Released for comment in 2011, the consultation phase for this directive ended in April 20121 and a planned adoption of the delegated act will be in force in 2013. The new legislation takes aim at manufacturers of active pharmaceutical ingredients (APIs) that are not compliant with good manufacturing practices (GMPs). The implications of the new directive go beyond API manufacturers and extend ultimate responsibility back to the drug manufacturer for GMP compliance. In addition, the onus is on the drug manufacturer to ensure that the API manufacturer is good distribution practice (GDP)-compliant. In the United States, there are no formal regulatory standards for good distribution practices.
In Europe, however, all manufacturers, distributors, and importers are expected to register with the competent authority of the European Union (EU) member state where they are established. Distributors and importers are responsible for confirming the quality and integrity of the API in the final drug product.
The European Commission further requires the 25 member states to take appropriate measures to ensure that all products within their respective territories comply with this requirement.
A global battlefield
History has no shortage of high profile public health disasters that can be traced to the industry’s newfound commitment to a global supply chain. In 2007, Baxter’s Heparin disaster exposed a number of significant supply chain management problems on the part of the manufacturer and the U.S. Food and Drug Administration (FDA). The post-mortem analysis showed shared culpability on all fronts and highlighted the complexity of doing business in another country.
For example, in 2008, when Baxter sent inspectors to retroactively evaluate its supply chain, they were denied access to upstream workshops and consolidators. The FDA was also denied access to two upstream consolidators of heparin. Further complicating the inspection, the API manufacturer had been classified within China as a chemical plant and therefore was not registered with the Chinese State Food and Drug Administration (sFDA). The FDA was unsuccessful in getting cooperation from Chinese authorities to investigate beyond the API maker.
Such are the realities of attempting to verify and enforce the new API directive. The threat has not been lost on FDA and EU authorities. In a January 2010 warning letter, the FDA claimed that employees at XiAn Libang Pharmaceutical Co. Ltd. were manipulating testing data. The agency informed the API manufacturing plant that it would not consider new marketing applications until the observed violations were sufficiently addressed. In February 2010, Indian manufacturer Glochem was found to have falsified batch-manufacturing records for clopidogrel, an antiplatelet medicine. EU inspectors discovered at least 70 batch-manufacturing records in the plant’s waste yard. All the records had been re-written, and in some cases, original entries had been changed. In 2008, the FDA cited Indian manufacturer Ranbaxy Laboratories Ltd. for a number of U.S. GMP violations, including alleged falsification of stability testing records.2
Up to now, quality auditors have evaluated API manufacturers against the requirements defined in Eudralex Vol. 4, Part II (ICH Q7A, titled Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients). The Falsified Medicines Directive 2011/62/EC seeks to extend the scope of the existing EU GMP directive (2003/94/EC) to include APIs. In effect, this would make no difference between the quality requirements for a drug substance (API) and its final drug product.
One could argue that this has been coming for some time. In 2011, the FDA started citing API manufacturers that could not meet the Stage 1 requirements of the new process validation guidance.
Similarly, the EU directive has raised the bar in terms of accountability, and opened the door to enforcement. Unlike a drug product, which can be verified by a regional authority, a drug substance must be verified by a Qualified Person (QP). The EU is extending this requirement as a prerequisite to marketing authorization, requiring a QP declaration of compliance prior to approval.
For drug manufacturers, the requirements for adopting an outsourcing plan have just become a lot more complex. Outsourcing strategies must begin to integrate the requirements of the drug substance manufacturer within the quality management system. Defining touch points that extend upstream to the pre-approval inspection (PAI) manufacturers’ suppliers and sub-suppliers, and downstream to the API intermediate and regulatory starting material should generate demonstrable evidence of compliance with ICH Q7A and the EU GMP Directive 2003/94/EC to obtain a QP declaration.
Even if it has no such requirement, the United States may be able to leverage the enforcement muscle of the EU to reduce the risk of importing falsified material. For final drug manufacturers, the barriers to outsourcing continue to rise. It remains to be seen if China, where a major portion of all APIs imported to the United States are currently manufactured, will support this new directive and allow greater transparency in the matter of qualifying manufacturers and suppliers.
1. Jenteges B, et al. EU Directive to Thwart Noncompliant APIs, PDA Letter, April 2012.
2. The Pew Health Group. After Heparin: Protecting Consumers from the Risks of Substandard and Counterfeit Drugs. July 2011.