Sean Milmo is a freelance writer based in Essex, UK.

Sean Milmo

	The European Union has been committed for several years to drawing up a strategy on allaying public concerns about contamination of the environment by pharmaceuticals. The strategy on pharmaceuticals in the environment (PIE) would deal in particular with worries among Europeans as well as health professionals and non-governmental organizations (NGOs) about environmental causes of antimicrobial resistance, including untreated waste from plants making antibiotics and their APIs. The objective was that the strategy, due to be published this year by the European Commission (EC), the EU’s Brussels-based executive, would include both legislative and non-regulatory proposals, as laid down in a 2013 EU directive (1) on control of water pollution by pharmaceuticals. The directive stipulates that the EC should propose measures with “a view to reducing discharges, emissions, and losses of [polluting pharmaceutical] substances into the aquatic environment.”

	The EC has decided to postpone making proposals for legislative measures, including a decision on whether to go ahead with the controversial option, strongly opposed by the industry, of laying down standards for waste treatment in pharmaceutical plants by extending good manufacturing practice (GMP) to cover environmental controls. After a series of studies by outside consultancies, workshops, and consultations with the public and stakeholders, the last of which was completed in February 2018, the commission was expected at last to fulfil its commitment by publishing a full strategy, including coverage of regulations, and then pressing ahead with its implementation.

	“When we met commission officials in early July [2018], it was clear that they were delaying the publication of any proposals on regulations, including any planned legislation on applying GMP to waste management in pharmaceutical plants,” Adela Maghear, pharmaceuticals officer at Health Care Without Harm (HCWH), told Pharmaceutical Technology Europe. “This could mean even more delays in the introduction of legislation on PIE,” commented Maghear, who was in a delegation of NGO representatives visiting the EC.

	The splitting of the PIE strategy into two stages, the first without regulations and the second with, will result in the existing EC passing to a new Commission the responsibility of proposing legislation. The new executive, with commissioners appointed by the governments of the EU member states, is due to take over in 2019. The slow pace at which the EC is adopting a PIE strategy is likely to work in favour of the pharmaceutical industry, which has been pushing forward with its own voluntary solutions to environmental problems with pharmaceuticals, especially those related to antimicrobial resistance. It gives the industry the opportunity to demonstrate that the voluntary approach is a viable alternative to regulation.

	An Antimicrobial Resistance (AMR) Industry Alliance, a global life-sciences coalition of more than 100 biotech, diagnostics, generic-drug, and research-based biopharmaceutical companies, has been combating AMR through work on the environment, as well as research, easing access to appropriate medicines and appropriate use of pharmaceuticals. In Europe, the three main pharmaceutical associations-European Federation of Pharmaceutical Industries and Associations (EFPIA), Medicines for Europe, and the Association of the European Self-Medication Industry (AESGP)-have set up the Inter-Association Task Force on Pharmaceuticals in the Environment. They have also cofounded the Eco-Pharmaco-Stewardship (EPS), which deals with the entire lifecycles of medicines, taking into account the responsibilities of public services, the pharmaceutical industry itself, environmental experts, health professionals, and patients.

	One priority behind EPS activities is the compilation of best industry practices in the management of pharmaceutical manufacturing effluents so that drug producers can minimize the risks to the environment and the spread of AMR. The assumption is that because the production processes for many medicinal producers are broadly similar to each other, potentially dangerous discharges into the environment should be equally controllable, as long as the knowledge about how to limit emissions is uniformly available.

	Thirteen members of the AMR Industry Alliance including leading pharmaceutical multinationals such as AstraZeneca, GlaxoSmithKline, Johnson & Johnson, Merck & Co, Pfizer, and Novartis have signed up to a roadmap committing themselves to a number of aims for clean antibiotics production. These aims include establishing a “common framework” for managing antibiotic manufacturing emissions based on “science-driven, risk-based targets for discharge concentrations for antibiotics.”

	The work being done by EPS and AMR Alliance will help demonstrate that international good environmental practice standards can be created, which make the use of GMP in the environmental area unnecessary. “We are strongly opposed to the use of GMP in environmental matters because we believe it should remain entirely focused on product quality,” Bengt Mattson, co-chair of the Inter-Association Task Force on PIE, told 

. “The environmental management standard would be entirely different,” he added. “It would be an alternative standard that could ultimately become the basis for a uniform global regulatory initiative.”

Harmonization of legal emission standards

	By the time the EC draws up proposals for tighter regulatory controls on emissions from pharmaceutical plants, it is likely to need the data on best practices and concentration thresholds collected by the industry. Because the vast majority of APIs in antibiotics marketed in Europe are produced in India and China, the EU will require harmonized legal emissions standards that can be applied to imported pharmaceuticals in the same way that uniform GMP standards are currently applied to them. 

