Compiled by the Inspection and Standards Division of the - Rules and Guidance for Pharmaceutical Manufacturers and Distributors

Rules and Guidance
for Pharmaceutical
Manufacturers and
Distributors 2017

Published by Pharmaceutical Press

6668 East Smithfield, London E1W 1AW, UK

Crown Copyright 2017

MHRA, a centre of the Medicines and Healthcare products Regulatory Agency 151 Buckingham Palace Road

Victoria

London SW1W 9SZ

Information on re-use of crown copyright information can be found on the MHRA website: www.mhra.gov.uk

Designed and published by Pharmaceutical Press 2017

is a trade mark of Pharmaceutical Press

Pharmaceutical Press is the publishing division of the Royal Pharmaceutical Society

First edition published in 1971 as the Guide to Good Pharmaceutical Manufacturing Practice, second edition in 1977, third edition 1983, fourth edition as the Rules and Guidance for Pharmaceutical Manufacturers in 1993, fifth edition as the Rules and Guidance for Pharmaceutical Manufacturers and Distributors in 1997, sixth edition in 2002, seventh edition in 2007, eighth edition in 2014, ninth edition in 2015, tenth edition in 2017

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Printed in Great Britain by TJ International, Padstow, Cornwall

ISBN 978 0 85711 285 9 (print)

ISBN 978 0 85711 291 0 (ePDF)

ISBN 978 0 85711 292 7 (ePub)

ISBN 978 0 85711 293 4 (mobi)

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The publisher makes no representation, express or implied, with regard to the accuracy of the information contained in this book and cannot accept any legal responsibility or liability for any errors or omissions that may be made.

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A catalogue record for this book is available from the British Library.

Contents

PART I
Basic Requirements for Medicinal Products

PART II
Basic Requirements for Active Substances Used as Starting Materials

PART III
GMP Related Documents

EU referendum

Following the outcome of the EU referendum, the Medicines and Healthcare products Regulatory Agency (MHRA) is working closely with the Government to analyse the best options and opportunities available for the safe and effective regulation of medicines and medical devices in the UK. While negotiations continue, the UK remains a full and active member of the EU, with all the rights and obligations of EU membership firmly in place.

For further updates from the Medicines and Healthcare products Regulatory Agency concerning this, please visit the website at www.gov.uk/mhra.

Preface to the 2017 edition

This is the 2017 edition of Rules and Guidance for Pharmaceutical Manufacturers and Distributors (the Orange Guide ). Now in its 10th edition the guide has been updated with revised sections on:

qualification of suppliers and customers;

parallel importation and parallel distribution;

temperature control and monitoring;

UK legislation; and

matters relating to unlicensed medicines.

There are also new MHRA sections on:

GMP for Excipients;

Guidance on revised Annex 16 of GMP; and

MHRA Data Integrity definitions and guidance for Industry.

Revised Annexes 15 and 16 are included. Also included is new Commission guidance on:

principles and guidelines of Good Manufacturing Practice for active substances;

principles of Good Distribution Practice of active substances;

setting health-based exposure limits; and

formalised risk assessment for ascertaining the appropriate GMP for excipients.

The EU regulation on safety features for medicines is added together with two Commission Q&As on:

importation of active substances; and

safety features for medicinal products.

There is also a new appendix on sources of useful information.

GMP Directive

The principles and guidelines of GMP are adopted by the European Commission under powers conferred by Council Directive 2001/83/EC. This is to ensure that all medicinal products for human use manufactured or imported into the Community, including medicinal products intended for export, are to be manufactured in accordance with the principles and guidelines of GMP. The objective of GMP is to ensure that products are consistently produced and controlled to particular quality standards. Commission Directive 2003/94/EC (the GMP Directive) sets out the requirements relating to the implementation of GMP for medicinal products for human use (currently including investigational medicinal products (IMPs)).

Regulation (EU) No 536/2014, on clinical trials on medicinal products for human use, requires the Commission to adopt delegated acts to specify the principles and guidelines of good manufacturing practice and the detailed arrangements for inspection for ensuring the quality of investigational medicinal products. Consequently it is therefore necessary that Directive 2003/94/EC be repealed and replaced by a Delegated Act on principles and guidelines of good manufacturing practice for investigational medicinal products and a new Implementing Directive on principles and guidelines of good manufacturing practice for medicinal products.

There will be three areas of GMP legislation when these two new Delegated Acts on principles and guidelines of GMP are in place alongside Delegated Regulation 1252/2014 on GMP for active substances.

A public consultation took place from 28 August to 24 November 2015 on the Commission Implementing Act on principles and guidelines on good manufacturing practice for medicinal products for human use. The new Delegated Acts for investigational medicinal products and finished products are planned to come into effect at the same time as the clinical trials Regulation 536/2014.

Changes to the Community Code

The Falsified Medicines Directive 2011/62/EU amends Directive 2001/83/EC in a number of places. The first tranche of these changes in relation to manufacturing, wholesale dealing, supervision and sanctions came into force from 2 January 2013 with others relating to the importation of active substances from countries outside the European Economic Area (EEA) taking effect from 2 July 2013. These provisions are implemented in the UK by Regulations amending the Human Medicines Regulations 2012. The headline changes are as follows: