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Amidst debate, the European Pharmacopoeia Commission is working to include physical or "functionality-related characteristics" of exipient materials in its monographs.
The current work by the European Pharmacopoeia Commission to include physical characteristics of excipient materials in its monographs has given rise to intensive debate (1). Strong opinions against the European project have been voiced by excipient manufacturers who question the engagement of pharmacopoeias in a field that is essentially the subject for mutual agreement between providers and users of excipients.
The commission's work on monographs for excipients focuses on the traditional health and safety issues associated with identity, purity, and assay of the material. Under the heading "Functionality-related characteristics" (FRCs), a new section of the monographs will list some physical characteristics of excipients that may impact the manufacturability and performance of the final preparation. Suitable methods that are already or will in the near future be included in the general chapters of the European Pharmacopoeia (PhEur) are indicated in the sections. The new sections on FRCs are meant to provide information to manufacturers and licensing authorities.
In addition to the work on specific monographs, a general chapter for information on FRCs has been drafted by the Working Party on Functionality-related Characteristics, established by the European Pharmacopoeia Commission in 2004. The draft has been in public inquiry, and a slightly revised version was adopted by the commission at its March 2007 session (2, 3). The intention of the chapter is to inform PhEur users about the FRC concept and to explain the proper uses of the FRC section of specific monographs.
The background for the work and its aims are discussed in this analysis. It is important to note that the European Pharmacopoeia Commission fully recognizes that the functionality of excipients can be evaluated only in the context of a particular formulation and manufacturing process. Thus, functionality goes beyond the excipient. R. Christian Moreton, PhD, chair of the Excipients Focus Group for the American Association of Pharmaceutical Scientists, is quoted by Rios in a September 2006 Pharmaceutical Technology article on this topic, saying, "Functionality, like beauty, lies in the eye of the beholder" (1). Despite this somewhat subjective truth, drug manufacturers are expected to establish specifications for their excipients to ensure a consistent product quality level. To do that, some insight into the functionality of each excipient in each formulation is required. The term "functionality-related characteristics" means such physical characteristics that relate to functionality are controllable and, therefore, may be subject to a specification where relevant.
The work on FRCs has to be viewed in context with recent developments within the pharmaceutical manufacturing industry such as the International Conference on Harmonization's guideline on pharmaceutical development (ICH Q8), and the European Medicines Agency guideline on excipients (4, 5). According to these guidelines, a company's marketing authorization application should discuss chosen excipients and their concentrations and demonstrate the characteristics of the excipients that may influence the performance of the end-product and its manufacturability. The information on excipient performance can be used to justify the choice and quality characteristics of the excipient.
A major implication of ICH Q8 is that regulatory bodies and industry are moving from blind compliance (quality by testing) into science and risk-based compliance (quality by design) based on enhanced process understanding and continuous improvements throughout a product's life cycle. Irrespective of this so-called revolution in pharmaceutical manufacturing, product and process specifications need to be based on a mechanistic understanding of how formulation and processing factors affect product performance. In addition to variables associated with manufacturing equipment and processing conditions, formulation variables, including the physical and chemical property variation of active pharmaceutical ingredients (APIs) and excipients, have to be considered as quality input variables. As part of development work with excipients, the pharmaceutical scientist has to make a full characterization of material properties and investigate the functionality of excipients in the concerned formulation as a basis for setting appropriate specifications.
How do pharmacopoeia monographs on excipients meet this quality concept? In light of the preference given to excipients that are described in pharmacopoeia monographs and the acceptance by licensing authorities of pharmacopoeia specifications, it is essential that the monograph specifies a material that is acceptable from a health point of view. This is the traditional purpose of pharmacopoeia monographs. A close look at the monographs of PhEur—as well as the US Pharmacopeia (USP)—reveals that chemical purity tests in many cases have been supplemented by tests for physical characteristics (e.g., apparent viscosity and degree of substitution of polymeric materials) that do not directly impose health risks, but that are highly important in terms of the performance of the finished product. It is likely that such tests originate from the need for identification of a specific physical grade. Another possibility is that manufacturers and expert groups of the related pharmacopoeia have asked for the tests during the standard drafting phase.