	What the EU has achieved by raising product quality through GMP requirements for API imports, India is now looking to the EU to do the same with environment waste controls in Indian pharmaceutical plants. Indian NGOs, health professional groups, and community rights activists sent a joint letter in early July 2018 (2) to the EC claiming that EU action was needed to deal with “the grave environmental and human health crisis” in India linked to the lack of regulatory controls on effluent from the country’s API plants. This issue was causing “rampant” pollution around the country’s pharmaceutical manufacturing hubs such as Hyderabad, which has led to a “huge” AMR problem in India, according to the letter (2). It argued that the only way to tackle the crisis was by the EU extending GMP to include environmental criteria.

	Partly as a result of the growing evidence from academic studies connecting AMR to manufacturing waste and the industry’s own collective initiatives on the issue, individual pharmaceutical companies have established their own “clean” or “green” supply chains extending, if necessary, from starting materials and API production to distribution. DSM Sinochem Pharmaceuticals (DSP), a joint Dutch-Chinese venture, has introduced in its plants in China, India, Mexico, and Spain a green fermentative and enzymatic process for antibiotic intermediates (3). In addition to eliminating solvents and achieving low-carbon footprints, the company is also committed to minimizing the release of antimicrobial active ingredients into the environment.

	Mylan, one of the world’s largest producers of antibacterial APIs, has switched its plants in Hyderabad to a system of zero-liquid-discharge (ZLD) so that antimicrobial compounds can be kept out of the environment. The technology is being extended to Mylan’s other plants in India.

	These pharmaceutical multinationals with audited green APIs supply chains are not only gaining business from international producers of finished medicines. They have also attracted the attention of a number of Scandinavian and other European governments that operate green procurement policies for drugs, particularly antibiotics. However, government buyers of antibiotics and other medicines in bulk as well as pharmaceutical companies purchasing APIs are using different criteria to judge whether the products are adequately green. There is, therefore, a pressing need for harmonization. But this uniformity is unlikely to be achieved until more evidence is available on the biological and chemical mechanisms that create AMR within pharmaceutical plant effluent.

	Signatories of the AMR Alliance Roadmap do not expect to be able to determine resistance-based limits on discharge volumes until 2020 at the earliest. These limits will then be used to devise good practice methods. Before it even considers PIE regulations, particularly in relation to AMR, the EU is likely to fund research projects to fill knowledge gaps on the hazards of AMR in the environment, including in manufacturing effluent.

	The pharmaceutical industry wants to be able to influence the direction of this research, as well as being closely involved in the deliberations of the new Commission on possible regulations. “There could be a lot of non-legislative initiatives following the [current] Commission’s publication of its strategy document and research will be a big part of these,” noted Mattson. “We can help to define what research is needed. We will also have a lot of information to share with the new Commission-not just on research issues but particularly when it comes to discussing possible regulations.”

	Once regulations are in place, the next stage will be efforts to extend the principles behind them to outside Europe so that they fit into a harmonized global approach to problems with pharmaceutical plant waste. 

	“We’ve still got a long way to go,” Mattson said. “The length of time it has taken for the EU to draw up a PIE strategy shows the difficulties of working out solutions. There will have to be a lot of discussion before a common framework can be established.”

Priority Substances in the Field of Water Pollution

(Brussels, 12 Aug. 2013).
	2. Gamana, Hyderabad, Community Environmental Monitoring, Chennai, and Other Groups, “Letter to Jean Claude Juncker, president of European Commision” (Hyderabad, Chennai, 2 July 2018).
	3. AMR Industry Alliance, 


	Vol. 30, No. 7
	July 2018
	Pages: 1–2

	When referring to this article, please cite it as S. Milmo, “Pharmaceuticals in the Environment,” 

Articles

Publication of proposed new regulations for pharmaceuticals in the environment has been postponed due to challenges in working out solutions and establishing a common framework.

Pharmaceuticals in the Environment

	The drive by the European Union, the United States, and other leading developed regions and countries to harmonize standards of good manufacturing practice (GMP) inspections to avoid duplications and gain other efficiencies seems already to be paying dividends. There are, however, at the same time, signs that the rate of progress may soon slow down because of a limited number of agencies capable of participating in mutual recognition schemes.

	The European Medicines Agency (EMA), the EU organization responsible for the centralized authorization of medicines and a major driving force behind international collaboration in GMP, has also warned it is having to slow down its activities in this area because of its need to concentrate resources on relocating its headquarters from London to Amsterdam due to Brexit. The agency has in fact reported a steep 43% decline (1) in GMP inspections in 2017, carried out on its behalf by inspectors from EU national agencies. Furthermore, it is forecasting an even sharper decrease this year to 100 inspections, equivalent to an annual drop of 68% (1). 

	In its latest annual report (2) published in May 2018, EMA linked the decrease in inspections mainly to a mutual recognition agreement (MRA) on GMP inspections between the US and the EU’s 28 member states, which came into operation in 2017 and is due to be fully implemented in 2019. It also benefits from MRAs on inspections between the EU and seven other non-EU countries and their agencies, the latest of which, in addition to the US and its Food and Drug Administration, includes Canada and its licensing authority Health Canada.

