16th APIC Conference in 2013

Active Ingredients: Aftermath clearly desired

One of the provisions of the Directive on combating counterfeit medicines 2011/62/EU, which regulates the import of pharmaceutical active substances into the European Community, caused considerable excitement for importers and manufacturers of medicinal products in the first half of last year. Therefore, this subject was also the starting point for intensive discussions at the 16 European API Conference in Madrid.
According to the Directive every active ingredient delivery has to be accompanied by a GMP certificate of conformity - a "Written Confirmation" - attesting the GMP compliant manufacturing of the active substance. These Written Confirmations have to be issued by the authority of the respective exporting country. This regulation became effective on 2nd July 2013. Since over 60% of the active ingredients imported into the EU come from India and China, the uncertainty was whether these countries would provide the required Written Confirmations until this date. Therefore many firms created extensive stocks in the months before, to bypass a possible supply shortage. Other exporting countries such as the United States, Japan, Australia and Switzerland made it on the "white list" just on time. This list comprises States which do not need to issue Written Confirmations due to their EU analogue monitoring systems to ensure GMP for active pharmaceutical ingredients. After India and China then did supply Written Confirmations, the situation eased and there were no bottlenecks in the supply of medicines.

Confusing Situation
However, the situation in relation to active ingredient imports into the EU is anything but clear. As Marieke van Dalen of the Dutch active ingredients manufacturer Aspen OSS says, the directive was not uniformly implemented in different EU Member States. This is also shown by the different control practices. In some countries, the active ingredient deliveries are checked by the respective Customs authorities directly at the borders, explains van Dalen. Other countries assign this task to the qualified person, who would then have to check that the delivery is properly accompanied by the Written Confirmation. Then again, other countries - Finland, Italy, Poland and Slovenia - have not implemented the directive into national law at all so far and therefore do not work according to the Directive already in place.
The question how meaningful Written Confirmations are in the first place and whether they can help to reduce or prevent inferior or fake drugs, is currently discussed in the entire industry. For Graham Cook from Pfizer, for example, the Written Confirmations' quality or validity is sometimes dubious. Occasionally stamp and signature of the issuing authority would be missing. In other cases, these documents were issued, even though the Certificate of Suitability (CEP) for the active substance has already been withdrawn by the EDQM. Manuel Ibarra Lorente from the Spanish authority AEMPS can report from similar defects frequently found in the review of Written Confirmations: E.g. address details on the document that do not match with the identification of the active ingredient delivery. On the other hand, the exporting countries' efforts have to be recognised to exhibit these conformity certificates in the required quality, says Ibarra Lorente. Nevertheless, serious doubts about the meaningfulness of Written Confirmation do remain. Marieke van Dalen even goes so far to describe the document as "A piece of paper that everyone can sign". Ultimately it does not contribute to the safety of patients, she says.
The GMP rules for active pharmaceutical ingredients have long been known and are a largely established standard, at least in the ICH countries. After all, the ICH guideline Q7 has been effective since the year 2000. A partial aspect in the manufacture of active ingredients repeatedly causes discussions between authorities and industry: the determination of the starting material. There is no provision regarding which chemical compound in a multi-stage synthesis path has to be defined as starting material for the production of the active ingredient. Due to the enormous variety of compounds and the variety of the synthetic routes such a provision is simply impossible. Ultimately, the definition of a starting material must always be justified on an individual basis according to scientific criteria. Exactly this is the problem. According to Rudy Peeters, Janssen Pharmaceutica and member of the Starting Material Task Force of APIC, there is a broader trend in industry, to specify as short as possible synthetic paths with the already highly complex molecules as a starting point in Active Substance Master Files (ASMFs) and Certificates of Suitability (CEPs). The underlying intention is clear: the less synthesis steps fall under the GMP requirement, the sooner costs can be saved. Authorities do interpret and handle this approach very differently. The Strasbourg-based European Directorate for the Quality of Medicines & HealthCare (EDQM), for example, requires that the molecular structure of the starting material has to be clearly different in composition and complexity from the final stage, the active ingredient. This still leaves room for interpretation; on the other hand there is a clear statement from the EDQM that one- or two-stage synthesis paths are generally not accepted. According to the Deputy Head of the Division Certification of Substances in the EDQM, Hélène Bruguera, the Starting Material issue is one of the most common reasons for delays in granting CEPs or for their withdrawal.
Disagreement among Authorities
Under regulatory authorities in and outside Europe there is little consensus with regard to the acceptance of starting material specifications as well. Although the ICH guideline Q11 "Development and Manufacture of Drug Substances" contains a chapter on the choice of starting materials, it remains very general and provides no specific guidance for their definition, though. Vicky Waddington from Johnson Matthey MacFarlan Smith in Edinburgh, Scotland, knows to report from cases where the starting material had to be redefined due to the different perspective of an authority, while it was accepted by assessors of other authorities. The resulting lack of uniformity in the registration documents is anything but encouraging for the affected companies. Finally this means in any case additional administrative time with possible delays in the approval process or applying for variations.
The very lively and constructive discussions during the 16th APIC Conference clearly showed again how big the demand for information exchange is between authorities and industry but also between the companies themselves. Hopefully this conference which has already been established for many years will again be able to stimulate an enhanced cooperation between the various interest groups - with the goal to create uniform and binding standards that ultimately benefit everyone.

Conference Tipp: The 17th European API Conference will take place in Vienna, Austria, from 5-7 November 2014.  There, top-ranking representatives from authorities as well as from industry will report about current key areas and developments regarding the supervision, manufacturing and distribution of pharmaceutical active ingredients.