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Without any GMP guidelines for excipients in Europe, change can't come soon enough for some industry groups.
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 GMPs
Organizations 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.
In the absence of any regulatory framework for GMPs, IPEC–Europe and EFCG are developing a third-party certification system. The project "could go a long way toward improving quality and, by extension, patient safety," says Iain Moore, chair of IPEC–Europe's GMP committee. IPEC–Europe and EFCG plan to consult the GMP auditing arm of IPEC–Americas known as IPEA (International Pharmaceutical Excipients Auditing).
Such an approach would allow third-parties such as BSI British Standards or SGS, which provide International Organization for Standardization (ISO 9001) certificates, to certify that excipient suppliers are operating according to GMP and GDP (good distribution practice) principles. The appropriate regulatory authority would provide accreditation to the auditing bodies, explained Tim Boelke, head of EFCG's excipient task force.
With thousands of excipients and suppliers serving the pharmaceutical industry, auditing every potential supplier is a daunting if not impossible task. Much like the situation in the US, Boelke believes the EU regulatory bodies lack the resources to carry out so many audits on their own. The authorities, however, can play an important role in auditing by providing independent oversight and monitoring the process, he says.
Third-party audits are included in the EC's pharmaceutical package but for APIs rather than excipients. In the package proposal, the regulatory authority's role would be to certify third-party auditing bodies who would then assess the GMP-compliance of API suppliers.
IPEC–Europe and EFCG, along with the United Kingdom's Pharmaceutical Quality Group, are developing a framework for certification of potential third-party auditors, including an excipient classification scheme and criteria for auditor qualification, training, and competency. The classification scheme, which may define a GMP level associated with the level of risk to patients, for example, is a top priority for the councils.
"We need to deliver a draft scheme quickly, as our aim is to present this and a detailed project plan to an invited group of stakeholders early in 2009 for their comment and feedback," says Moore.
At press time, IPEC–Europe's annual general meeting was taking place in France. Many of the issues addressed here were discussed and will be reported on at www.ipec–europe.org.
Phil Taylor is a consultant and writer for the International Pharmaceutical Excipients Council of Europe (IPEC–Europe), firstname.lastname@example.org. IPEC is made up of four independent associations: the Americas, China, Japan, and Europe (www.ipec-europe.org).
1. Europe Economics, Excipients: Impact Assessment Report (London), Dec. 19, 2007, available at www.europe-economics.com, accessed Jan. 13, 2009.