	The relative success of the current international collaboration projects has also been highlighted in a report (3), published in April 2018, on the activities in 2011–2016 of the International Active Pharmaceutical Ingredients Inspection Programme. This 10-year-old scheme, in which 12 national and international agencies are participating, aims to make more efficient use of inspection resources through greater international co-operation and information sharing. 

	The programme’s members, the majority of them European, include EMA; the European Directorate for Quality of Medicines (EDQM), run by the Council of Europe, a body separate from the EU; the World Health Organization (WHO); and a number of national agencies including FDA and those of Australia, Japan, Canada, as well as the EU national licensing authorities in France, Italy, and the United Kingdom. Over the past six years, the project has focused mainly on sharing information on inspection plans and outcomes. On specific sites of common or high interest, inspection reports have been exchanged or joint inspections carried out. 

	The report (3) on the programme’s activities in 2011–2016 was based on a review of inspections of 944 API sites in third countries by the participants. The vast majority of the sites were in India or China. Most of the objectives behind the programme were being achieved during the period, according to the report’s conclusions. There was an increase in the number of API sites inspected by the participating authorities. As a result of this rise, “more information was shared by participating authorities and, therefore, the programme brought more transparency and efficiency for the planning and realisation of GMP inspections,” the report said (3).

	The number of duplicated inspections went down, although by exactly how much has been difficult to estimate because of factors such as separate inspections by authorities after a site has been declared non-compliant, according to the report. EDQM, for example, called off 36 planned inspections of sites in 2016 after they were inspected by other authorities in the programme (3).

	Overall, 28% of the sites in the review that had been found to be non-compliant were inspected an average of 3.6 times. This figure contrasted with 72% of sites with a history of compliance, which were inspected 2.7 times. The number of sites of common interest has shown the potential for shared information and tools such as joint inspections. At least two participating European authorities, including EDQM, had 350 sites of common interest with FDA, 136 with the Australian agency Therapeutics Goods Administration (TGA), and 41 with WHO. 

	The report (3) conceded that some aims were not achieved, such as the implementation of recommendations from a 2008–2010 pilot scheme. These aims included a shared database with a comprehensive list of API manufacturers and a common policy framework on the re-inspection of sites in third countries.

	“These ambitious undertakings would likely require many years of work beyond what has occurred to date,” the report warned (3). If the programme is to achieve even bigger objectives, it will have to increase not only the number of participants but also the involvement of existing members. The report said that gaining a more active participation among members of the group remained a challenge.

	The relatively limited participation by some members has demonstrated how much collaborative schemes in areas such as GMP inspections relied on the work of well-established and resourced agencies. Ireland’s Health Products Regulatory Agency (HPRA) has had to limit its involvement because of other responsibilities. “The HPRA is a participant of the programme, but we have not been in a position to take part in it in an inspection capacity,” an agency spokesperson said.

	When the programme was set up in 2008, nine agencies and organizations-EMA, EDQM, and the national agencies of the US, Australia, France, Italy, Ireland, UK, and Germany-took part in a pilot project to prove the scheme’s long-term viability.

	In the years after the pilot trial, comparatively few new participants have been recruited, although one of the new members was WHO, a large player in global GMP inspections. The inspections covered in the 2011–2016 report were also conducted by nine authorities and organizations, but compared to the pilot, excluded the agencies from Germany and Ireland and included Denmark’s agency, a new member, and WHO. Japan’s Pharmaceuticals and Medical Devices Agency (PDMA), Health Canada, and WHO became full members of the programme in 2016 but they were too late to participate in the 2011–2016 review. 

	Even for European organizations, it has been a tough task meeting the criteria laid down for membership. ZLG, Germany’s co-ordinator of the GMP inspections by the country’s Laender states, withdrew from the programme altogether after the end of the pilot trail because of legal issues over the confidentiality of inspection information. In fact, the matter of confidentiality still remains a difficulty with Germany’s participation in international GMP collaboration projects. It has become a problem with its participation in the EU–FDA mutual recognition agreement. 

	“Discussions between Germany and FDA regarding the signing of a confidentiality commitment for the German Laender in the context of the MRA are ongoing,” a ZLG spokesperson told 

Among recommendations made by the report (3) were improvements to the generation and sharing of information through the establishment of a central repository with write access or updating capabilities. This is a role that has been taken on by EudraGMDP, the EU database of information on GMP inspections and those for good distribution practice. The database is run by EMA, which further underlines the important position assumed by the agency in international GMP collaboration schemes.