Many excipient monographs, therefore, contain a mix of impurity specifications and test methods, some of which include acceptance criteria for physical and even some chemical properties that are important for manufacturing and end-product performance. Current tests for physical characteristics are generally insufficient when it comes to implementing quality by design or ICH Q8. Not all characteristics are critical in terms of affecting formulation quality. In some cases, it may be questioned whether compliance with current specifications of physical grades of excipients meets the needs of controls based on process analytical technology (PAT) and establishment of a proper design space.
The European Pharmacopoeia Commission decided already in 1995 that tests for physical properties should be moved from the body of the monographs to a new nonmandatory section on FRCs. At the same time, additional FRCs such as particle-size may be introduced in the new section, listed according to the intended function of the concerned excipient. When FRCs are listed according to the function of the excipient, it is clear that the section serves an information purpose. Acceptance criteria for FRCs are often not provided; when they are provided, it is often as an example of a typical acceptable specification. Compliance testing does not include the listed FRCs.
The European Pharmacopoeia Commission has found that the FRC section with indication of suitable test methods helps to facilitate the communication between suppliers and users of excipients. The referenced test methods can provide regulatory bodies involved in marketing authorization with data generated by recognized, independently assessed methods.
The work on FRCs has until now mainly been a reorganization of the PhEur monographs. New FRCs have been limited to tests widely used by pharmaceutical companies.
The work program on FRCs comprises excipients marketed in several physical grades by more than one manufacturer. The first monographs containing a FRC section were published in 2001. For example, magnesium stearate referenced a test on specific surface area identical with the test in the USP monograph; Anhydrous lactose referenced a test for α– and β–lactose and general methods for particle-size and bulk-density determination. Lactose monohydrate also had references to general methods for particle-size and bulk density determinations.
The Working Party on FRCs is currently reviewing the monographs contained in the European Pharmacopoeia Commission's work program. In most cases, existing tests for physical characteristics are moved to the FRC section without any addition of new FRCs. Where it is obvious, characteristics such as particle-size distribution, specific surface area, or powder flow are added.
The work program includes several cellulose derivatives, some of which have already been published in the new format. The transfer of tests for apparent viscosity from the mandatory to the nonmandatory part of the monographs has given rise to lengthy discussions that demonstrate some of the implications of the European project. The internationally harmonized monographs on cellulose derivatives present the methodology to determine the apparent viscosity and provide acceptance criteria for the nominal viscosity that has to be labeled. For example, some have claimed that the test for apparent viscosity in the monograph on hypromellose is needed to allow verification by users of the desired grade of hypromellose. By requiring that verification, the test is an indentification test and should be kept in the mandatory part of the monograph. This viewpoint seems invalid when compared with other physical characteristics, including particle-size distribution.
Users of excipients are familiar with the importance of particle-size distribution in certain uses and, for the most part, have no problems specifying an appropriate quality or verifying the correct grade of a supply. It is hard to see any difference in principle between these two physical properties. It is important that the methodology for determining the apparent viscosity be presented in the monograph, as is the case in the newly adopted monograph containing the FRC section—users can apply the test to identify the desired grade (See Table I).
Table I: Sample implementation of FRC section to hypromellose monograph.
Acceptance criteria for nominal viscosity are kept in the FRC section in accordance with internationally harmonized monographs because of obligations to publish a standard identical with the sign-off text. Acceptance criteria for the nominal viscosity of other polymers are included as well because manufacturers and users of the concerned excipients base their respective specifications on information included in the pharmacopoeia, and because deviations from the established acceptance criteria may have economical consequences.
It is a consequence of the nonmandatory status that previous labeling requirements to state the nominal viscosity are deleted. The first drafts on cellulose derivatives submitted to public inquiry contained the labeling requirement, a regrettable mistake that gave rise to confusion. This error has been corrected in all adopted and published monographs.
The review on cellulose derivatives made by the Working Party showed that current methods for determining the degree of substitution should also be moved to the FRC section. In cases where such a test already existed in the monograph, it was simply moved unchanged to the FRC section. In other cases, efforts were made to establish a method. A proposal on a general method for determining the degree of substitution of cellulose derivatives has been submitted to the Pharmacopoeial Discussion Group (PDG) coordinating international harmonization among PhEur, USP, and the Japanese Pharmacopeia. TriPEC is involved in the assessment of the proposed method as well.
