API GMP requirements update

Written by Dr. Paolo Biffignandi, Advisory Board member of the pan-European pharmaceutical regulatory affairs organisation ELC Group and former President of TOPRA (The Organisation for Professionals in Regulatory Affairs), in collaboration with Chetan Javia, Senior Project Manager at ELC Group in India.

In order to ensure that APIs meet the requirements for quality and purity that they purport or are represented to possess, the Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (Q7) was developed by the International Conference on Harmonization (ICH) in November 2000. This document provides guidance regarding GMP for the manufacturing of APIs under an appropriate system for managing quality and has been accepted as the reference guidance by most of the countries across the world, including the EU.

The European Legislation does not require mandatory routine GMP inspections for active substance manufacturers, unless the manufacturer performs sterilisation and subsequent aseptic handling of the active substance, since, as per Article 46(f) of Directive 2004/27/EC, the responsibility for only using active substances that have been manufactured in accordance with GMP is placed on the holders of a marketing authorisation.

In recent times, the GMP requirements for APIs have come back into limelight with the introduction of Directive 2011/62/EU, which will come into force from July this year. In order to prevent the entry of falsified medicinal products into the legal supply chain, all APIs manufactured outside the EU that are being imported into the EU will have to be accompanied by a ‘Written Confirmation’, unless they are being imported from a country that has been assessed by the EU Commission and is considered to have equivalent rules for GMPs to those in the EU. The ‘Written confirmation’ is to be issued from the regulatory authority of the country where the manufacturing site is located and must confirm that the active substance that is being imported into the EU has been manufactured in compliance with standards of GMP of the EU or ICH Q7.

Further, based on the practical experience of implementation of ICH Q7, the following issues have been identified so far and will be addressed by a Q&A document on ICH Q7:

• Output from the review of existing Q&As (e.g., from PIC/S Expert Circle on APIs, from initial Regulatory/PDA training 2002) that is currently underway by PIC/S teams will be considered for endorsement.

• Technical issues for clarification such as application in the supply chain control, contractor/supplier management (outsourcing), monitoring of impurity profiles, quality systems, applicability to biologicals/biotech and relationship with Q5D and GMP expectations in the development phase (manufacturing for clinical trials).

• Impact of the implementation of ICH Q8/Q11, Q9 and Q10 on Q7.  

The final Concept paper for ICH Q7 was endorsed by the ICH Steering committee on 17 October 2012 and Step 2/4 is expected to be in 2014.

Dr. Paolo Biffignandi, paolo@elc-group.com.