Improvement of the Controls on Quality of APIs and Excipients
The FMD requires that the manufacturer of APIs should be subject to Good Manufacturing Practice (GMP) regardless of whether those active substances are manufactured in the European Union or whether imported. In order to achieve this, the FMD amends the Directive 2001/83/EC with the following requirements:
The application for the marketing authorization shall be accompanied by a “written confirmation (issued by the so called Qualified Person, QP) that the manufacturer of the medicinal product has verified compliance of the API manufacturer with with principles and guidelines of GMP by conducting audits. […] The written confirmation shall contain a reference of the date of the audit and a declaration that the outcome of the audit confirms that the manufacturing complies with the principles and guidelines of of GMP.”
“The holder of a manufacturing authorization is obliged to verify compliance by the manufacturer and distributers of APIs with GMP and GDP by conducting audits at the manufacturing and distribution sites. The manufacturing authorization holder shall verify such compliance either by himself or through an entity acting on his behalf under a contract.
“The holder of the manufacturing authorization shall ensure that excipients are suitable for use in medicinal products.” To evaluate the appropriate level of GMP a formalized risk assessment should be conducted for every excipient. The related draft of the Guidelines on the Formalized Risk Assessment for Ascertaining the Appropriate Good Manufacturing Practice for Excipients of Medicinal Products for Human Use was open for public consultation until 30 APR 2013. This draft guideline gives detailed instructions on how to conduct the required formalized risk assessment and to determine & confirm the appropriate GMP. This is detailed in sections covering:
- the type of excipient & the application in the drug product,
- the determination of the excipient manufacturer’s risk profile,
- how to confirm the application of appropriate GMP.
Based on the documented risk profile of the excipient the manufacturing authorization holder should establish and document the elements of EU-GMP that he believes are needed to be in place in order to control the quality of the excipients (e.g. EU-GMP part I, Annex 1 or Annex 2 or EU GMP part II, etc.). The requirements may vary depending on the source, the supply chain and the subsequent use of the excipient. Therefore the guideline gives a list of high level GMP principles that have to be followed at minimum by the excipient manufacturer. These minimum GMP principles are somewhat comparable to ISO 9001 quality management requirements including specific GMP elements. Depending on the manufacturer’s risk profile different risk mitigation strategies (e.g. audit, document retrieval and testing) should be established. Also an on-going risk review should be performed through mechanisms such as: defects on received batches of excipients, loss of relevant quality system accreditation of the excipient manufacturer, trends in medicinal product quality attributes or results of (re-)audits of the excipient manufacturer.
Importers of medicinal products must have the risk assessment/management documentation for appropriate GMP for excipients available on site.
EU Member states must ensure that manufacture, import and distribution of APIs on their territory comply with GMP and GDP. APIs may only be imported if the following conditions are fulfilled:
- APIs have been manufactured in accordance with GMP at least equivalent to EU GMP part II (i.e. ICH Q7 or WHO 44. Technical Report, no. 957, 2010, Annex 2)
- After 01 JUL 2013 APIs must accompanied by a written confirmation from the competent authority of the exporting third country certifying that
- the GMP standards of the plant manufacturing the exported API are at least equivalent to EU GMP part II,
- the manufacturing plant concerned is subject to regular, strict and transparent controls and to the effective enforcement of GMP, incl. repeated & unannounced inspections
- in the event of non-compliance, information on such findings is supplied by the exporting third country to the EU without delay.
Exceptionally and where necessary to ensure the availability of medicinal products a waiver may be issued for single APIs after a successful EU GMP inspection by a member state authority.
The European Commission published a Template for the ‘written confirmation’ for active substances exported to the European Union for medicinal products for human use, in accordance with Article 46b(2)(b) of Directive 2001/83/EC and a “question and answers” document on “Importation of Active Substances for Medicinal Products for Human Use”, which details the requirements about the written confirmation.
If the exporting country is included in the list of countries with regulatory framework for APIs with a level of protection equivalent to that of the EU, no written confirmation is required. Currently Switzerland, Australia, Japan and USA are contained in this list. Brazil is currently being assessed.