OR WAIT null SECS
Sean Milmo is a freelance writer based in Essex, UK.
Resolving the problem will require more communication between the industry and regulatory bodies.
Incidents of drug shortages in Europe have been increasing over the past few years with few signs of an overall reduction in scarcities across the region. Most of the initiatives to deal with the issue at the production stage are being taken by the manufacturers themselves. The European Medicines Agency (EMA) and the variety of national competent authorities (NCAs), such as licensing bodies and government ministries responsible for drugs supplies at the national level, seem content to leave it to manufacturers to put forward proposals for dealing with disruption of output at their production plants.
EMA believes that the industry’s risk management tends to “to be very reactive rather than proactive.” An agency official toldPharmaceutical Technology, “Sustained pressure is needed to bring about a change in a manufacturer’s approach to quality risk management and supply chain security.” The agency’s policy has been to encourage “the pharmaceutical industry to develop its own solutions to address the prevention of drug shortages caused by manufacturing and quality issues,” the official added.
Nevertheless, medicine manufacturers want more action on the issue from the European Union and the governments of the 28 member states. They reckon the problem has to be resolved through a broader approach embracing manufacturers, distributors, healthcare professionals, and even the patients themselves.
Recommendations from industry groups
A number of industry groups have been drawing up or are close to finalizing proposals for dealing with shortages stemming from manufacturing disruptions. Patient associations and management consultancies have also been making recommendations.
The Drug Shortages Prevention Plan of the International Society for Pharmaceutical Engineering (ISPE) was discussed at a meeting in early October 2014, attended by EMA representatives, national regulatory authorities, and representatives of the industry and ISPE itself, even before it was officially published. Its recommendations focus on the need for manufacturers to improve their quality systems, use metrics to identify and mitigate risks, foster a corporate quality culture, and improve communication with the authorities on potential shortages.
“We believe that the industry needs to adopt the proposals in the ISPE plan,” John Berridge, ISPE advisor, told Pharmaceutical Technology. “We would like EMA and NCAs to help us make manufacturers aware of the proposals by, for example, putting details of them on their websites and by joining us in training programmes.”
The Parenteral Drug Association (PDA) is planning to publish a technical report on the prevention and management of drug shortages. Among its suggestions will be the adoption of concepts on the control of drug shortage risks based on the criticality of the product and an overall product risk evaluation.
The European Federation of Pharmaceutical Industries Associations (EPIA), the European Generic Medicines Associations (EGA) along with two other pharmaceutical associations for wholesalers and biopharmaceuticals producers have been working on an improved process for communications on shortages. This process would relate to the way manufacturers inform regulatory agencies of “meaningful interruptions of supply” (1).
EURORDIS, a rare disease patients group, together with other patients organizations and professional associations, including those representing community and hospital pharmacists, have drawn up a set of proposals, in the form of a Common Position, on medicines shortages (2). These proposals include a requirement on drug approval applicants to provide supply shortage risk assessment plans to regulatory agencies before gaining marketing authorization. Manufacturer and/or marketing authorization holders (MAH) would have to inform the regulatory agencies as soon as a shortage becomes possible. If a shortage occurs, a calendar of production until the expected end of the shortage would have to be provided.
An unclear definition of drug shortages
Although there is broad agreement in the pharmaceutical sector that the problem of shortages has been worsening in recent years, groups differ in their judgement of the prevalence and severity of the problem, depending on their position in the supply chain. The European Association of Hospital Pharmacists (EAHP) told Pharmaceutical Technology that 87% of 600 hospital pharmacists it surveyed considered it to be a problem, particularly with oncology drugs and antibiotics. There is, however, a lack of consistent and in-depth data on shortages mainly because it is collected by national agencies, if at all, and there is no Europe agreement on the definition of a “shortage.” Some NCAs have turned down a request from EMA for the drawing-up of catalogues of drug shortages in their countries because what was meant by the term was unclear, especially since the term can have different connotations in different languages.
“We cannot agree on a definition of shortages,” says Marten Forrest, spokesperson for the Swedish Medical Products Agency (MPA), explaining why his agency had not created a shortages list. “For example, there is the question of what sort of supply difficulties can be referred to as a ‘shortage’ and whether these difficulties are global, European, or national,” he continues. “It is difficult to draw up a list of medicines shortages without a definition.”
