Ensuring product quality is of utmost importance to the pharmaceutical industry, and appropriate controls and oversight are
required for both the drug-manufacturing process and the supply chain for pharmaceutical ingredients. Several key measures
in the United States and European Union that address these issues are progressing with either implementation or further discussion
slated for July 2013.
European Falsified Medicines Directive
On top of the agenda is the implementation of the European Falsified Medicines Directive. The directive seeks to prevent falsified
medicines entering the legal supply chain in the EU. The directive was adopted in July 2011, and EU member states began applying
provisions in January 2013. The directive harmonizes and strengthens safety and control measures across Europe in four main
areas: safety features of medicines, supply chain and good distribution practices (GDPs), active substances and excipients,
and Internet sales (1, 2).
On the pharmaceutical ingredient side, beginning in July 2013, all active substances manufactured outside the EU and imported
into the EU must be accompanied by a written confirmation from the regulatory authority of the exporting country. These statements
are to be issued per manufacturing site and per active substance to ensure that standards of GMP equivalent to those in force
in the EU are upheld, according to the directive (1, 2). Several countries have already committed to issuing written confirmations.
Exporting countries with an "equivalent" regulatory framework will not need to issue these written confirmations. The European
Commission (EC), together with the European Medicines Agency and member states, is assessing the regulatory frameworks of
countries applying for equivalent status (1, 2).
To meet the requirement for the import of APIs under the European Falsified Medicines Directive, FDA reported on June 21,
2013, that the US is now a "listed country" within the EC so that US companies need not obtain an export certificate from
FDA before shipping certain pharmaceutical products to Europe. Without the waiver, all US companies shipping APIs to Europe
after July 1, 2013 would have had to first submit documentation from FDA that the product was manufactured in accordance with
Europe's GMPs (3).
To avoid that burden for companies, FDA filed a formal "listing request" with the EC in January 2013 requesting that FDA's
GMPs be considered at least equivalent to those in Europe. The EC approved that request following an audit of FDA's regulatory
and inspectional oversight of APIs. The audit took place from May 13–20, 2013 (3).
The news of the waiver was welcomed by industry groups representing contract API manufacturers and fine-chemical producers.
"We are pleased that US drug manufacturers will not be required to provide written confirmation of quality for the exportation
of active pharmaceutical ingredients into the EU," said John DiLoreto, executive director of the Bulk Pharmaceutical Task
Force (BPTF), an affiliate of the Society of Chemical Manufacturers and Affiliates (SOCMA), in a June 21, 2013 SOMCA statement.
SOCMA represents batch and custom manufacturers. "We hope FDA and EU officials will continue to attain the maximum achievable
level of information sharing and greater harmonization on implementation of GMPs throughout the drug-supply chain," DiLoreto
added. BPTF said it supports negotiations between the US and the EU to eliminate trade barriers, to promote greater global
harmonization of GMPs, and to improve the safety of drugs throughout the supply chain.
The European Falsified Medicines Directive also puts into place measures on the distribution side of the pharmaceutical supply
chain. It includes new responsibilities for wholesalers and a definition of brokering activities as well as new responsibilities
for brokers. EMA's revised GDP guideline, which was finalized in March 2013, includes specific provisions for brokering activities
Reflecting the inclusion of GDP into European provisions, the EudraGMDP database also now includes information on GDP. EudraGMDP
is a modification of the EudraGMP database, which was launched in April 2007, to facilitate the exchange of information on
compliance and noncompliance with GMP among the regulatory authorities within the European medicines network. The new database,
now called EudraGMDP, was a deliverable of the European Falsified Medicines Directive. It is gradually being updated by medicines
regulatory authorities in EU member states with distribution-related information and will maintained on an ongoing basis (5).
The additional information will include: wholesale distribution authorizations; GDP certificates; statements of non-compliance
with GDP; and registrations of manufacturers, importers (including information on their suppliers), and distributors of active
The other two main areas in the European Falsified Medicines Directive relate to end-market activity. The directive requires
that barcodes be printed on or attached to every single pack of medicines subject to prescription and other medicines at risk
of being falsified. The barcodes must be checked into a database by the manufacturer and checked out when dispensed by a pharmacy.
These safety features are intended to make sure that there has been no tampering of the outer packaging of pharmaceuticals
The directive also introduced an obligatory logo to be placed on the websites of legally operating online pharmacies to allow
patients and consumers to identify authorized online pharmacies providing authentic, authorized medicines. These online pharmacy
websites must also register with a member state. Medicines regulatory authorities in EU members states will publish lists
of authorized internet pharmacies on their websites (1, 2).