	However, work by EMA on international collaboration schemes will be disrupted over the next few years because of pressure on its resources from the relocation of its headquarters from London to Amsterdam in time for the UK’s departure from the EU at the end of March 2019. The agency has had to set itself priorities so that some activities such as international collaboration will be given less importance. Some will be reduced or suspended altogether. “While EMA will continue to be an active participant in the programme, its activities will be prioritized as per the agency’s business continuity plan [on relocation],” an EMA spokesperson told 

	As many as 20% of the agency’s staff are likely to leave the organization because of the move to Amsterdam (1). In addition, the agency will have to operate in temporary offices in the city until a newly built headquarters is completed.

	One casualty has been a scheme for the training of existing or potential GMP inspectors in third countries. The project is now being restricting to inspectors in India and China, which accounts for 85% of API inspections by EU inspectorates or their non-EU partners. But even the training support for inspectors in these countries is being reduced this year and in 2019. Other schemes for the training of not only inspectors but also assessors and international regulators in third countries are also being reduced or suspended. 

	A three-year project, due to end in 2020, to develop guidance on data integrity in collaboration with the Geneva-based Pharmaceutical Inspection Co-operation Scheme, a Geneva-based organization with 52 participating inspectorates, has been suspended (1), even though a draft guidance had already been published.

	Data integrity remains a major importance because of the key part it plays in GMP standards. It also fits in with the agency’s top priority-the maintenance of uninterrupted supplies of medicines and the assurance that medicines will continue to be authorized and supervised at the same high quality level as previously. Nonetheless, the collaborative development of a consistent approach to data integrity may have to wait, like other matters requiring international co-operation, until the EMA is firmly settled in its new headquarters.

	1. EMA, Multi-Annual Work Programme 2018–2020 (London, 3 March 2018).
	2. EMA, Annual Report of European Medicines Agency 2017 (London, 2 May 2018).
	3. EMA and 11 other organizations, Report on International Active Pharmaceutical Ingredients Inspection Programme (March 2018). 


	Vol. 30, No. 7
	July 2018
	Pages: 8–9

	When referring to this article, please cite it as S. Milmo, “Collaboration on GMP Inspections Has Been Successful but Challenges Exist,” 

	Sean Milmo is a freelance writer based in Essex, United Kingdom, seanmilmo@btconnect.com. 

EMA, the leading driver behind GMP inspection collaboration schemes, will be cutting back its involvement because of the need to concentrate on its relocation to Amsterdam.

Collaboration on GMP Inspections Has Been Successful but Challenges Exist

	The European pharmaceutical sector is bracing itself for the introduction early next year of a European Union scheme for the serialization or identification of individual packs of medicine. There are increasing worries that pharmaceutical manufacturers, particularly small- and medium-sized producers (SMEs), will miss the deadline on 9 Feb. 2019 for compliance with the serialization regulation. More significantly, organizations responsible for running the project at the national level may not have the IT infrastructure in place for doing their job.

	Medicine manufacturers are working hard to modernize packaging lines in their production plants with new printing presses, real-time monitoring systems, and software necessary for the serialization of drug packs and for the connecting of labelling information with data repositories at national and European hubs. They may, however, find on 9 Feb. 2019 that the national repositories and their connections with pharmaceutical production plants are not fully operational.

	“It is quite likely that the whole serialization system across Europe will not be ready to meet the deadline in February,” said Bart Vansteenkiste, global life-sciences business development manager at UK-based Domino Printing, a serialization specialist in printing and coding. “The European hub is ready, and individual countries such as Germany have their repositories operating with countries such as the United Kingdom, Netherlands, and Scandinavian states not far behind,” he told 

“But a large proportion of countries look at the moment unlikely to meet the deadline. There is still a lot of work to be done.”

	The Belgium-based European Medicines Verification Organization (EMVO) at the centre of the scheme’s European hub has been uploading the serialization data of pharmaceutical manufacturers for distribution around those national verification organizations (NMVOs) ready to receive it. The pharmaceutical industry is hoping that with the EMVO being so well prepared, the worst-case scenario of countries not having their IT infrastructure operating on time will be avoided.

	“The countries, which at the moment are behind schedule, will be doing whatever they can to be ready by the deadline,” said Johan Verhaeghe, national policy liaison manager at Medicines for Europe, the Brussels-based trade association for generics and biosimilars producers. “They don’t have any other option but to get things done on time,” he explained to 

“The 9 February deadline is written in the text of the serialization regulation, which has been transferred into the national laws of each of the EU’s 28 member states. If they don’t keep to the deadline, they will be breaching their own national laws.”

	The serialization scheme is being introduced under the EU’s Falsified Medicines Directive (FMD) of 2011 to combat counterfeiting of drugs through a regulation (1), issued in 2016, which lays down specific safety features for medicines packaging. The main requirement of the regulation is that the packaging should carry a unique identifier comprising a product code, a serial number based on a randomized algorithm, a reimbursement number required by countries in which the medicine is marketed, a batch number, and expiry date.

