As 2008 drew to a close, the headlines around Europe tied to the pharmaceutical industry focused on the European Commission's new pharmaceutical package. The bundle of initiatives and legislation is intended to modernize the regulation of pharmaceuticals throughout the European Union. The package has provided some welcome clarity on the future regulatory environment for the pharmaceutical sector as a whole, but for suppliers and users of pharmaceutical excipients, there is still much uncertainty, particularly in the area of good manufacturing practice (GMP).
Even though excipients often make up the largest percentage of a drug's ingredients, there is no legal requirement for excipient GMPs in Europe. (In the United States, there are excipient GMPs but they are not very specific.) In practice, a European pharmaceutical company's "qualified person" (identified as being responsible for quality) regulates excipients on the grounds of compliance with internal specifications and pharmacopeial monographs.
Push for excipient GMPsOrganizations such as the European branch of the International Pharmaceutical Excipients Council (IPEC–Europe) and the European Fine Chemicals Group (EFCG) have long argued that formalized GMPs should be applied to excipients. They stipulate, however, that such GMPs should be applied at an appropriate level and take into account the fragmented nature of excipient suppliers whose products may have nonpharmaceutical applications (e.g., food and personal care products).
Delegates to IPEC–Europe's inaugural conference on GMP for Pharmaceutical Excipients, held in Munich in December, heard first-hand from European regulators about the prospects for excipient GMPs. In addition to proposing various anticounterfeiting and pharmacovigilance measures, the EC's package, for example, contains elements that will affect GMPs with regard to controlling starting materials, said Sabine Atzor of the European Commission's DG Enterprise and Industry pharmaceutical unit at the conference. Atzor said, however, that a number of issues need to be resolved before the EC can issue a Directive on GMP for Excipients, as mandated by the 2004 overhaul of EU pharmaceutical legislation. Work has been stalled by the need to tackle increased counterfeiting of medicines in the region.
Additional momentum has been lost as a result of the European Commission–contracted impact assessment on GMPs for "certain excipients." Those certain excipients are: glycerine, propylene glycol, excipients with the claim "endotoxin or pyrogen controlled," excipients claimed to be sterile and used without further sterilization, excipients derived from human/animal material with a potential for viral contamination risk, and excipients prepared from materials derived from transmissible spongiform encephalopathy relevant animal species (excluding lactose) (1). The EC called out these excipients based on the probability and severity of adverse events that could occur if they are not made according to GMP.
The assessment report, prepared by the consultancy firm Europe Economics, however, recommended that the status quo be maintained for excipient regulations because the risks to patients are low. With European Parliamentary elections taking place this year, more delays are likely.
Katrin Nodop, mutual recognition agreement coordinator at the European Medicines Agency (EMEA), told the IPEC–Europe audience that the agency intends to release in 2009 a revision to Part II of its GMP guide covering active pharmaceutical ingredients (APIs). The revision will incorporate risk-management principles along the lines of the International Conference on Harmonization Q9 Quality Risk Management guideline. The revision will ideally be used as a guide for the creation of excipient GMP guidelines.
This potential new guideline would bring the EU more in line with the US Food and Drug Administration's excipient proposals on GMPs for excipients, which may include a risk-management approach. FDA currently looks at the excipient's usage (parenteral or oral product), origin (natural or synthetic), supply-chain length, and whether the excipient participates directly in drug delivery. Nodop noted that the proposed revision of Pharmaceutical GMP 9 (Part 1) Chapter 5, which includes sections on the qualification of suppliers and testing of starting materials, would have affected excipients directly. The Chapter 5 revision was due to take place in 2008 but has been delayed.