On 10 July 2012, the European Commission published the final template for the 'written confirmation' for active substances exported to the European Union for medicinal products for human use, in accordance with Article 46b(2)(b) of Directive 2001/83/EC.
We have already reported about the draft version of this template and published an article about the possible consequences for the import of APIs from third countries (like India or China) to the European Union.
The new template is now the fifth document which has been published under Part 3 of the EU GMP Guide. Part 1 contains GMP for Medicinal Products, Part 2 GMP for APIs and Part 3 contains additional requirements for Site Master Files, Quality Risk Management (ICH Q9), Quality Systems (ICH Q10) and the MRA Batch certificate.
In parallel to the template for a written confirmation the EU Commission has published a Question and Answer document with the most frequently asked issues in relation with the new procedure. Some key topics and first comments about the potential consequences are listed below:
MRA countries also need to issue a written statement
Even countries who have a MRA with the EU would be required to issue the written confirmation as long as they have not asked for an assessment by the EU.
Equivalent GMP standard
According to the new requirements the non EU authorities have to confirm that the manufacturer concerned complies with EU GMP or an equivalent standard. This means that only those countries who inspect on the basis of ICH Q7 (which is identical to EU GMP Part 2) or for example WORLD HEALTH ORGANISATION (WHO) - FORTY-FOURTH TECHNICAL REPORT, NO. 957, 2010, ANNEX 2) can issue such a confirmation. Many experts state that India and China (the main sources of APIs coming to the EU) have not introduced binding GMP requirements in their laws equivalent to the EU GMP and that there is no comprehensive system of GMP supervision for all API manufacturers in place.
Verification that each consignment will be accompanied by a written GMP confirmation
The manufacturer of the finished medicinal product will be responsible to check that each batch of the API is accompanied by a written confirmation. Also the importer may check this upon its importation. But the verification will not be harmonised in Europe. The procedure will depend on the transposing law of the individual member state where the API is imported. In some countries the relevant authority might verify the written confirmation upon importation whereas in other member states this might be verified in the context of an inspection of the importer of the API or in the context of an inspection of the manufacturer of the medicinal product manufacturer that uses the imported API.
Responsibility to check the authenticity of the written confirmation
The importer and the manufacturer of the medicinal product who uses the API should contact the manufacturer of the API or the issuing authority of the non EU country to check the authenticity of the written confirmation. This might cause difficulty in practice as the non EU authority might not be prepared (and willing?) to answer such requests. What about fraud? It is only a question of time until fake versions of written GMP confirmations will be prepared by counterfeiters. It is unclear how manufacturers of medicinal products can avoid such a situation. But without any proven evidence that they have done everything to verify the authenticity they will be in a difficult situation. Is this feasible?
No central register - no validity requirement
No European Regulatory Agency will collect the written confirmation and there are no further requirements other than the format and the fact that each imported consignment has to be accompanied by the written confirmation. As a consequence the certificate must not be an original it can be a copy. This will make it even more difficult to verify the authenticity. There is even no validity period defined for the written confirmation. This might lead to the situation that once a non EU authority has issued a written confirmation they might never reassess the GMP compliance situation again. But what is the benefit of a 5 or 10 year old written GMP confirmation?
Official EU GMP inspection will have no impact on the written confirmation
No inspection by EDQM or by any EU member state will waive the requirement to have a written confirmation for each imported consignment of the API.
First countries who applied for assessment from EU commission
The only exception from the requirement to issue written confirmations is a successful assessment by the EU respective authority. So far, two countries applied for the assessment: Israel and Switzerland. The EU hasn't expressed any judgement yet.
Although the Q&A document provides answers a lot of questions, a number of questions remain unanswered. In any case, the written confirmation is a move in the right direction to fight against counterfeiters and non GMP compliant manufacturers.