EU Directive 2001/83/EC lays down the rules for the manufacture, import, marketing and supply of medicinal products and ensures the functioning of the internal market for medicinal products while safeguarding a high level of protection of public health in the EU.

The falsification of medicinal products is a global problem, requiring effective and enhanced international coordination and cooperation in order to ensure that anti-falsification strategies are more effective, in particular as regards sale of such products via the Internet. To that end, the Commission and Member States are cooperating closely and supporting ongoing work in international fora on this subject, such as the Council of Europe, Europol and the United Nations. In addition, the Commission, working closely with Member States, is cooperating with the competent authorities of third countries with a view to effectively combating the trade in falsified medicinal products at a global level.

Active substances are those substances which give a medicinal product its therapeutic effect. They are the Active Pharmaceutical Ingredient (API).

Falsified active substances and active substances that do not comply with applicable requirements of Directive 2001/83/EC pose serious risks to public health.

The Falsified Medicines Directive 2011/62/EU amends Directive 2001/83/EC in order to facilitate the enforcement of and control of compliance with Union rules relating to active substances. It makes a number of significant changes to the controls on active substances intended for use in the manufacture of a medicinal product for human use.

A number of new terms have been introduced into the 2001 Directive by the Falsified Medicines Directive, including “falsified medicinal product” and “active substance”. The aim of this is to ensure that other amendments introduced by the Falsified Medicines Directive are consistently interpreted and applied across the EU.

The 2001 Directive has been amended to permit the European Commission to adopt the following:

● the principles and guidelines of good manufacturing practice for active substances, by means of a delegated act; and

● the principles of good distribution practice for active substances, by means of adopted guidelines.

To provide a greater level of control, and transparency of supply, for active substances within the European Community manufacturers, importers and distributors of active substances have to notify the relevant competent authorities of their activities and provide certain details. In the UK this will be MHRA. The competent authority has an obligation to enter these details into a Community Database (EudraGMDP) following the determination of a successful application for registration. The competent authority may then conduct inspections against the requirements of the relevant good practices before permitting such businesses to start trading. Manufacturers, importers and distributors of active substances will not only be subject to inspection on the basis of suspicions of non-compliance, but also on the basis of risk-analysis.

Authorised manufacturers of medicinal products who also manufacture and/or import active substances, either for use in their own products or products manufactured by other companies, are not exempt from the requirement to register.

Persons who are requested to import an active substance from a non-EEA country that provide facilities solely for transporting the active substance, or where they are acting as an import agent, imports the active substance solely to the order of another person who holds a certificate of good manufacturing practice issued by the licensing authority, are not required to register.

The registration regime for manufacturers, importers and distributors of active substances will be subject to an application procedure, followed by a determination procedure completed by MHRA.

The person applying for registration must notify MHRA immediately of any changes which have taken place as regards to the information in the registration form, where such changes may have an impact on quality or safety of the active substances that are manufactured, imported or distributed. These changes shall be treated as incorporated in the application form.

MHRA must grant or refuse an application for registration within 60 working days beginning immediately after the day on which a valid application is received.

MHRA will notify the applicant within 60 days of receipt of a valid application for registration whether they intend to undertake an inspection.

The applicant may not undertake any activity before either:

● 60 days have elapsed and the applicant has not been notified of the Agency’s intention to inspect, or

● following inspection the Agency has notified the applicant that they may commence their activities.

After inspection MHRA will prepare a report and communicate that report to the applicant. The applicant will have the opportunity to respond to the report. Within 90 days of an inspection MHRA shall issue an appropriate good practice certificate to the applicant, indicating that the applicant complies with the requirements of the relevant good practices. Where an applicant is found to be non-compliant with the requisite standards, a statement of non-compliance will be issued by MHRA.

If after 60 days of the receipt of the application form MHRA has not notified the applicant of their intention to carry out an inspection, the applicant may commence their business activity and regard themselves as registered. MHRA will issue a certificate to the applicant and enter the details into the Community Database .

This Community Database which is publicly available will enable competent authorities in other EEA Member States or other legal entities, to establish the bona fides and compliance of manufacturers, importers and distributors of active substances established in the UK and those in other EEA territories. MHRA will investigate concerns with regards to UK registrations of non-compliance and reciprocal arrangements will apply with other EEA Member States.

Figure 4.1 Registration requirements for UK companies involved in the sourcing and supply of active substances (ASs) to be used in the manufacture of licensed human medicines.

A person in the UK may not import, manufacture or distribute, an active substance for use in a licensed human medicine unless they are registered with MHRA in accordance with the Human Medicines Regulations 2012 and the respective conditions of those Regulations are met.

