Excipient industry calls for Euro master file system

This was the message that emerged strongly at the annual meeting of the International Pharmaceutical Excipients Council (IPEC) Europe meeting last week, at which leading lights in the excipient sector gathered to discuss the issues facing the industry in the coming year.

The operating environment for European excipient companies is getting more and more difficult, with a tightening regulatory framework, increasingly demanding quality standards and a customer base that expects more and better services. These elements, coupled with downward pricing pressure and the ongoing commoditisation of the industry, make the development of innovative products not just desirable but imperative.

IPEC Europe vice chair Prof Henk de Jong, speaking with In-PharmaTechnologist.com in the wake of the meeting, explained the key issues raised by the lack of an 'excipient master file' (EMF).

"The development of an excipient requires a full development programme of stability testing, toxicity studies and clinical trials etc, and takes three to seven years to complete,"​ he said. This can cost between €0.5 to €30 million.

But the excipient company has no way of filing a confidential dossier with the regulatory authorities in Europe - filings can only be made as part of the Marketing Authorisation Application (MAA) for a finished product. In addition, the nature of the ingredient used means that often a patent is not enforceable. An EMF, which could be reviewed and held by a regulator and contain both open and closed portions of data, would provide the excipient company with some much-needed protection for its investment.

For APIs, this is a well-established vehicle. For example, it allows generics companies to source actives for its products, referring to the Drug Master File (DMF) in its marketing application. The API manufacturers' process and production approach remains confidential.

In the US, a DMF system exists not only for inactive ingredients, but also for other aspects of a medicinal product such as packaging, while Japan is also working on a DMF system for both APIs and excipients which should come into force this year. "This clearly puts companies operating in Europe at a disadvantage,"​ said Prof de Jong.

IPEC Europe is lobbying hard to get this message across, and recently issued a statement noting that 'efforts to develop new formulations to improve manufacturability, stability or drug delivery is dependent upon innovation in the development and manufacture of pharmaceutical excipients. However, the lack of protection of intellectualproperty of new and novel pharmaceutical excipients discourages this.'

IPEC's proposal is that a novel excipient which successfully went through the EMF registration procedure would be granted 10 years' marketing exclusivity, after which generic versions could reach the marketplace via the usual pharmacopoeial monograph system.

And once granted, an EMF would eliminate the need for excipient manufacturers to re-submit the same documentation for the review of each marketing authorisation from multiple end-users of the same ingredient.

The European Commission remains unconvinced about the value of an EMF, convinced that it would increase bureaucracy, costs and also appears to have concerns about it being a barrier to free trade. It also notes that there is an approval process in the form of the European Directorate on the Quality of Medicines (EDQM) Certificate of Suitability system excipients having a monograph in the European Pharmacopoeia. But there are limitations: this is only open to approved excipients, and effectively excludes novel ingredients and biotech products.

The pharmaceutical industry, for its part, has a mixed view of the issue. On the one hand, drug companies can see the benefit of improved excipients at a time when they are developing increasingly complex active ingredients that need excipients to overcome solubility issues, improve bioavailability and enhance their release profile in the body. On the other, there is an inherent mistrust among pharma when data on its products are not all in-house, and there are concerns that EMFs could promote too much reliability on one supplier, putting them at risk of higher costs, according to IPEC chair Adrian Bone.

But perhaps the strongest argument for an EMF comes from a concrete example of a novel excipient that has gone through a European review process, smoothly and efficiently, and with a clear benefit to industry.

Europe has already allowed the equivalent of Master Files for excipients to be submitted when it became necessary to replace ozone-depleting chlorofluorocarbon (CFC) propellants with HFA propellants (norflurane or HFA-134a) in metered dose inhaler products.

The result was that in Europe 75 per cent of CFCs used in metered dose inhalers have been phased out. The US has only just started the switch, and at present has only signaled an intention to phase out around half of its CFC usage by 2006/7.