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The US and EU move forward with measures to fortify the pharmaceutical supply chain.
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 (4).
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 substances (5).
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 (1, 2).
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).
Charting US measures
In the US, later this month (July 12, 2013), FDA will hold a day-long public meeting to discuss how to implement the drug supply-chain provisions found in Title VII of the Food and Drug Administration Safety and Innovation Act of 2012. Title VII gave FDA new authorities to address the challenges posed by an increasingly global drug supply chain. According to FDA, 40% of finished drugs are imported, and nearly 80% of active ingredients come from overseas sources (6).
The purpose of the July 12th meeting is to provide an overview of Title VII, discuss how FDA plans to implement it, and hear public comment about those provisions that specifically address imported drugs and importers. Under Title VII, FDA is authorized to require that importers submit information demonstrating that their drug complies with applicable requirements of the Federal Food, Drug and Cosmetic Act before their products can enter the US. In addition, commercial importers must register with FDA and meet good importer practices (6).
Focus on Excipients
Another key milestone this month is the end of the public comment period for FDA's draft guidance, Contract Manufacturing Arrangements for Drugs: Quality Agreements. The draft guidance, which was issued in May 2013, describes the agency's current thinking on defining, establishing, and documenting the responsibilities of parties involved in contract cGMP manufacturing of drugs. Public comment on the draft guidance is open until July 29, 2013 (7).
The draft guidance describes how parties involved in contract manufacturing of drugs can use quality agreements to delineate their responsibilities and ensure drug quality, safety, and efficacy. The guidance applies to the commercial manufacturing of APIs (drug substances or their intermediates), finished drug products, combination products, and biological drug products. The draft guidance describes how contract manufacturing operations fit within the larger scheme of pharmaceutical quality systems. FDA says the draft guidance incorporates provisions from ICH guidelines, including ICH Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, ICH Q9 Quality Risk Management, and ICH Q10 Pharmaceutical Quality Systems (7–10). The draft guidance notes that although written quality agreements are not explicitly required under existing cGMP, owners and contracted facilities can draw on quality-management principles to carry out the complicated process of contract drug manufacturing by defining, establishing, and documenting the responsibilities of all parties involved in drug manufacturing, testing, or other support operations. Accordingly, FDA recommends that owners and contracted facilities implement written quality agreements as a tool to delineate responsibilities to ensure the quality, safety, and effectiveness of drug products.
1. EMA, "Falsified Medicines," www.emaeuropa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000186.jsp&mid=WC0b01ac058002d4e8, accessed June 16, 2013.
2. EC Directive 2011/62/EU, Falsified Medicines Directive (Brussels, July 2011).
3. FDA, "FDA Obtains Waiver from European Commission to Facilitate Export for US Pharmaceutical Manufacturers," Press Release (June 21, 2013).
4. EMA, Good Distribution Practice of Medicinal Products for Human Use (London, March 2013).
5. EMA, "Key Deliverable of Falsified Medicines Directive Achieved," Press Release (Apr. 8, 2013).
6. FDA, "Food and Drug Administration Safety and Innovation Act Title VIIDrug Supply Chain; Standards for Admission of Imported Drugs, Registration of Commercial Importers and Good Importer Practices; Notification of Public Meeting; Request for Comments," Fed. Regis. 78 (118) 36711-36715 (June 19, 2013).
7. FDA, Draft Guidance for Industry–Contract Manufacturing–Arrangements for Drugs: Quality Agreements (Rockville, MD, May 2013).
8. ICH, Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (Geneva, 2000).
9. ICH, Q9 Qualified Risk Management (Geneva, 2005).
10. ICH, Q10 Pharmaceutical Quality Systems (Geneva, 2008).