The 2008 Heparin crisis uncovered serious deficiencies in supply chain security for a rapidly changing global pharmaceutical industry. The crisis resulted in over 80 patient deaths in the United States, a further 70 deaths across 11 other countries and hundreds of adverse patient reactions. These injuries and deaths were traced to an adulterant that had been introduced during manufacture of the drug in China (Pew Healthcare, 2012).
In a detailed analysis of the crisis, Pew Health Group published a white paper entitled After Heparin: Protecting Consumers from the Risks of Substandard and Counterfeit Drugs. The white paper provides several insights into the complexities of modern pharmaceutical supply chains and the potential risks which now threaten the product lifecycle, from supply and manufacturing through to distribution of the finished drug. The white paper highlights some of the key contributing factors as:
Globalization, increased outsourcing of manufacturing, the complexity of pharmaceutical distribution and the existence of criminal actors willing to capitalize on supply chain weaknesses has created the potential for counterfeit or substandard medicines to enter the system and reach patients (Pew Healthcare, 2012).
This assessment of supply chain risks was confirmed by Dr. Janet Woodcock, FDA CDER Director when she described the supply chain for medicinal products as “stressed, complex and fragmented”, in her 2014 plenary address to the joint PDA/FDA Regulatory Conference (Woodcock, 2014).
Increased merger and acquisition activity, network consolidation, fragmentation of the product lifecycle, the explosion of outsourced manufacturing, complex licencing deals and the emergence of virtual organisations have all became commonplace within the 21st Century pharmaceutical industry. Driven by economic factors and fuelled by the 2008 global recession, these structural changes have resulted in increased and complex risks to supply chain security and ultimately to patients. These risks were not envisioned within the traditional GMP regulations nor are they necessarily adequately covered by typical supply agreements, legal contracts or supplier auditing programs.
This article provides an overview of a recent academic study undertaken by the Pharmaceutical Regulatory Science Team (PRST) based at Dublin Institute of Technology (DIT), Ireland. The study was conducted as part of a masters degree research project that examined the impact of a recent update to Annex 16 of the EU GMPs Certification by a Qualified Person and Batch Release, which came into operation in April 2016. Specifically, the study examined the impact of a new Annex 16 requirement to ensure that the ‘entire supply chain of the active substance and medicinal product up to the stage of certification is documented and available for the Qualified Person (QP)’(EU Commission, 2015). This requirement has led to the development and introduction of Supply Chain Maps within some pharmaceutical organisations. The research findings shared here include the results of an industry survey, interviews and learnings gained from a case study which involved the implementation of a supply chain maps management program with a global pharmaceutical organization.
Examining Recent Regulatory Drivers for Securing the Supply Chain
To gain a greater understanding of the drivers and context for the EU GMP Annex 16 update the researcher first reviewed the current EU regulatory environment for other recent changes related to securing the supply chain.
The greatest impact stems from the Falsified Medicine Directive (FMD) (EU Commission, 2011) which came to effect in 2013 within the EU and introduced new requirements for Manufacturing Authorisation Holders (MAHs) to minimise the likelihood of counterfeit medicinal products entering the supply chain. The FMD also introduced the requirement for auditing and certification of all API manufacturers and distributors. Most significantly, from a patient transparency perspective, new track and trace or serialization requirements ensure the ability to verify the authenticity of a medicinal product, down to individual pack-level and includes checks for whether the outer packaging of medicines have been tampered with. Finally, the FMD also introduced a new approved EU logo for online pharmacies, a growing, highly competitive marketplace for products which heretofore has been difficult to regulate. The last phase for implementation of the new FMD requirements is scheduled to be completed by 2019.
Staying within the EU regulatory framework, Chapter 7 on Outsourced Activities (European Commission, 2013b) of the EU Good Manufacturing Practice (GMP) guidelines, Eudralex Volume 4 was also updated in 2013 to provide further guidance. Chapter 7 now sets out the need to have clearly defined responsibilities for both the contract giver and the contract acceptor in quality agreements. To control the use of third parties, contract acceptors cannot use any subcontractors to execute elements of the supply contract without prior approval of the contract giver. Furthermore, the contract giver may now extend their audits to include subcontractors of the contract acceptor or contract manufacturing organization (CMO).