In January 2013, three important developments regarding the EU’s good manufacturing practice (“GMP”) rules for medicinal products were made public:
- the European Commission published significant revisions to the EU GMP guidelines for public consultation, including on supply chain traceability, complaint investigations, and prevention of cross-contamination;
- the Commission’s ‘written confirmation’ template that must be used as of 2 July 2013 for active substances imported into the EU was amended; and
- the Commission’s Implementing Decision on the assessment of the EU equivalence of third countries’ regulatory and enforcement framework regarding the manufacturing of active substances was published in the EU’s Official Journal.
Public Consultation on Revisions to EU GMP Guidelines
The public consultation relates to Chapters 3 (Premises and Equipment), 5 (Production), 6 (Quality Control) and 8 (Complaints, Quality Defects and Product Recalls) of the EU GMP guidelines. The revisions are intended to, inter alia:
- improve guidance on preventing cross-contamination, and refer to a new complementary toxicological assessment guidance;
- reflect the legal obligation of manufacturing authorization holders to ensure that active substances are produced in accordance with GMP as well as supply chain traceability;
- include a new section on the technical transfer of testing methods and other items, including out of specification (“OOS”) results; and
- clarify requirements and responsibilities with respect to the investigation and reporting of quality defects/complaints, and deciding on preventive and risk-mitigating actions.
Stakeholders should review the revisions and consider making use of the opportunity to submit comments and suggestions to the European Commission’s DG SANCO (SANCO-pharmaceuticals-D6@ec.europa.eu) by 18 July 2013. More information can be found here.
Stakeholders also have until 30 June 2013 to comment on the mentioned toxicological assessment guidance set out in a draft guideline from the European Medicines Agency on “setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities”, available here.
Amended ‘Written Confirmation’ Template for Imports of Active Substances
Under the new EU import restrictions that were introduced by the EU Falsified Medicines Directive and that apply as of 2 July 2013, active substances imported into the EU must be accompanied by a ‘written confirmation’ in which the competent authority of the country where the active substances were manufactured confirms, inter alia, that the active substances were manufactured in accordance with EU equivalent GMP standards.
The European Commission published a template for the required ‘written confirmation’ in July 2012, which has now been amended. The revised template (1) indicates that the GMP standards set out in WHO/ICH Q7 are equivalent to those of the EU, and (2) reflects that the authority issuing the written confirmation can base itself not only on inspection results from EU authorities, but also from non-EU authorities applying equivalent GMP standards. The relevant Commission Questions and Answers document has also been amended, and mentions the U.S. FDA as an example of such a non-EU authority.
Importantly, the revised template also reiterates the manufacturing authorization holder’s ultimate responsibility to ensure the quality of medicinal products. Manufacturers of medicinal products are therefore advised to review the new import requirements, and to ensure that their supply chain complies with these requirements.
Equivalence Assessment of Non-EU GMP Frameworks
The European Commission’s Implementing Decision on the assessment of the EU equivalence of third countries’ regulatory and enforcement frameworks regarding the manufacturing of active substances is also part of the implementation of the stricter EU import requirements for active substances introduced by the EU Falsified Medicines Directive.
The above-mentioned requirement for a ‘written confirmation’ does not apply if the country where the imported active substances were manufactured is included on a Commission list of jurisdictions with EU equivalent GMP standards. Countries must apply and undergo an assessment in order to be included on the list. So far, only Switzerland has been included on the list, while Israel’s application was placed on hold. Australia, Brazil, Japan, Singapore, and most recently the United States, have applied for inclusion on the list and are currently being assessed.
The European Commission’s Implementing Decision published on 24 January 2013 sets out in more detail which aspects and documents are taken into account as part of the equivalence assessment, and should therefore facilitate the inclusion of non-EU countries on the list.
Pharmaceutical companies and active substance manufacturers should take note of these important developments and prepare for the application of the new import rules for active substances.