Comments received to date on the European Commission's FRC work suggest that all FRCs should be dealt with in the general chapter on FRCs. Specific monographs should be cleaned up for tests on physical characteristics. Take for example, hypromellose. As previously discussed, the FRC section of the monographs contains rather voluminous texts on apparent viscosity and degree of substitution. It will not be user-friendly to hide all FRCs in a general chapter separated from the specific monographs. In many cases, the suitable method for a FRC is specific for the excipient. Of course, there are rather simple FRCs such as particle-size distribution that could be listed in the general chapter. This example and similar examples, however, are trivial and should not give rise to any concern when presented in specific monographs.
The intended content of the FRC section is to list important physical characteristics and to indicate suitable methods for their determination. To meet these aims, it is necessary to provide suitable methods in as many cases as possible. It is important that a range of general methods (e.g., methods for powder characterization) be included in the work program for those international harmonization efforts coordinated by PDG.
In addition to PDG's work, some revisions and updating of European monographs has been done already, including an update of rheological methods to include generally used viscometers. It is expected that the work on FRCs will reveal a need for new general methods, including laser diffraction for particle-size measurements. In this particular case, the general method was accepted for the PDG work program. It is the hope of the European Pharmacopoeia Commission that other proposed methods can be elaborated in the same manner.
From a European point of view, it would be attractive if the discussion on physical tests and their inclusion in excipient monographs could be addressed by PDG. This review has not been possible so far, although the importance of FRCs has been recognized by pharmaceutical manufacturers in all three ICH regions (Europe, Japan, and the United States) and in other countries.
Critical comments from TriPEC, the three regions that make up the International Pharmaceutical Excipients Council, on the general draft chapter on FRC work have claimed that the European work jeopardizes international harmonization of excipient monographs. The presentation of the European monograph differs from the presentation of the USP monograph. Apart from labeling requirements, the content of the PDF sign-off texts have been reproduced exactly in the European monograph.
The different formats have no implications on manufacturers' ability to specify excipient characteristics, which, according to regulatory guidance, should focus on the characteristics critical for actual formulation and manufacture. European legislation requires that compliance testing include every test in a monograph. The presentation of physical characteristics in the nonmandatory FRC section should therefore be seen as a pragmatic solution to a legal problem.
The new format of excipient monographs in PhEur was discussed at the European Directorate for the Quality of Medicines Conference on Excipients in 2002. Although there was support among many participants, some raised the question: Is this just additional testing? It should not be considered as such because the testing to be done is dictated by the pharmaceutical development work, not by the pharmacopoeia. This criticism has been voiced several times since then (6). TriPEC has recently expressed that there is great potential for extra, unnecessary testing for all listed FRCs when the user of an excipient does not fully understand which FRCs are appropriate for the intended use and application. This argument is supported by excipient manufacturers reporting that customers with reference to the listed FRCs have asked for data. This seems to be the essence of much of the criticism that has been raised against the FRC project. There is a significant need for information and training of all parties involved in the supply, uses, and assessments of excipients. The problems can be overcome once users of the pharmacopoeia have become familiar with the aim and uses of the new FRC section.
Henning G. Kristensen, DSc, is chair of the Working Party on Functionality-Related Characteristics at the European Pharmacopoeia Commission and a professor of pharmaceutical sciences at the University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark, firstname.lastname@example.org
Submitted: Feb. 13, 2007. Accepted Mar. 27, 2007.
1. M. Rios, "Debating Excipient Functionality," Pharm. Technol. 30 (9), 50–60 (2006).
2. "Functionality-related Characteristics of Excipients (5.15)," Draft General Chapter, Pharmeuropa 18 (3), 434–435 (2006).
3. Council of Europe, "Supplement 6.1, Chapter 5.14," PhEur (2007).
4. ICH Q8 Pharmaceutical Development (Brussels, Belgium, November 2005).
5. EMEA Committee for Medicinal Products for Human Use, Guideline on Excipients in the Dossier for Application for Marketing Authorization of Medicinal Product (London, November 2006).
6. R.C. Moreton, "Functionality and Performance of Excipients," Excipient Performance Supp. to Pharm. Technol. 30 (Excipient Performance Suppl.), s4–s14 (2006).