeias, on the grades of products marketed, and on the potential analytical procedures. 

The coordinating pharmacopeia reviews the comments received and prepares a harmonized document (Stage 4 draft) accompanied by a commentary discussing comments received about the previous text and providing reasons for action taken in response to those comments. 

The Stage 4 draft and the commentary are published in the revision document of each pharmacopeia in a section entitled International Harmonization. The draft is published in its entirety. 

The corresponding secretariats may have to add information essential to the understanding of the implementation of the texts (e.g., the description of an analytical procedure or of reagents that do not exist in the pharmacopeia) and a translation is added by the European and Japanese Pharmacopoeias. The style may be adapted to that of the pharmacopeia concerned or global style may be used. A pharmacopeia can add text, either to amplify some of the requirements with additional information or because national requirements and compendial policy dictate that the addition is necessary. However, there must be a clear indication that this additional information is not part of the harmonized document. This will avoid additional text being included after the harmonization process is completed, but will allow interested parties to review a complete text. The three pharmacopeias endeavor to publish the drafts simultaneously or as close together as possible. 

The document is submitted for adoption to the organization responsible for each pharmacopeia. Each pharmacopeia incorporates the harmonized draft according to its own procedures. Stylistic and editorial differences may occur. 

Users of the pharmacopeias are appropriately informed of the harmonization status of monographs and general chapters. In the European Pharmacopoeia (EP) and USP-NF, for general chapters, this is done via a preliminary paragraph. For the JP, a notification is made by the MHLW and information is given in a general chapter. 

The date of implementation of a harmonized document varies in the three PDG regions depending on their legal requirements, need of translation, and publication schedules. Each pharmacopeia generally allows some period of time after publication for implementation to allow manufacturers and other users to achieve conformity. Harmonization is not achieved until the text becomes official in all the three pharmacopeias. 

---