	The unique identifier has to be encoded in a two-dimensional barcode within a machine-readable data matrix that can be accurately decoded using common scanning equipment before the medicine is dispensed to the patient. The printing of the two-dimensional barcode has to be of sufficient quality to ensure accurate readability of the data matrix for at least one year after the expiry data of the pack or five years after the pack has been released for sale. In additional to the unique identifier, the pack’s safety features have to include an anti-tampering device, although the nature and quality of the device is not stipulated by the regulation. An important requirement laid down in the regulation is that the repositories system for the storing and verification of serialization data are to be set up by the manufacturers and marketing authorization holders (MAHs) with each repository being established and run by non-profit legal entities. 

	In addition to the EU’s 28 member states, the regulation will also be applied in Norway, Iceland, and Liechtenstein-which are non-EU states. Switzerland, another non-EU country, is introducing it as a voluntary measure. The UK plans to implement the regulation even though it will be leaving the EU at the end of March 2019.

	Among the drug manufacturers in Europe, research-oriented multinationals seem to be in the most advanced state of readiness for the regulation. “[Our] members are on schedule to deliver the coding and serialization on their medicines packs in line with the regulation by the deadline of 9 Feb. 2019,” says a spokesperson for the European Federation of Pharmaceutical Industries and Associations (EFPIA), a high proportion of whose members are large R&D-based international producers. Such proactivity is not unexpected because serialization schemes are being introduced across the world so drug companies with extensive international operations would tend to be at the forefront of the switch to individual pack identification. 

	For many SMEs, however, compliance with the FMD regulation is turning out to be a much bigger challenge in terms of administrative and managerial resources and above all costs. The total costs of adopting all of the 10,000 pharmaceutical production and packaging lines serving the EU market is estimated to be €5 billion (US$6 billion), according to figures from Medicines for Europe, Verheaghe pointed out at a Paris conference on 5 Apr. 2018, organized by Adents International, a serialization system specialist (2). Installing a new packaging line could cost up to €500,000 (US$600,000) (2). The cost of setting up the European Medicines Verification System (EMVS), comprising the EMVO and NMVOs and their infrastructures, will be €90 million (US$108 million), while its annual running costs will be another €90 million, said Verhaeghe (2). 

	Suppliers of serialization equipment and software are warning pharmaceutical manufacturers that time will soon be running out for the installation or re-equipping of packaging lines. “It can take at least six months to install and integrate a serialization system,” says Vansteenkiste. “As a supplier of the printing and coding facilities, we have to work with partners such as cameras and software suppliers. If there is a rush of companies wanting serialization systems, the suppliers will not have enough capacity to cope. They are already fully booked.”

	An indication of the level of preparation among manufacturers has been figures from EMVO (3) showing the number of pharmaceutical companies that have uploaded data with the organization on all the licensed products of their MAHs in Europe. The data are provided for security reasons by a special corporate legal entity called an on-boarding partner (OBP), which will be responsible for all its company’s information being handed to the EMVO including that from contract manufacturing organizations (CMOs) and third-party logistic providers (3PLs).

	By March 2018, approximately a quarter of 2000 pharmaceutical companies covered by the regulation had become OBPs and had uploaded details of their MAH products to the EMVO. “The on-boarding figures are still far behind schedule, while the deadline is getting closer,” EMVO admitted when announcing the OBP figures. The OBP data would be passed on to NMVOs with whom MAHs would have fee-paying agreements to handle the verification of their individual medicine packs from the time they are released to the market through to the dispensing of the drug to the patient.

	Some states are lagging behind in the complicated process of setting up national verification organizations with data repositories connected with the serialization operations of pharmaceutical plants, as well as with wholesalers, pharmacies, and other dispensing points. 

	Although the NMVOs are being established and operated by trade associations and other groups representing manufacturers, the NCAs are also deeply involved in their activities. They have the job of ensuring the NMVOs comply with the FMD regulation, which even gives them the right to sit on the organizations’ management boards.

	The EMVO has also been helping with the formation of national verification organizations through the introduction of a standard verification scheme. As a result, manufacturers and other stakeholders do not have to start from scratch when building a national system, according to Verhaeghe. The European verification organization also announced on 26 Apr. 2018 that the Czech NMVO had become the eight national organization to link up with the European hub, with another 10 that are due to do the same by the end of July 2018 (4). 

	Nonetheless, the weak point in the serialization network emerging across Europe is the connectivity between the MAHs with national verification systems. The integration or “on-boarding” of the MAHs is “far behind schedule” with 50% of countries appearing to be “too late for the February 2019 deadline,” Verheaghe said (2).

	NCAs can help make serialization easier by limiting their right to require specific safety features, such as reimbursement data on barcodes, and showing a willingness to accept items like multi-market coding. “It helps generic manufacturers, for example, to have few specific national requirements for the same product,” Verhaeghe explained to 

“If a product has a different status in each country, then that could require different packaging lines. Many countries now understand the need for a smooth transition to serialization with as few national specifics as possible.”

