August 30, 2013

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 August 2013, the European Medicines Agency (EMA) updated its pre-authorisation procedural advice for users of the centralised procedure to outline the most common mistakes detected by the Agency during the validation of initial marketing authorisation applications and provide guidance on how to avoid them. This document is intended to help applicants complete their submissions correctly and avoid any delays in the validation process. The issues are classified in different categories:

• good manufacturing practice (GMP)

• good clinical practice (GCP)

• paediatrics

• quality

• non-clinical and clinical.

Although specifically addressed to users of the centralised procedure, this document and related hyperlinks constitute an exceptional source of relevant information to all applicants. This guidance document addresses a number of questions that users of the centralised procedure may have. It provides an overview of the EMA’s position on issues that are typically addressed during the course of pre-submission meetings.

Among the hundreds of points of information provided, many are of interest for professionals in pharmaceutical quality — some are well-known but now clearly explained, some others are rather new. Among them, a March 2013 revision emphasised that the concept of the active substance master file (ASMF) shall only apply to a well-defined active substance and cannot be used for excipients, finished products and biological active substances. In addition, active substances, which are present in certain medicinal products such as vaccines or cell therapy medicinal products, do not fit with the concept of a ‘well-defined’ active substance, similarly to blood derived medicinal products and vaccine antigens.

From 1 September 2013, ASMF holders submitting their ASMF dossiers relating to a centrally authorised product (CAP) are asked to send it to the Agency and committee members only once. According to the new ASMF submission rules, the Agency will assign a reference number on request prior to submission of the ASMF. The EMEA/ASMF/XXXXX number is an internal reference number sequentially assigned by the EMA to enable an appropriate data lifecycle management of ASMFs used in one or more centralised marketing authorisation. The EMEA ASMF reference number does not replace the responsibility of the ASMF holders to version control their ASMF (in accordance with GMP) nor does it replace their own ASMF numbering system. Up to two weeks before submitting a complete ASMF or an update to an already submitted ASMF, the ASMF holder should request the EMEA ASMF reference number. The request should be sent to:

The EU/ASMF reference number allows for the identification by all competent authorities (national competent authorities and EMA) of ASMFs used in centralised and national (decentralised and mutual recognition) marketing authorisation applications (MAAs) or marketing appliction variations (MAVs), therefore enabling the ASMF Assessment Report Work Sharing (ASMF AR WS) procedure. More information on the ASMF AR WS will be made available closer to the start of the pilot phase (1 December 2013) on the dedicated ASMF WG webpage.

The EMA emphasises the importance of pre-submission meetings between applicants and EMA (Co-) Rapporteur. Pre-submission meetings — which should take place approximately seven months prior to the anticipated date of submission of the application — are a vital opportunity for applicants to obtain procedural, regulatory and legal advice from the EMA. The product team is available to address any questions marketing authorisation holders (MAHs) may have regarding their pre-authorisation application.

The July 2013 update of this guidance provides information to avoid the most common validation issues related to quality, GCP, GMP, paediatrics, pharmacovigilance, clinical and non-clinical validation issues and so on, making this document a practical regulatory vademecum for all of us.

Dr. Paolo Biffignandi,

August 30, 2013

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