The European Medicines Agency (EMA) recently released a proposal for how it can help mitigate potential and real drug shortages stemming from manufacturing problems, reported FiercePharmaManufacturing. The six-page proposal notes that “Recent unexpected disruptions to the manufacturing supply chain due to manufacturing/GMP (good manufacturing practices) compliance problems have resulted in acute and chronic shortages of important medicinal products in the European Union (EU) requiring changes to prescribing information, and initiation of patient allocation programs.”
The Reflection Paper is concerned with public health crises that arise due to unforeseen disruptions within the manufacturing process, caused by manufacturing/GMP compliance problems and affecting medicinal products for human use, independent of their route of authorisation, where a need for co-ordination of the assessment and risk reducing actions at a Community level has been identified. Supply disruptions not caused by manufacturing/GMP compliance problems fall outside the scope of this Reflection Paper.
EU legislation currently requires mandatory pre-notification by Marketing Authorisation Holders (MAHs) of disruption of supply in the case of permanent or temporary cessations and for manufacturers of medicines in the case of any defect that could lead to an abnormal restriction in supply.
It will be interesting to see if the Food and Drug Administration (FDA) and the EMA work together on this proposal, perhaps by entering into a Memorandum of Understanding (MoU).
The regulators’ dilemma
Over the past two to three years there have been a number of public health crises caused by acute and chronic supply shortages as a result of manufacturing/GMP compliance problems. Experience obtained has been analysed by EMA and a number of lessons learned have been identified.
In some cases defective medicines had to be left on the market to prevent shortages of life saving medicines as there is no available alternative and the risks linked to a possible exposure with the defective product are considered less than those linked to the unavailability of the product. In some cases of GMP non-compliance the ability of Regulators to take action against a manufacturing site was restricted in order to avoid product shortages. Very difficult risk-benefit judgements had to be made between poor quality processes or product, or no product at all.
The switching of patients to alternatives may also be hindered by factors other than supply per se and beyond the control of the Network. For example, the exclusive link between peritoneal dialysis solutions from a certain MAH, the patient and the connector meant the exclusion of competitor products so that patients were inextricably linked to products from that MAH and could not be switched without undergoing a surgical procedure to change the connector further increasing the risk to patients.
The impact of globalisation
The globalisation of manufacture has continued to increase in importance so that many medicinal products have extended manufacture and supply chains, which increases the risk of supply disruption including new vulnerabilities. Many sources of active substances for life-saving medicines, e.g. antibiotics, are now wholly located outside the EU, some located in countries that have uncertain political and regulatory systems and which may be prone to natural disaster. The 2011 tsunami in Japan illustrated how natural disasters can impact the supply chain of pharmaceuticals.
Manufacturing is in consolidation, leading to one or very few manufacturing sites supplying at a global level so failure at these sites leads to global supply shortages. There may be no redundancy or fail-safe capacity built into the global supply chain. EMA has seen the case of a single contract manufacturer with particular capabilities may be depended upon for several key products. With the arm’s length involvement of the MAH, contract manufacturing can be prone to marginal GMP compliance and consequent potential quality problems leading to supply problems.
The industry’s approach
EMA noted that “industry’s risk management tends to be very reactive rather than proactive.” As a result, they called for “Sustained pressure” “to bring about a change in a manufacturer’s approach to quality risk management and supply chain security.”
The current regulatory framework
Unprecedented import of large quantities of unlicensed versions of medicines by Member States to prevent a shortage had to be supported by rapid and sustained pressure on MAHs to introduce variations to regularise the situation. The need for urgent variations or better still pre-planned inclusion of failsafe manufacturing site capacity in marketing authorisations needs to be considered.
Even if there are several potential suppliers at a global level, only one or two may have been included in a given marketing authorisation to the EU. It, therefore, can be difficult to add these quickly in a time of crisis – all the more so in the case of biological medicinal products where there are greater regulatory hurdles as a result of concerns about the equivalence of product from different manufacturing sites.
