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.