MHRA-Orange Book-Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2017

This publication brings together the main pharmaceutical regulations, directives and guidance that manufacturers, wholesalers and brokers of human medicines are expected to follow when making, distributing or being involved in the supply of medicinal products in the European Union (EU) and European Economic Area (EEA).1 It also covers the main directive and guidance which affect manufacturers, importers and distributors of active substances. It is of particular relevance to all holders of manufacturer’s licences and wholesale dealer’s licences and to their Qualified Persons (QPs) and Responsible Persons (RPs), and persons registered to broker finished medicinal products or manufacture, import or distribute active substances within the Community. All these players have a responsibility for ensuring compliance with many of these regulatory requirements.

The obligation on governments of all Member States of the EU to ensure that pharmaceutical manufacturers are authorised is stated in Title IV of Directive 2001/83/EC, as amended (products for human use) and of Directive 2001/82/EC (veterinary products). These titles, or sections, are also the source of requirements for compliance with Good Manufacturing Practice (GMP), employment of QPs and repeated inspections by the regulatory authorities. Title IV also requires importers, manufacturers and distributors of active substances who are established in the Union to  register their activity with the competent authority of the Member State in which they are established. 

Title VII of the Directive 2001/83/EC requires all wholesale distributors to be authorised, to have available RPs and comply with the guidelines on Good Distribution Practice (GDP). Title VII also requires brokers of medicines within the Community to be registered with their competent authority and to comply with appropriate GDP requirements. The principles and guidelines of GMP are set out in two Commission Directives: 2003/94/EC for medicinal products for human use (replacing Directive 91/356/EEC) and 91/412/EEC for veterinary medicinal products In the UK, the provisions for manufacturers and wholesale dealers have been implemented by requirements and undertakings incorporated in the Human Medicines Regulations 2012 [SI 2012/1916]. Compliance with the principles and guidelines of GMP is a statutory requirement. The European Community (EC) Guide to GMP2 (including its annexes) provides detailed guidance which interprets and expands on the statutory principles and guidelines. Changes in technical knowledge and in regulations are reflected by additional and revised annexes.

GMP includes elements of the International Standard for Quality Management Systems ISO 9001:2000 with additional requirements specific to medicines. The UK first produced a national guide to GMP (known traditionally as the Orange Guide) in 1971. Guidance on good pharmaceutical wholesaling practice was added in the 1977 edition and a further edition was produced in 1983. The EC guidance, first issued for GMP in 1989 and for GDP in 1993, supersedes this and all other national guides of Member States, although much that was familiar in the old UK Guide can still be recognised in the EC guidance. The Pharmaceutical Inspection Co-operation Scheme has adopted the text of the EC Guide to GMPs ensuring harmonisation of guidelines by its member inspectorates throughout the world. Mutual Recognition Agreements between the EC and several third countries have recognised the equivalence of GMP requirements of the parties concerned Manufacturers are required to name a QP on their manufacturer’s licence. 

No batch of medicinal product may be released to the market within the EU unless a nominated QP has certified that it has been manufactured and checked in compliance with the laws in force. Guidance to QPs in fulfilling their responsibilities is given in the EC Guide to GMP and in the Code of Practice3 for Qualified Persons which they are expected to follow. In similar spirit, wholesalers are required to appoint an RP who has the knowledge and responsibility to ensure that correct procedures are followed during distribution. Notes on the qualifications and duties of RPs are given to assist this. 

The distribution network for medicinal products has become complex  and involves many players. Revised guidelines for GDP assist wholesale distributors in conducting their activities and to prevent falsified medicines