Most non-European pharmaceutical and virtual companies are now aware of the requirements of EU Directive 2001/20/EC relating to Investigational Medicinal Products (IMP) produced for use in clinical trials carried out in the European Union.  It should be noted that these Directives contain legal requirements, unlike "Guidelines" or "Notes for Guidance" which are just guides to best practice.  

Although the Directive applies to all countries of the EU, the competent authorities of each individual Member State may place a different emphasis on the various regulatory requirements and also on certain aspects of Good Manufacturing Practice (GMP).  This short discussion includes just a few of the current areas of interest to the authorities in general.  It is intended just to give a flavour (flavor) of the topics which should be considered.
 
Probably the most important requirement is that IMPs produced outside of the EU must be imported into a European facility which holds the correct authorisation and they must be released by a European Qualified Person (QP) who is named on that authorisation and who is therefore assessed by the Regulatory Authority.  The QP's responsibilities include ensuring that the products have been produced in accordance with the approved IMPD (EU equivalent of an IND) and also ensuring that the GMP processes at the manufacturer are in general agreement with those of the EU.  The latter is usually done by means of an audit which, when successful, allows the QP to sign a GMP Declaration which becomes part of the Clinical Trial Application.  The process is not complicated if the Sponsor is aware of it in advance so that it can be dealt with.  When the release has been given in the importing country there is free movement between EU Member States with no further control required unless further labelling or processing takes place.

 It is a European requirement that Quality Agreements are in place between Sponsor and CMO.  Whilst these may seem like extra paperwork, they are very useful documents as they should define all the responsibilities for production (including supply and control of components), QC testing and release.  They should also define where the finished IMP will be used so that the CMO can give appropriate advice and use procedures and facilities that comply with EU regulations.  This is particularly important for aseptic manufacturing where the EU requirements are different from those specified by FDA; for example, for EU use Water for Injection must be produced by distillation whereas in the US it can be produced using any validated process.  Further requirements for the production of sterile products can be found in the EC Guide to Good Manufacturing Practice, Annex 1 and it is advisable that this is read carefully by anyone intending to supply sterile products to Europe.  Furthermore, for sterile products, the EU authorities do not accept a lower standard of GMP for the production of Phase I supplies.

 Another area which is currently high on inspectors' hit lists is the use of formal Risk Assessments (ICH Q9) for the introduction of new products into a manufacturing facility.  Essentially the inspector wants to see that the CMO and Sponsor have determined any potential adverse effect on current products.  Again, this can be a very useful exercise particularly when combined with ICH Q8 guidelines on pharmaceutical development as the process could identify possible production problems before they actually occur in the production environment. 
 
The final area I would like to discuss is the assessment of GMP standards for Active Pharmaceutical Ingredients (API) used to produce IMP.  It is already a requirement that this is formally carried out for biological drug substances but several Member States are demanding the same assessment for small molecules.  It is currently a legal requirement for the Marketing Authorisation Holder and importer to confirm GMP standards for API used to produce commercial products but the Member States involved are now extending this into investigational API.  It is likely that this will spread to all Member States in the medium term.
 
So, the rules in the EU are different from those in the US.  These rules must be applied to the production of the IMP whenever the clinical trial is to be carried out in the EU so it is important that Sponsors use a CMO which has experience of multi-agency requirements as this will prevent any delays or adverse issues.  Of course, it is also useful if the CMO has direct contact with a European Qualified Person (a defined and licensed role in the EU) who can help with up-to-date GMP and regulatory information. 
 
Ken Caldicott, Ph.D., QP 
24th July 2009
ken@millps.co.uk 

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