EMA Publishes Reflection Paper On Supply Shortages Caused By Manufacturing/Good Manufacturing Practice Compliance Problems
Alarmed by recent medicinal product supply shortages caused by manufacturing/Good Manufacturing Practice Compliance problems EMA has published a Reflection paper that summarises the lessons learned from previous supply shortages and explains the way to address them. Furthermore, EMA presents short and mid-term actions in the reflection paper to address this sort of shortages. EU legislation requires marketing authorisation holders and manufacturers of medicinal products to notify the authorities if there is the risk of supply shortages.
As a result of a high number of shortages of medicinal products, FDA has published a draft Interim Rule at the end of last year regarding revised notification requirements for manufacturers in case of such shortages. The EU also has recognised this problem and has made it a central issue in all meetings of the Committees for Humans Medicinal Products (CHMP). The concept paper for revising Chapter 8 of the GMP Guide points out that requirements concerning the reporting procedures relating to restrictions of supply should also be addressed in a revision of Chapter 8 - whether or not this supply shortage relates to a quality defect.
Now a European Network is intended to help the Member States that may experience difficulties when faced with pan-European problems in the case of still occurring shortages in the supply of medicinal products. The Network's help will be provided in the form of risk management.
The Reflection paper summarises the lessons learned from previous supply shortages and explains how to manage these shortages. EMA talks among other things about the regulators' dilemma. This dilemma stands for the cases in which defective but life saving medicinal products had to be left on the market. In other cases of GMP non-compliance no action could be taken in order to avoid supply shortages. Globalisation is seen as a further source of danger. Extended manufacture and supply chains also present increased dangers. The production of some active substances for life-saving medicines, e.g. antibiotics, is now wholly located outside the EU. Uncertain political and regulatory systems and the danger of natural disaster may lead to shortages in the supply. The 2011 tsunami in Japan is given as an example of how natural disasters can impact the supply chain of pharmaceuticals. The trend to focus manufacturing to a few manufacturing sites supplying at a global level also gives rise to risks. EMA continues to state that industry's risk management tends to be reactive rather than proactive. Here EMA is of the opinion that sustained pressure is needed to bring about a change so that industry takes a proactive approach to quality risk management - also with regard to supply chain integrity.
The possibly necessary import of unlicensed medicines to prevent a shortage is also discussed. This leads to variations that can be extensive and are not intended in such a way. EMA reflects upon considering this already in the marketing authorisations. Furthermore, EMA declares to be in favour of a better international contact amongst regulatory authorities at a global level. More consideration should also be given to the interfaces between medicinal products and medical devices. Some medicinal products are tailored to a certain medical device. According to EMA there is a need to further discuss the risks of the existence of monopolies in supply chains.
In this context EMA has been asked to develop further measures in such events. It then has proposed ten short term and three medium term actions in the Reflection paper. The following are short term actions:
- Establish an internal catalogue of products that have experienced known shortages of supply. This concerns Centrally Authorised Products (CAPs). In the case of non-CAPs, the EU is required to take a coordinating role.
- Maintain the public catalogue mentioned above (marketing authorisation holders will be invited to report shortages caused by manufacturing/GMP compliance problems on a voluntary basis).
- Develop a common understanding of the concept of "essential" medicinal products at national level and develop a decision tree to assist in deciding what shortages should be dealt with at EU level.
- Provide clarification on how to best manage national influence as part of the EU communication and how to best coordinate national and EU measures.
- Establish an SOP for handling reports of shortages in supply due to quality defects and manufacturing problems and for the decision where an assessment by the EU is necessary. The SOP should outline the interlinking of regulatory, pharmacovigilance, GMP inspection, assessment and communication aspects of dealing with shortages due to unforeseen events in the manufacturing supply chain.
- Revision of the the Community Procedure "Procedure for Handling Rapid Alerts Arising From Quality Defects" and of Chapter 8 of the GMP Guide as concerns restrictions of supply due to manufacturing problems and quality defects. The addressee is the Inspectors Working Group (IWG) for Good Manufacturing and Distribution Practice (GMDP).
- Explore if "crisis" situations arising from shortages in the supply of medicinal products due to quality defects and manufacturing problems can in the future also be addressed in the context of the EU Regulatory Network Incident Management Plan for medicines for human use.
- Develop international co-operation in this area and sharing of information on best practices on risk management and prevention strategies.
- Raise the awareness of the impact of medicinal product shortages. Organisation of a public workshop between Regulatory Authorities, industry, patients and healthcare representatives to improve industry's business continuity planning.
- Undertake a survey of past initiatives taken by national health authorities as concerns their initiatives to manage/prevent shortages. The aim of the survey is to point out best practices and to develop an inventory of possible tools available to all national health authorities.
The medium term actions include:
- Facilitate the risk benefit evaluation with regard to supply shortages due to product defects.
- Promote a better and proactive risk management by marketing authorisation holders. The aim is to identify any weaknesses of the manufacturing process by means of a risk analysis. Depending on the severity of the weaknesses, the marketing authorisation holder will have to provide a contingency plan and proposals to strengthen the identified weaknesses.
- Development of a process that could be suitable for measuring the impact of medicinal product shortage in patients experiencing its consequences, e.g. lowered dose or switch to an alternative product.
The short term actions are due to be completed by the fourth quarter of 2013. The medium term actions are scheduled until the end of 2015. The pharmaceutical industry will be affected especially by the concept paper on proactive risk management. This concept paper is planned for the first quarter 2014.
Conclusions: EMA has addressed the topic of supply shortages in the area of medicinal products very seriously. It has planned that until the end of 2015 strategies will have been elaborated by means of short and medium term activities about possible ways to address the problem. The pharmaceutical industry will be affected especially by changes with regard to supply shortages in Chapter 8 of the GMP Guide. Furthermore, the planned requirements for a proactive risk management of the marketing authorisation holder are addressed to the pharmaceutical industry.