Harmonization excipients

The International Pharmaceutical Excipient Council in the United States (Arlington, Virginia 703-521-3338) has issued a GMP guideline for excipient bulk pharmaceutical chemicals. In conjunction with both the European and Japanese Pharmaceutical Excipient Councils, the council is currently engaged in establishing international harmonization excipient monographs for the more popular pharmaceutical excipients. A list of important and popular pharmaceutical excipients is given in Table 1. 

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. 

Perhaps the first international attempt at harmonization involved excipients and a collaborative effort between scientists in the United States and the United Kingdom. The goal was to develop common descriptions and physical standards for the most commonly used excipients. The project was supported by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain, who together... 

Z. T. Chowhan, Progress and impediments in the harmonization of excipient standards and test methods,... 

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. 

It also asked respondents to identify the specifications, tests, and assays in the monographs for these excipients that are most important to be harmonized. 

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. 

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]. 

Experience gained by harmonizing the first of the excipients. Lactose and Magnesium Stearate showed that because so many parties are affected and many expert groups must be convened, forward, retrospective harmonization is intrinsically a lengthy process. 

At the first biennial meeting of the International Conferenee on Harmonization in Brussels in November 1991, the U.S., Japanese, and European Pharmaeopeias presented papers relating to progress being made in harmonization of pharmaeopeial standards for excipients [19]. Other topies, such as stability, validation, impmities. 

The U.S. Food and Drug Administration (FDA) defines novel (new) pharmaceutical excipients as those substances used in the United States for the first time in a human drug product or by a new route of administration (1). The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) includes sections in its Common Technical Document (CTD) that details the information required for the approval of novel (new) excipients. Information on the control of excipients is included in Section P.4 of the CTD, and any additional information that may be required should be included in Appendix A.3 of the CTD. 

A timely and systematic approach is needed for the independent review of excipients to encourage the development of new excipients. A number of independent review models are used in other industries, such as food, cosmetics, and medical devices, and could be adapted to the review of excipients. IPEC is currently surveying its members to determine which system might be most useful (28), and IPEC has developed an Excipient Master File Guide to standardize and harmonize the information needed to review a new excipient (29). The format of the master file is modeled after the electronic ICH CTD for presenting chemistry, manufacturing, and controls and safety information. 

In all, 61 excipient monographs and some general chapters (Table 2) are in various stages of the seven-stage harmonization process that are described below. 

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,... 

Tableting process, since being introduced in the early 1840s, has witnessed numerous changes in the form of stringent regulatory requirements for the excipients and product stability. Increasing regulatory pressure on purity, safety, and standardization of the excipients has catalyzed the formation of an international body, the International Pharmaceutical Excipients Council (IPEC) (13). IPEC is a tripartite council with representation from the United States, Europe, and Japan, and has made serious efforts to harmonize requirements for purity and functionality testing of excipients (14).

The long-term stability of an oral liquid formulation can also be affected by a number of unexpected reasons. Contamination by solvents used during the tank cleaning or even in the manufacture of excipients or API can be a source of instability of an oral solution. Uncontrolled levels of Class I, II, or III solvents could lead to the rejection of a batch or an excipient vendor. Class III solvents have a permitted daily exposure of 50 mg or less per day. (See the International Conferences on Harmonization, Impurities Guidelines for Residual Solvents. Q3C, Federal Register 1997 62(247) 67377 and also http //www.fda.gov/cvm/Guidance/guidelOO.PDF). 

---