Centralised manufacturing

Globalisation of manufacturing processes has led to a situation where active pharmaceutical ingredients may only be manufactured in one or two sites worldwide, and some of these are located in countries with uncertain political and regulatory systems.10 Therefore, disruption at an early point in the supply chain can quickly impact on all sources of that medicine.

Similarly, in order to increase production efficiency, many multinational drug companies now manufacture medicines in a very limited number of sites.2 Production schedules are often planned a long way in advance, which limits flexibility to respond when a manufacturing problem does arise. This lack of flexibility is accentuated by financial pressure to adopt policies such as ‘just in time’ inventory systems to reduce stockholding. Disruption in manufacturing may quickly impact on patient care if insufficient buffer stocks are available to meet demand until the problem is resolved.

In addition, a shortage of one medicine may increase demand for therapeutic alternatives. However, manufacturers may not be in a position to respond quickly enough to change in demand, which can lead to shortages of alternative products.2 In the USA this has led to shortages of general anaesthetics, chemotherapy agents and nutritional products over the last 5 years.

Regulatory issues

Manufacturing can also be interrupted by problems identified during quality assurance processes. Examples of quality failures that have occurred in manufacturing plants during the last few years include the contamination of drugs with mould, bacteria, glass, metal and other materials.2 In addition, a regulatory body (e.g. European Medicines Agency [EMA], Medicines and Healthcare products Regulatory Agency [MHRA]) has the authority to shut a manufacturing facility when it has identified concerns about adherence to Good Manufacturing Practice (GMP) or other issues (e.g. flawed clinical studies).15,16 Resolution of manufacturing quality issues may require prolonged factory closure that can trigger shortages across the range of medicines produced in that factory and this can have an impact on product availability internationally.

Product discontinuation

A manufacturer may decide to discontinue a medicine because of a lack of availability of the active pharmaceutical ingredient; ongoing manufacturing or quality assurance issues; the product is deemed to be no longer financially viable; or to transfer manufacturing capacity to a more commercially advantageous product. This has been a particular problem with some injectable medicines.17 A decision to discontinue production can also destabilise the market for other manufacturers who may only have a limited ability to meet an increase in demand.2

Other factors

There are occasions when natural disasters cause supply chain difficulties. In 2011, a tsunami in Japan was highlighted by the EMA as having had direct implications for the medicine supply chain.10 Shortages can also be inadvertently exacerbated by the activities of wholesalers and pharmacies. Knowledge of a potential supply problem may lead to stockpiling of a medicine to maintain supply continuity for patients. When this response is replicated across the supply chain, even a minor disruption can quickly become a major shortage. Pharmacies or dispensing doctors have little incentive to collaborate to ensure that supplies are reserved for the highest priority patients. NHS hospitals are encouraged to have a robust mechanism in place to work collaboratively to ensure that the limited stocks that are available are used in the most appropriate patients.18 However, there is no overarching structure in place to ensure that this happens in practice.

Trading of medicines

As with any commodity, medicines can be bought and sold for profit and there is evidence that some traders have actively created grey markets for medicines in short supply.19 This has involved stockpiling supplies of such medicines, thereby exacerbating the shortage and forcing an increase in the price that providers are willing to pay to get access to stocks.

For branded medicines, some operators in the supply chain have been accused of buying up supplies of some medicines at relatively low prices paid in the UK and exporting them to markets in Europe where they can generate a higher price—a practice known as parallel exporting.3 In 2013, it was estimated that 10–15% of the country's 12,500 community pharmacies were using a wholesale dealer's licence to export medicines to other EU states.20 Manufacturers and wholesalers introduced quotas for medicines most susceptible to export from the UK—typically they claim to restrict supply to between 115% and 130% of the level they would expect to be prescribed in the UK.3 However, when the amount of medicines exported into European markets exceeds this threshold then it can result in supply issues for patients based in the UK. In 2012, the APPG identified parallel exporting as the major cause of shortages of branded medicines in the UK and called for the government to examine the public health exemption in EU law with a view to protecting the interests of UK patients.

Although shortages of branded medicines are now less visible than they were 2 years ago, the problem has not gone away.4 Furthermore, the number of shortages involving generic medicines has increased and the APPG has identified a need to stabilise the supply chain for generic medicines.

European action

In 2001, the EU made legislative efforts to minimise shortages of medicines by approving Article 81 of Directive 2001/83 that makes manufacturers and distributors responsible for ensuring appropriate and continued availability of medicinal products for human use across EU states. These were enshrined in UK law in 2005.5,6

In 2012, the EMA published a document on medicine supply shortages caused by manufacturing and compliance problems with GMP.10 The EMA outlined an extensive number of short- and medium-term actions that needed to be taken to help minimise the impact of medicines shortages on patient care. These actions include steps to improve communication and to establish closer linking of regulatory, pharmacovigilance, GMP inspection and assessment of shortages. It also recommended that the EMA should maintain a public catalogue of current shortages of medicines. Although this has been available since 2013, at present it only provides details of five products that are in short supply.24

Associations representing European pharmaceutical industry working in conjunction with the International Society for Pharmaceutical Engineering and the Parenteral Drug Association have responded by issuing reports that promote a shift from reactive to proactive prevention of shortages at both the individual product and system levels, and advocate adoption of harmonised communication principles across the European Union.25,26

UK action

In 2007, the DH in conjunction with the Association of the British Pharmaceutical Industry (ABPI) and the British Generic Manufacturers Association (BGMA) issued best practice guidance on the notification and management of medicines shortages for branded medicines and generic medicines.5,6 These documents describe how the DH, the NHS Purchasing and Supply Agency (now known as the Commercial Medicines Unit) and the MHRA will work with companies to help prevent, mitigate and resolve shortages by:

• expediting regulatory procedures for critical products;

• managing existing stocks;

• identifying and liaising with other manufacturers to increase the production of the product or alternative medicines;

• expediting imports from abroad for individual patients; and

• liaising with the NHS (which may include investigation of whether there is any potential for the NHS to support manufacturing of the medicine during the period of the shortage).

The guidance states that manufacturers should consider notifying the DH as soon as they are aware that there is likely to be a shortage and that the communication should include the reason for the shortage, the expected duration of the shortage, and steps taken or planned to address the shortage.

A national supply chain group, which comprises representatives from all parts of the supply chain and includes the DH and the MHRA, have issued two documents that highlight the responsibilities of manufacturers, wholesalers, NHS Trusts, registered pharmacies and dispensing doctors and prescribers in maintaining the medicine supply chain.7,8 The documents remind wholesalers that they may only legally obtain medicines from licensed manufacturers or other licensed wholesaler dealers in the UK or other European Economic Area (EEA) member states (and not from NHS Trusts, registered pharmacies or dispensing doctors without wholesale licenses); NHS Trusts are advised that the DH regards the export of medicines for short-term financial gain as unacceptable because it threatens the supply chain and may harm patient care; registered pharmacies are reminded of the General Pharmaceutical Council's standards of conduct, ethics and performance; and dispensing doctors are advised to carefully consider their ethical responsibilities to their patients and the public. In addition, prescribers are reminded to advise patients to request their prescriptions in good time, especially those who are taking medicines with a significant clinical consequence to missing any doses.