	Hopefully, by next February’s deadline, all the verification systems and their data repositories should be operating. The pressure for compliance will be intense. The vast majority of drug producers should also have their serialization processes working effectively. But for a few, particularly generic-drug manufacturers, the expense in terms of money and human resources will have been so high that they will have had to withdraw low-margin products from the market.

	1. European Commission, Delegated Regulation Laying Down Rules for the Safety Features Appearing on the Packaging of Medicinal Products for Human Use, Delegated Regulation 2016/161 (Brussels, February 2016).
	2. J. Verhaeghe, “Where Will FMD Lead Us?’” Presentation at Adents Serialization Innovation Summit (Paris, April 2018).
	3. EMVO, “Announcement-500 participation agreements signed,” Press Release, 12 Mar. 2018.
	4. EMVO, “Announcement-One Additional Country Connected to EU Hub,”’ Press Release, 26 Apr. 2018. 


	Vol. 30, No. 6
	June 2018
	Pages: 8–9

	When referring to this article, please cite it as S. Milmo, “Meeting the EU Serialization Deadline,” 

Pharmaceutical companies and their contractors are reorganizing their manufacturing lines and logistics to ensure compliance with the serialization requirements, but many SMEs are struggling to meet the deadline.  

Meeting the EU Serialization Deadline

	The European Union’s medicines agencies, coordinated by the European Medicines Agency (EMA), are currently putting a lot of effort into establishing an international platform for the improvement of good manufacturing practice (GMP) and other quality standards. A cornerstone for this drive is a mutual recognition agreement (MRA) on GMP inspections between the EU’s 28 member states and the United States, which started coming into operation in late 2017 and is due to be fully implemented in 2019. The agreement is gradually coming into force with the help of a close working relationship between the EU medicines agencies and the Geneva-based Pharmaceutical Inspection Co-operation Scheme (PIC/S). Both have collaborated together with the Canadian medicines agency, Health Canada, to develop similar guides for evaluating the competency of inspectorates.

	PIC/S was set up in 1995 as a co-operative arrangement between the inspectorates of regulatory authorities to harmonize GMP inspection procedures. Approximately two thirds of its 52 participating authorities come from Europe, most of them from the EU. The overall objective of PIC/S is the harmonizing of inspection procedures worldwide through key groups such as the EU’s inspectorates as well as through guidance documents and training programmes for inspectors. In fact, the only major European country that is not yet a member of PIC/s is Russia. But even Russia may soon be joining because it has started the pre-accession procedure for becoming a member. 

	PIC/S participants, all with GMP inspection systems of equivalent competence, share the objective of spreading uniformity in inspection and other quality standards in their own regions and across the world. The EU–US MRA is an important landmark in this endeavour because it means that, with Canada also having a GMP inspections MRA with the EU, there is now trans-Atlantic harmonization of inspection standards.

Mutual recognition of inspection competence

	The mutual recognition deal with the US comes fully into force once the US Food and Drug Administration (FDA) recognizes that all the EU’s national competent authorities (NCAs) with responsibility for inspecting pharmaceutical plants have equivalent inspection standards to those in the US. FDA started bringing the MRA into operation in November 2017 after it confirmed the capability of eight EU member states agencies to carry out GMP inspections at the level equivalent to that in the US. The EU countries-Austria, Croatia, France, Italy, Malta, Spain, Sweden, and the United Kingdom-were the first foreign states to have their GMP inspection competence mutually recognized by FDA. The confirmation of equivalence in these EU states came four months after the European Commission decided, after an audit in the US, that FDA had equivalence to EU inspection standards (1) and eight months after the signing of the agreement in early November 2017 (2). In March 2018, FDA announced it had recognized the inspections capabilities of four more EU states-Czech Republic, Greece, Hungary, and Romania (3). 

	All FDA’s assessments and approvals of the EU’s remaining agencies will have to be completed by a deadline of 15 July 2019 so that the MRA can be fully implemented across the EU (2). Then the major benefits of the MRA-a big reduction in duplication in inspections in the US and EU and a channelling of more resources into GMP inspections of high-risk plants outside Europe and North America-should start to become clearer. 

	A key role in FDA’s assessments of EU national agencies is played by the joint audit programme (JAP) under which teams of EU inspectors regularly audit the inspection capability of individual agencies. The JAP is part of the work of the GMP/GDP Inspectors Working Group, which, though supported by an EMA-run secretariat, reports to the heads of medicines agencies (HMA), representing the national regulatory authorities. 

	FDA has been attending JAP audits of individual member states agencies as an observer. The JAP auditors use an evaluation guide virtually identical to the joint reassessment programme (JRP), which is PIC/S’ own joint auditing scheme. Both guides apply a basic auditing tool developed by Health Canada. This guide has been adapted to EU legislation, the legal needs of the three non-EU states in the EU medicines approval network, PIC/S itself, and MRA audit programmes. It was the confidence of FDA-a PIC/S member itself since 2017 after a five-year accession process-in the JAP that is laying the foundations for its approval of the inspection systems of all EU states. 

