On 11 April 2008, the International Conference on Harmonisation (ICH) published a concept paper with the title "Q11: Development and Manufacture of Drug Substances (chemical entities and biotechnological/biological entities)". In ICH's standardised harmonisation process, drawing up a concept paper is the first of five steps on the way to the finalisation of a guideline and its acceptance by the three big industrial regions Europe, USA and Japan. The concept paper contains a proposal for a new guideline and explains why it is necessary.

Which issues are meant to be harmonised and regulated through ICH Q11?

The requirements on the information about the manufacturing process of active pharmaceutical ingredients to be included in the dossier for a marketing authorisation differ from one region to another and confront the drug manufacturer with the problem of having to create several versions of the CTD sections S 2.2 - S 2.6 when applying for a marketing authorisation. The answer to the question which data on API production a registration authority expects and in how much detail they should be described in the dossier is either not clear or differs between countries. In addition, divergent requirements on APIs manufactured by chemical synthesis and biotechnological methods are the cause for further unnecessary complexity. This leads to a harmonisation gap, which is intended to be filled by means of ICH Q11.
The advantages of such a harmonisation of requirements are obvious: Saving time and resources when first submitting a dossier and, of course, when submitting an application in case of post-approval changes or variations.

The description of and grounds for the development of an active ingredient and its manufacture must be oriented towards the principles of ICH Q8, Q9 and Q10. The authors of the concept paper consider the following aspects of the development of APIs to be particularly in need of harmonisation:

• Selection of the starting materials for API production
• Identification of important and critical manufacturing steps, process controls, process parameters and the corresponding explanations; moreover, the selection of analytical methods and acceptance criteria for completely controlling and ensuring product quality and consistency
• The capacity of processes to deplete or remove impurities and chemical compounds similar to the product
• The assessment of process robustness
• The proof that methods are suitable for validation on a small scale
• The identification and control of critical intermediates

This guideline is meant to reduce efforts not only on the part of the pharmaceutical and API industries; the harmonisation of the requirements in connection with the authorisation process should also bring benefits to the assessors from the registration authorities.

ICH Q11 is currently in "Step 1", called the consensus-building phase. The intermediate steps in the harmonisation schedule of this guideline leading to "Step 2" are as follows:

• Approval of the guideline topic/definition of the rapporteur and members of the expert working group (EWG): April 2008
• First EWG meeting: June 2008
• Formal confirmation that the EWG members have reached a consensus on the guideline content by signing the "Expert Sign-off Sheets" (= finalisation of Step 1): 4th quarter 2009

It will be interesting to get to know the detailed requirements of the guideline; however, a consensus guideline can hardly be expected before the beginning of 2010.

The Q11 concept paper can be found here:
http://www.ich.org/LOB/media/MEDIA4523.pdf
The appertaining business plan with the description of the perceived problems and a cost-benefit assessment can be viewed here:
http://www.ich.org/LOB/media/MEDIA4524.pdf

Author
Dr Gerhard Becker
On behalf of the European Compliance Academy (ECA)