Registration holders must submit to MHRA an annual update of any changes to the information provided in the application. Any changes which may have an impact on the quality or safety of the active substance which the registrant is permitted to handle must be notified to the Agency immediately.

An annual compliance report will need to be submitted:

● in relation to any application made before 31 March 2013, the date of application; and

● in relation to each subsequent reporting year, 30 April following the end of that year.

Directive 2001/83/EC has been amended to include a new definition of “active substance” which means any substance or mixture of substances intended to be used in the manufacture of a medicinal product and that, when used in its production, becomes an active ingredient of that product intended to exert a pharmacological, immunological or metabolic action with a view to restoring, correcting or modifying physiological functions or to make a medical diagnosis.

The manufacture of active substances should be subject to good manufacturing practice regardless of whether those active substances are manufactured in the Union or imported. Where active substances are manufactured in third countries it should be ensured that such substances have been manufactured to the relevant European standards of good manufacturing practice (GMP), so as to provide a level of protection of public health equivalent to that provided for by EU law.

A manufacturer or assembler of an active substance will have to comply with the principles and guidelines for GMP for active substances. Manufacture, in relation to an active substance, includes any process carried out in the course of making the substance and the various processes of dividing up, packaging, and presentation of the active substance. Assemble, in relation to an active substance, includes the various processes of dividing up, packaging and presentation of the substance, and “assembly” has a corresponding meaning. These activities will be the subject of a GMP certificate.

Importers of an active substance from a third country have to comply with the guidelines for Good Distribution Practice (GDP) in relation to the active substance. This activity will be the subject of a GDP certificate.

Distributors of an active substance within the UK which has been sourced from a manufacturer or an importer within the EU will have to comply with the guidelines for GDP for active substances. This activity will be the subject of a GDP certificate.

The 2001 Directive has been amended to permit the European Commission to adopt the following:

● the principles and guidelines of good manufacturing practice for active substances, by means of a delegated act; and

● the principles of good distribution practice for active substances, by means of adopted guidelines.

GMP for active substances is contained in Part II of the EU guidelines on Good Manufacturing Practice.

In February 2013 the European Commission consulted on its draft “Guidelines on the principles of good distribution practices for active substances for medicinal products for human use”.

The draft text sets out the quality system elements for the procuring, importing, holding, supplying or exporting active substances. However the scope of the proposed text excludes activities consisting of re-packaging, re-labelling or dividing up of active substances which are manufacturing activities and as such are subject to the guidelines on GMP of active substances. The draft text of the guidelines covers:

● Quality System

● Personnel

● Documentation

● Orders

● Procedures

● Records

● Premises and Equipment

● Receipt

● Storage

● Deliveries to Customers

● Transfer of Information

● Returns

● Complaints and Recalls

● Self-inspections.

The Falsified Medicines Directive modifies EU Medicines Directive 2001/83/EC and from 2 July 2013 introduces new requirements for active substances imported into the EEA for use in the manufacture of authorised medicinal products.

The Falsified Medicines Directive requires importers of active substances to obtain written confirmations from competent authorities in non-EEA countries (“third countries”) that the standards of manufacture of active substances at manufacturing sites on their territory are equivalent to EU good manufacturing practice (EU GMP). These confirmations are required before importation of active substances into the EU.

Each shipment of active substance received should be accompanied by a written confirmation from the competent authority of the exporting third country, stating that the active substance has been:

● manufactured to GMP standards at least equivalent to those laid down in the European Union;

● the third country manufacturing plant is subject to regular, strict and transparent inspections, and effective enforcement of GMP;

● in the event of non-conformance of the manufacturing site on inspection, such findings will be communicated to the European Union without delay.

The template for the written confirmation has been published in Part III of EudraLex, Volume 4 and is included in Chapter 2 of the Orange Guide.

The Falsified Medicines Directive provides two waivers if written confirmations are not provided. The first is where the regulatory framework applicable to active substances in those third countries has been assessed by the European Commission (EC) as providing an equivalent level of protection of public health over active substance manufacture and distribution to those applied in the EU. This assessment follows a request from the exporting third country’s competent authority, and considers the regulatory framework for active substance manufacture and control and its equivalence to EU standards. Only if the exporting country is on the EC’s (“white”) list is the requirement for a written confirmation from that country’s competent authority removed.

The second waiver is where the third country active substance manufacturing site has been inspected by an EU Member State, has issued a certificate of compliance with EU-GMP and that it remains within its period of validity. This is an exceptional waiver intended to apply where it is necessary to ensure the availability of medicinal products. Member States using this waiver should communicate this fact to the European Commission in accordance with the legislation (Article 46b(4)). MHRA has notified the European Commission of its intent to use this waiver should that be necessary.