	“The FDA’s assessment of EU member state authorities is predominantly based on observing the [JAP] audits,” said Ian Rees and Mark Birse, two inspectors at the UK Medicines and Healthcare products Regulatory Agency (MHRA), in a joint blog in November 2017 (4). Birse led and Rees was a member of the EU team that audited the FDA inspection capabilities under the terms of the MRA in 2017. 

	The Compliance Group that runs the JAP and is chaired by Rees “has been managing a demanding programme in order to meet the challenging reporting deadlines set out in the mutual recognition agreement so that the FDA could assess the EU authorities” by the scheduled completion date, the blog added (4). The deadline for the completion of the assessments will come a few months after the UK is due to leave the EU on 29 Mar. 2019. Brexit could cause problems with the UK’s participation in the EU–US MRA, but also, even more significantly, its position in the mutual recognition system that covers the whole of the EU and in which the MHRA’s expertise has been an important contributor to its success. 

	The UK and US may have to negotiate an MRA that would be separate to the EU–US agreement but probably identical. An MRA between the UK and the EU on GMP inspections will be more complicated because it is likely to have to be part of a free-trade agreement between the two. This agreement is scheduled to be thrashed out during a transition period to the end of 2020 to allow full implementation of an EU–UK Brexit agreement. Both sides will be anxious to avoid differences that could undermine current efforts to harmonize GMP inspection standards, especially through collaboration with PIC/S.

	Uniformity between EMA and PIC/S guidelines on GMP has been coming under pressure, mainly because of divergences resulting from additions and alterations generated by the EU’s relatively busy programme for making GMP improvements. The EU has tended to make changes to its own guidelines without synchronizing with PIC/S.

	According to the 2018 work plan (5) of the GMP/GDP Inspectors Working Group, the group is or will be preparing new GMP or quality guidance covering imported medicines, pharmaceutical quality systems, a risk-based approach to medicine shortages, data integrity, computerized systems, sterile drugs, finished dosage form manufacturing, and lifecycle management.

	A major split opened up in 2017 between the European Commission, which is ultimately responsible for GMP guidelines, and PIC/S over a new EU stand-alone GMP guide (6) on gene and cell therapies and tissue-engineered treatments or advanced therapy medicinal products (ATMPs). The guide, based on amendments to two annexes of the EU GMP guide, is due to come into force in May 2018.

	In a letter (7) sent to the European Commission, the organization warned “about the impact on public health and the safety of patients that the [EU] ATMP GMP guideline would cause.” The letter protested that as a result of “lowering the GMP requirements for ATMP,” the PIC/S and EU GMP guide would “no longer be equivalent” after nearly 20 years of being developed in parallel and on the basis of a harmonized consultation procedure. The decision to amend the existing guidelines was “a serious setback in terms of co-operation between the EU and PIC/S” and will “add barriers in the field of GMP and make harmonization efforts more difficult,” the letter said. PIC/S has acknowledged that the European Commission dealt with some of its worries before finalizing the guidelines, but that it still had a “number of serious patient safety concerns.”

	The dispute, unless resolved, could have implications for countries that require medicine manufacturers to comply with both sets of GMP guidelines. Switzerland, which is a not an EU member but whose Swiss Agency for Therapeutic Products (Swissmedic) is a participant in PIC/S, stipulates, for example, compliance with the two guidelines. Swissmedic issued a statement (8) in February 2018 saying that where there are discrepancies between the two guidelines, “compliance with both sets can in fact only be guaranteed if the more stringent requirements of the two are observed.”

	The statement does not mention the EU ATMP guideline, referring only to the need to comply with an EU GMP update on avoidance of contamination risks because it is in line with current state of science and technology. In the light of the Swissmedic’s clarification, it would appear that drug companies will have to follow the stricter PIC/S code on ATMPs. Compliance to the stricter code could have repercussions for pharmaceutical companies in Switzerland, which is a centre for the development and production of advanced medicines. It could also be a hindrance to moves in Europe to harmonize GMP inspection standards because these standards are based on GMP codes. 

	1. European Union, Notification to the Joint Sectoral Committee by European Union Under Article 7 of Sectoral Annex of the Agreement on Mutual Recognition between European Community and the US, Official Journal of European Union-document 22017X0915 (Brussels, 15 Sept. 2017).
	2. EMA, “Europe US regulators Agree Mutual Recognition of Inspections of Medicine Manufacturers,” Press Release, 2 Mar. 2017.
	3. FDA, “EU–US MR Joint Sectoral Committee-List of Recognized Authorities Under Article 7 of the Sectoral Annex, Countries Recognised 1 Mar. 2018.” (Washington DC, March 2018).
	4. MHRA blog, “EU–FDA Mutual Recognition of Inspections of Medicine Manufacturers Enters Operational Phase” (1 Nov. 2017).
	5. EMA, “Work Plan for GMP/GDP Inspectors Working Group for 2018,” EMA/INS/GMP/504401-2017 (London, 30 Nov. 2017).
	6. European Commission, 

Good Manufacturing Practice for Advanced Therapy Medicinal Products, 

C(2017) 7694 final (Brussels, 22 Nov. 2017).
	7. PIC/S, “PS L 11 2017 Letter to EC Concerning GMP ATMP” (Geneva, 2 Mar. 2017).
	8. Swissmedic statement, “Good Manufacturing Practice-Procedures for Discrepancy between EU and PIC/S GMP” (Berne, 7 Dec. 2017). 

