European norms for drug development

Dr Vipin Bihari Gupta deals with norms for drug development in European Union in the concluding part of the article

The European Union (EU), an initial consortium of six countries, now consists of 25 member countries representing over half-a-billion strong consumer base. While Bulgaria, Romania, Turkey and Croatia are waiting to become members, Russia is worried whether EU would engulf the Ukraine and Belarus also. The current member countries are Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxemburg, Netherlands, Portugal, Sweden, Spain, Cyprus, Check, Estonia, Hungary, Latvia, Lithuania, Malta, Poland, Slovakia, Slovenia and Britain.

In a recently held meeting in Hague, EU has granted India the same status of importance as it has for USA, Canada, Russia, China and Japan. Hence, India’s relations with EU has reached a new height and so is its bilateral trade, which currently is 13 billion Euros. Another interesting fact about EU is that in most of its members countries population growth rate is lower than the required and there is a declining trend in the number of researchers in science and technology, hence, several EU nation are looking towards India, not only for enhancing trade-volume, but also for outsourcing human resources.

Application procedures

The member countries of EU enjoy combined as well individual sanctity, henceforth, there exists plural procedures for obtaining marketing authorisation. These are national, mutual recognition and centralised procedures.

National procedure: This is used when a product is to be marketed in a single country and is applicable for almost all products except certain biotechnology-based ones. Once a product is approved in any one country through this procedure and should the approval be desired in other countries of European Economic Area (EEA), it proceeds through mutual recognition procedure, baring certain exceptions, which haven’t been subjected to harmonisation procedures. In these cases, different countries require different ‘Summaries of Product Characteristics’ (SmPCs), and consequently, approval calls for individualised national procedures.

Mutual recognition procedure: As mentioned above when a product is approved in one country and line-extension in another country is required, Mutual recognition procedure follows. Perhaps, in most of the cases the application is rarely accepted without additional questions being asked and these questions aren’t only between the applicant and the regulatory agency of the concerned country but also between originating member state (i.e. the agency in the country whose original approval has formed the basis for the mutual recognition application) and the concerned member state (i.e. the agency that has been asked to accept it as valid in their country) and the Mutual Recognition Facilitation Group (MRFG).

The MRFG regularly meets in London on Mondays before Committee for Proprietary Medicinal Products (CPMP) meetings. The successful applications are granted approval in the concerned member state, which may be extended to other member state by undertaking another Mutual Recognition application.

Centralised procedure: This procedure is available for a defined list of product types (as annexed in the regulation) and for Orphan Drugs (as defined by Orphan Drug Committee). The route involves appointment of members of the CPMP as rapporteur and co-rapporteur, who hold the responsibility for preparation of an assessment report.

Initially, two assessment reports and two draft lists of questions are prepared and then they are consolidated into single report and list of questions after the discussions and input from the members of CPMP. If required, the applicant can submit additional information and a specific appeal mechanism also exists.

When CPMP reaches to a positive ‘opinion,’ the European Commission (the Pharmaceutical Sector of the Enterprise Directorate General) converts the ‘opinion’ to a legally binding ‘decision’ after seeking the input from the member states. The centralised procedure approvals are valid in all member states of the European Economic Area.

Data requirement

The requirements of data on development pharmaceutics are stated in the Directive 75/318/EEC. These includes:

• Explanation/justification for the choice of composition, constituents and container and the intended function of the excipients in the finished products. The explanation should be supported by scientific data on development pharmaceutics.
• The overages and their justifications.
• Analytical methods along with their validation data.

Format and contents of application: The Commission has suggested format and contents of applications, and although these do not have legal bindings, still the applications not complying with the suggested format are liable to be returned.

The application is required to have following four parts:

Part I: Application form, labelling and product information and expert report.

Part II: Data on pharmaceutical and manufacturing aspects of the product

Part III: Non-clinical data

Part IV: Clinical data

The Expert Report is supposed to include accurate summary of the supporting evidence for the application and should include a critical discussion on the information.

Legislation/information source: Rules governing medicinal products in the EU

Pharmaceutical legislation: Medicinal products for human use are available from Commission of the European Communities, Luxembourg or from Enterprise Directorate General’s website at http://dg3.eudra.org.

Various applicable rules and guidelines are:

1. Rules governing medicinal products in the EU, Vol. 2:

a. Procedures for marketing authorisation

b. Presentation and contents of the dossier

2. Rules governing medicinal products in the EU, Vol. 3A:

3AQ1a:Development pharmaceutics and process validation

3AQ2a:Manufacture of the finished dosage form

3AQ3a:Limitations to the use of ethylene oxide in the manufacture of medicinal products

3AQ4a:The use of ionizing radiation in the manufacture of medicinal products

3AQ9a:Excipients in the dossier for application for marketing authorisation of a medicinal product

3AQ10a:Plastic primary packaging materials

3AQ13a:Validation of analytical procedures-methodology

3AQ14a:Validation of analytical procedures-definitions and terminology

The writer is Director, B R Nahata College of Pharmacy, Mandsaur (MP)