This lack of clarity about what are shortages can lead to gaps in the reporting of them or of manufacturing disruptions that could cause shortages. “Not all manufacturers are notifying us about problems they are having which are or could cause shortages,” said Forrest. “One of the important signals of existing shortages is phone calls or email messages from pharmacists asking for more information about a shortage of a particular medicine we don’t know about.”
Underlying reasons and root causes
The industry now wants much more research into the causes of shortages, particularly into incidents linking them with manufacturing difficulties. “We don’t know what are the amount of shortages arising from manufacturing problems,” says Berridge. Some governments see the influence of globalization on patterns of pharmaceutical manufacturing as being a major cause of shortages. “The globalization of the pharmaceutical industry means that medicines are often manufactured in just a few sites worldwide,” explains a spokesman for the UK Department of Health, which is responsible for drug supplies in the country. “Production schedules have to be planned months in advance and this along with the move to ‘just-in-time’ manufacture to reduce the cost of stockholdings means that there is little flexibility in the system when problems do arise,” she adds.
In a recent report on medicines shortages in Europe, birgli AG, a Swiss-based management consultancy linked government-initiated price-curbs on medicines and legislative support for parallel trading to reductions in manufacturing sites and the use of ‘just-in-time’ supply chains.
“Before shortages can be reduced, the underlying reasons and root causes of shortages should be well understood,” explained Julie Marechal-Jamil, EGA’s senior manager quality and regulatory affairs, in an interview with Pharmaceutical Technology. For quality and manufacturing-related issues to be tackled properly in relation to shortages, a combination of measures had to be taken, Marechal-Jamil added. In addition to the initiation of shortage-prevention plans at the corporate level, she said there had to be a harmonized definition of drug shortage, a harmonized shortages reporting process with identical trigger points, triaging procedures and timelines, as well as an improved flow of information along the supply chains.
One key issue yet to be resolved and upon which there are divergent views even among the regulators is the relation between GMP rules and supply disruptions caused by weaknesses in quality control systems, which could lead ultimately to medicine shortages. “Quality defects are usually caused by some kind of GMP failure but not always,” says the EMA official.
However, a different view is taken by some national agencies that believe they can deal with production deficiencies causing supply disruptions without reference to GMP rules. “The obligation to ensure the continuous supply of medicines so that the needs of patients in the UK are met is a condition of a manufacturer’s licence [so] this is not a GMP matter,” says a spokesperson for the Medicines and Healthcare products Regulatory Agency (MHRA), the country’s licensing authority, which deals with possible manufacturing deficiencies related to shortages. “MHRA routinely inspects manufacturers for compliance with the conditions of their licence and with EU guidance on GMP,” he continues. “To date there has been no occasion where MHRA has needed to take action against a manufacturer in relation to this obligation (in respect of its licence conditions).”
Nonetheless, ISPE reckons there is a close enough connection between GMP standards and those underpinning systems preventing supply disruption and procedures for reporting potential shortages to the authorities. “Since the EU’s revised GMP guidance will say that manufacturers must notify competent authorities about impending interruptions in supplies due to quality issues, GMP inspectors would seem to be in a position to ask for details about what steps are being taken in manufacturing plants to avoid disruptions,” says Berridge “[They will also be able to ask] for details of the company’s procedure for making notifications of disruptions to the authorities.” The issue of medicines shortages in Europe will clearly require a lot of dialogue between the industry and regulators before significant progress is made in resolving it. More communication between the industry regulators is required to resolve the problem.
1. Birgitte Holst, Novo Nordisk A/S, “Communications Principles in cases of Q and Manufacturing driven supply disruptions,” presentation at the PDA Drug Shortage Workshop (Washington DC, September 2014).
2. EURORDIS and six other organisations, “Common position between patients’, consumers’ and healthcare professionals’ organizations involved in the activities of the European Medicines Agency on supply shortage of medicines,” accessed Oct. 15, 2014.
About the Author
Sean Milmo is a freelance writer based in Essex, UK, firstname.lastname@example.org.