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Hardly any other subject is as extensively discussed in the GMP environment as the so called Written Confirmation (confirming the GMP compliance of an API / of the API manufacturer).

The 'Falsified Medicines Directive' 2011/62/EU has been adopted in June 2011 and published on 1 July 2011. It introduces (for the first time) EU-wide rules for the importation of active substances for medicines for human use. As of 2 July 2013, all active substances have to be manufactured in accordance with EU Good Manufacturing Practice (GMP), or (if imported) with equivalent rules. Starting from 2 July 2013, all APIs manufactured outside the EU have to be accompanied by a Written Confirmation, otherwise they cannot be imported into the EU. Many countries outside the EU have not yet commented yet whether - and if yes, when - Written Confirmation will be issued. Therefore there is a risk that single APIs will not be available any more after 2 July. The table below shows the state of play with regard to the preparation of exporting countries for the Written Confirmation.

In this article we have summarized the current situation and the key information with regard to the procedure of the Written Confirmation.

There are only two alternatives to a Written Confirmation. The first option is the admission to the list of "Third Countries" with comparable inspection standards. Currently only Switzerland and Australia are on that list and therefore have not to issue Written Confirmations (see table above).

The second option is an exception according to the "Counterfeit Directive": Exceptionally and where this is necessary to ensure the availability of medicines, the need for the Written Confirmation can be waived by a Member State if it has inspected the plant and found it compliant. However, the resources of the EU GMP Inspectorates are very limited and it seems very unlikely that all inspections which have been requested by companies can take place before July 2nd.

The EU Commission has published a Question and Answer document with the most frequently asked issues in relation with the new procedure. This document has been revised three times already in order to reflect upcoming questions. The following paragraphs summarise some of the key topics and first comments about the potential consequences.

MRA countries also need to issue a written statement

Even countries having an 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 that inspect on the basis of ICH Q7 (which is almost identical to EU GMP Part 2) or for example WORL D 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. However, companies may ask their competent authority to perform an inspection (second option - as explained at the beginning of this article)

To find out how this issue is handled in pharmaceutical companies in the EU, the European QP Association conducted a brief survey amongst its members beginning of this year. Almost 300 QPs gave answers to the questions. At the time of the survey almost 50% of the companies replied that they had already tried to get a Written Confirmation for APIs manufactured outside the EU. Only 15% were confident that their company will get the Written Confirmation for all APIs imported from outside the EU by 2 July 2013. 35% didn't think so. For the rest it was too early to say.

The answer to the question: Who has been appointed in your company to assure that APIs imported from countries outside the EU are accompanied by the "Written Confirmation"? provide some interesting information (see graph on the left).

This shows that companies are using all their resources to receive the necessary documentation. However, it also shows that a strategic approach in the companies to deal with the new requirement is still missing. It is impossible to predict whether the current challenges will lead to supply shortage from 2 July on. As a precautionary measure, many pharmaceutical manufacturers are currently increasing their stocks of APIs from non-EU countries.

Oliver Schmidt

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