An Update On The EU's Plans For Excipient Regulation

Jan 07, 2011

Q: What progress has been made so far regarding the EU plans to regulate excipients?

Dr Iain Moore
With all the different groups editing and proposing amendments to the counterfeit directive, it's quite difficult to work out what the preferred position is when it comes to excipients. However, it seems highly probable that the requirement that only excipients manufactured to GMP are used in drug products will make it through the legislative process. As ever, the devil will be in the detail though and it remains to be seen what the final draft will look like. The latest committee drafts are not available for public viewing at this point.

IPEC Europe is currently engaged in advocacy on the basis that the requirement for GMP will be adopted, but that two amendments/clarifications are made:

  • The definition of an excipient be amended to clarify that only intentional additives be classified as excipients (in line with WHO and USP definitions of an excipient).
  • The requirement to apply GMP only to certain classes of excipients be removed. IPEC's position is that proportionate GMP should be applied to all excipients.

At the moment, it seems likely that the responsibility for ensuring that GMP is applied to excipients will lie with the marketing authorisation holder (i.e., be a QP responsibility — as it is with APIs). This builds on the current situation where excipient users are responsible for qualifying their excipient suppliers and making sure they are of suitable quality. The big question, however, is what GMP should be used?

Europe Economics' impact assessment,1 which was conducted to evaluate the impact of a list of certain excipients (as requested by Art. 46(f) of Directive 2001/83/EC) concluded that compared with current legislation, implementing GMP for certain excipients was not expected to lead to a proportionate benefit to patients in relation to the costs of conforming to those GMPs. In short, if the bar is set too high then many excipient suppliers will no longer supply them; after all many excipients are predominantly manufactured for use in other industries (e.g., food additives, cosmetic ingredients etc.) and the quantity sold to pharmaceutical is very small in proportion.

IPEC's position is to aim to have basic and proportionate GMP for all excipients that should not be more demanding on the industry than, for example, the current widely accepted IPEC-PQG GMP Guide, which is freely available to download from the IPEC Europe website.2

Q: Do you agree that all excipients for pharmaceutical use should be fully audited, similarly to APIs, and how feasible is it that such regulations will be instated?

Current legislation and expectations are that the marketing authorisation holder has a mechanism to qualify their suppliers, including those that provide excipients. When we consider the spectrum of the pharmaceutical industry, it is clear that so-called innovative pharma and some of the larger generic manufacturers are trying to achieve this standard of auditing their suppliers. In many cases, however, they are applying quality risk management to determine which ones to audit because even these organisations cannot afford to physically audit every supplier on a regular basis.

Secondly and more importantly here is the maths. How many audits are going to be necessary if full audits of all suppliers is mandated? How many competent auditors will be required? And critically from a suppliers side, how many audits are they going to have to host? Just recently, for example, one part of one multinational blue chip company in the US decided that they would have to audit all their suppliers before the end of the year, which involves 1000 audits! What would the number then be over the entire industry? It would not be a question of being audited to death — more a case of trampled to death by the tsunami of auditors!

In the US, the FDA is becoming very forceful on this topic. Only recently the revised Chapter 5 of the EU GMP Guide also strongly suggests that physical audits of all suppliers should be performed by marketing authorisation holders. The tragedy is that the reason for this pressure is because there are some low quality and fraudulent suppliers out there who have been exploiting the lack of physical audits, which we have seen time and again for APIs. And yet, who will end up bearing the brunt of the pain of these audits? The genuine suppliers who are trying to do the right things but are being penalised because of criminal activities.

It comes then that IPEC fully supports that there should be a means of assessing the suitability of an excipient supplier without the need for every user of that excipient to audit every supplier themselves. Our proposal is to utilize third party audit organisations to perform the audit once on behalf of all excipient users, and to reaudit and follow up on a regular basis to ensure continued conformance. A certificate is then issued and renewed on subsequent audits to confirm the suppliers conformance with the GMP and GDP requirements. This way, we can remove the sea of audits from the equation and yet minimise the risks whilst maximising the benefits. This is the essence of our Excipact project.

It is not for IPEC to comment about APIs as we do not represent that part of the industry, but I do note that there are similar third party audit schemes in operation for APIs.

However, will the authorities legislate on this specific matter? I would guess not because they probably have enough mandate already to implement this standard on the pharmaceutical manufacturers.