What was the reason for issuing the FMD?

At the beginning of the so called Falsified Medicines Directive (Directive 2011/62/EU) it is stated, that there is an “alarming increase of medicinal products detected in the European Union which are falsified in relation to their identity, history or source. Those products usually contain sub-standard or falsified ingredients, no ingredients at all or ingredients in the wrong dosage thus posing an important threat to public health.” Furthermore it reads “Past experience shows that such falsified medicinal products do not reach patients only through illegal means, but via the legal supply chain as well. This poses a particular thread to human health and may lead to a lack of trust of the patient in the legal supply chain.” It is evident, that not only drug products but also active pharmaceutical ingredients (APIs) are affected. Therefore substandard APIs e.g. falsified active substances or active substances, having been manufactured without compliance to the respective applicable EU GMP part II guideline (or at least equivalent standards) are also regarded to pose serious risks to public health. The underlying directive 2001/83/EC (covering drug products for human use in Europe) was therefore amended in order to respond to these increasing threats.

In the following paragraphs the main contents of the FMD are summarized. Special attention is given to the implications for Chinese companies exporting medicinal products, APIs or excipients to the member states of the European Union.

Legal Background

The “Falsified Medicines Directive” 2011/62/EU relates to the protection of the legal supply chain from the infiltration of falsified medicinal products and is one of the several amendments of the directive 2001/83/EC. The FMD was adopted by the European Council in May 2011.

The Falsified Medicines Directive has the following key objectives:

Improvement of the controls on quality of active substances and excipients

Introduction of safety features for medicinal products at risk of counterfeiting

Strengthening of inspection activities

Strengthening of obligations on wholesalers and extending the regulation to brokers

Harmonization and strengthening of rules for internet supply of medicines

Regulating medicines imported for re-export

Some of the mentioned items have more or less implications on Chinese companies exporting medicinal products, APIs or excipients to the European Union and will be explained in more detail in the following text.

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:

Article 8:
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.”

Article 46:
“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.

Article 46/47:
“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.

Article 46b:
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.

Article 111b:
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.

Strengthening of Inspection Activities

Inspections of manufacturers are regarded as important means in Europe to maintain and support the GMP compliance level. However, due to limited personnel resources and many additional tasks, inspections by national competent authorities (NCA) are in most cases limited to the mandatory inspections.

Due to the valid regulations in place, the competent authorities of the EU member states should perform inspections in third countries in the following cases:

• routinely for manufacturers of medicinal products in third countries
• when there are grounds for non-compliance with legal requirements, the competent authority may carry out inspections of manufacturers and distributers of APIs in third coun-tries.
• in relation to a CEP application the EDQM together with a national authority may conduct inspections
• upon specific request of the manufacturer the competent authority of the member state concerned may carry out inspections.

Voluntary GMP inspections of EU NCAs to obtain an EU GMP certificate for e.g. API manufacturers in third countries such as China have therefore to be triggered early in advance through local EU manufacturers and/or distributors.

Introduction of safety features for medicinal products at risk of counterfeiting

The Directive states that these features must be applied – in principle – to all prescription-only medicines and to non-prescription medicines if they are at risk of counterfeiting. These safety features should enable wholesale distributers and pharmacists to verify the authenticity of medicinal products and to identify the individual packs. Certain medicinal products might be excluded from this requirement based on a risk assessment. This risk assessment should e.g. consider the price, previous cases of falsified medicinal products and the implications of falsification.

The exact nature of the safety features and the characteristics and the technical specifications of the unique identifier of the safety features will be decided by the European Commission in a separate legislation (a delegated act). The concept paper of the “Delegated Act on the Detailed Rules for a unique identifier for Medicinal Products for Human Use, and its Verification” has been launched for public consultation until 27 April 2012 and was commented by several stakeholders. For identification every pack it is given a serialization number. The serialization number on the pack is checked against its entry in a repositories system by wholesale distributers and pharmacies, thus verifying its authenticity. The following ways to carry the serialization number on the outer packaging are currently discussed: linear barcodes, 2D-barcodes and Radio-frequency identification (RFID). The delegated act is expected to be in place by 2014. EU Member States will have three years after adoption of the delegated act (until 2017) to ensure the requirements are put in place.

Implications of the Falsified Medicines Directive for Chinese Manufacturers Exporting Medicinal Products, APIs or Excipients to the European Union

Excipients manufacturers:
Excipient manufacturers can expect to obtain an increase of audit requests from their European clients. Since these audits should be risk based, the highest number of audit requests can be expected for excipients used for medicinal products with high risk (e.g. parenterals, ophthalmic or pulmonal medicinal products) or for excipients from sources associated with higher risk (e.g. animal source). Manufacturers should consequently start to evaluate which level of GMP their customers are expecting based upon the supplied excipients. Independent excipient certification such as the EXCiPACT scheme or 3rd party audits of the respective excipients by independent inspection service providers with or without sharing of audit reports may be interesting tools to cope with this potential increase in customer audits.

API manufacturers:
API manufacturers need to have a written confirmation for export of their APIs to the European Union. Only upon exception a waiver may be issued to import APIs into Europe without such written confirmation (e.g. if there is a necessicity to ensure the availability of the respective medicinal product and for such API & manufacturing site a successful EU GMP inspection (by a NCA of an EU member state) has been conducted.) The application for a new marketing authorization or for variation of an existing one (e.g. addition of a new API manufacturer) the QP of the manufacturer located in EU must issue a confirmation that the Chinese manufacturer complies with GMP and that this knowledge is based on an audit (with date). So audits concerning new authorizations must be performed before first commercial sales.

China will only issue “written confirmations” for those manufacturers, which have been subject to on-site GMP inspections. The Chinese CFDA issued instructions to the provinces authorities on May 7th with accompanying forms on the requirements for certifying API manufacturers accordingly. Under two scenarios an API will be granted written confirmation: (a) company with production license & drug approval number (b) company with production license but no drug approval number at the time being. Once written confirmation is issued, the province level CFDA will pass on this information to the CFDA headquarters in Beijing. All written confirmation data will be updated in a database and published to public accordingly. If a site does not comply with the current GMP requirements or does not comply with the conditions for certification, local authorities must inform CFDA headquarters within 24 hours so that the information can be forwarded to the EU.

• CFDA (China) instruction with requirements for issuing written confirmations (Chinese)
• CFDA (China) template for requesting written confirmation (Chinese/English)

Manufacturers of medicinal products:
Importers of medicinal products to the European Union must have the risk assessment/management documentation for appropriate GMP for excipients available on site.
Concerning the safety features, which need to be on the outer packaging of medicinal products from 2017 on, manufacturers should observe the development and be ready to install the necessary technical solutions.