Collaboration and cooperation within the Network
Actions at national level are taken to address local supply shortages without information being shared within the Network. Proactive risk management and clear and transparent communication by the MAH are essential measures to maintain trust between all stakeholders. International collaboration amongst Regulatory Authorities at a global level is vital to ensure better supervision of these globalised supply chains. There may be a need to mobilise resources from outside the Network in order to assess problems and provide solutions.
The interfaces between medicinal products and other products such as medical devices can be important and there is a need for further discussion about how best these interfaces can be managed. The existence of monopolies in supply of medicines restricts options for risk mitigation. There is a need for further discussion in order to address this issue.
While the causes of shortages are varied and complex, the challenge remains to effectively co-ordinate an assessment, to develop risk minimisation measures to alleviate the impact on patients, and to communicate within the Network, with international partners and with healthcare professionals, patients and the general public. On occasions, EMA is being asked to coordinate the follow-up to an emerging event in the absence of an appropriate legal framework.
In some cases, the need for rapid implementation of risk minimisation measures is paramount. Short and medium term measures will be undertaken to enhance the current approach. In addition, there are some aspects which will require discussion with bodies outside the Network, e.g. in the area of medical devices.
Short term actions
Based on the findings and analysis noted above, EMA proposed ten (10) short term actions the agency will be taking to combat drug shortages
1. Establish an internal catalogue of Centrally Authorised Products (CAPs) and non-CAPs requiring coordination at EU level (e.g. referrals) that have experienced product shortages to facilitate future analysis of trends and communication on shortages.
2. Maintain a public catalogue of current shortages of CAPs and medicinal products where an EU co-ordination of assessment has been undertaken with links to all relevant Opinions, communications, etc. MAHs will be invited to report shortages caused by manufacturing/GMP compliance problems on a voluntary basis.
3. Develop a common understanding of the concept of “essential” medicine for subsequent application at national level and develop a decision tree to assist National Competent Authorities (NCAs) in deciding what shortages should be dealt with at EU level (also providing clarification on the most appropriate regulatory framework to be applied).
4. Provide clarification on how to best provide national input into the development of EU advice/ communication and how such EU advice/communication and national advice/communication can be complementary.
5. Establish and publish a Standard Operating Procedure (SOP) for handling reports of shortages in supply of medicinal products due to quality defects and manufacturing problems and where an EU co-ordination of assessment is necessary. The procedure 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.
6. Revise through the GMDP IWG the Community Procedure “Procedure for Handling Rapid Alerts Arising From Quality Defects” to include transmission of alerts in the event of a shortage in supply of medicinal products due to quality defects and manufacturing problems, whilst ensuring that this will not result in non-urgent information being transmitted. Revise through the GMDP IWG Chapter 8 of the GMP Guide “Complaints and Product Recall” to clarify reporting requirements relating to restriction of supply in case this relates to a quality defect and a recall of batches.
7. Explore if “crisis” situations arising from shortages in 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.
8. Develop international co-operation in this area so that there is a sharing of information on specific shortages (with or without impact on other territories) and sharing of information on best practices on risk management and prevention strategies.
9. Raise the awareness of the impact of medicinal product shortages and stimulate industry reaction and improvements (whereby industry should propose solutions) in business continuity planning guaranteeing better access for patients to essential medicines by organising a public workshop between Regulatory Authorities, industry, patient and healthcare representatives to outline the problems encountered.
10. Undertake a survey of past initiatives taken by NCAs to manage/prevent shortages in order to develop an inventory of possible tools available to NCAs and to share best practice.
Medium term actions
- Facilitate risk benefit evaluation where risk of shortage has to be balanced with potential risk due to presence of a product defect.
- Promote better and proactive risk management by MAHs by requiring submission by all MAHs of a risk-analysis of their manufacturing process identifying any weaknesses and, depending on the severity, provide a contingency plan and proposals to strengthen the identified weaknesses.
- Investigate processes that could be used to measure the impact of medicinal product shortage in patients experiencing its consequences, e.g. lowered dose or switch to an alternative product.