	When referring to this article, please cite it as S. Milmo, “Harmonizing GMP Inspections,” 

is a freelance writer based in Essex, United Kingdom, seanmilmo@btconnect.com. 

The European Union is collaborating with the Pharmaceutical Inspection Co-operation Scheme to develop similar guides for evaluating inspectorates’ competency.

Harmonizing GMP Inspections

	As the world’s economy is increasingly threatened by new barriers to trade, the pharmaceutical sector through the Geneva-based International Council for Harmonization (ICH) has been stepping up its efforts to dismantle obstacles to global trade in medicines. At a time when ICH has been restructuring itself to give regulators more clout in the organization, it issued in December 2017 a draft guideline (1) aimed at more uniformity in rules on the quality of medicines throughout their lifecycles, particularly in the period after marketing authorization. It adopted, in December 2017, a guideline (2) on the planning and design of multi-regional clinical trials (MRCTs) to facilitate their acceptance across the world.

	The Q12 guideline of lifecycle management, although still in draft form, is already turning out to be controversial because it has been issued without the support of industry, which claims its degree of harmonization does not go far enough. The ICH Q12 proposals, now undergoing a year-long public consultation that started in December 2017, makes up the last of a series of five quality guidelines covering product and process development (ICH Q8 and Q11), application of risk management principles (Q9), and an effective pharmaceutical quality system (Q10). It aims to fill the gaps in the way the four Q8–11 guidelines cover issues relating to lifecycle management, particularly in relation to chemistry, manufacturing, and controls (CMC).

	The new guideline underlines the continued progress by a reinvigorated ICH in helping to integrate the management of medicines at the international level through the harmonization of regulations. But the restructuring of the ICH is largely an initiative of the regulators to put themselves in a stronger position to obtain the changes they want, if necessary, without the backing of industry.

	ICH was founded in 1990 by the regulators and research-based industry associations in Europe, the United States, and Japan with the objective of issuing jointly agreed harmonized standards on the quality, safety, and efficacy of medicines. In recent years, it has been in danger of losing its legitimacy as the world’s leading body for drawing up medicines standards because its partnership consisted of only six regulatory and industry organizations in Europe, the United States, and Japan. It has, therefore, been creating a governance structure that enables new members, particularly from the developing world, to join the ICH. But the strategy behind this expansion has been to put the regulators in charge.

	The ICH Assembly, at a meeting in Geneva in November 2017, approved as a new member Singapore’s regulator, Health Sciences Authority (HSA). This approval gave it a total of 15 members-nine regulatory agencies, including the medicines authorities of Brazil, China, and South Korea and six industry associations including the US-based Biotechnology Innovation Association (BIO), the World Self-Medication Industry association (WSMI), and the International Generic and Biosimilar Medicines Association (IGBA).

	Under the terms of the reorganization of the ICH, which although initiated three years ago is still not complete, the technical content of guidelines is drawn up by a working group of regulatory and industry scientific experts. Their adoption, however, is the responsibility of the regulators, who can finalize guidelines without the agreement of industry representatives.

Incompatibility with established framework

	During the final stages of the drafting of the Q12 guideline, the European Commission, the European Union executive, discovered after a review of EU rules that parts of the guideline could not be implemented in the EU without changes in legislation. This is despite large sections of the guidelines already being implemented in the Union. At the Commission’s insistence but with the backing of regulatory representatives on the experts working group (EWG) drawing up the guidelines, additions were made to the guideline’s introduction about the incompatibility of the guideline with the “established legal framework” in certain ICH regions.

	These differences are mainly centred on the guideline’s concepts of established conditions for manufacturing and control for categorizing quality elements requiring regulatory submission if changed and for product lifecycle management (PLCM), which will provide a central repository on details of established conditions.

	The draft guideline (1) allows a degree of incomplete harmonization under which its proposals for established conditions and PLCM could be implemented under existing but possibly incompatible regional or national regulations until the regulations themselves are amended. “These concepts will be considered when the legal frameworks will be reviewed and, in the interim, to the extent possible under the existing regulation in these ICH regions,” the guideline says.

	Both the established conditions and PLCM concepts are at the core of the Q12 guideline. The established conditions provide a basis for a key objective behind the guideline of enabling marketing authorization holders (MAHs) to commit themselves, with the agreement of their regulatory agencies, to their own lifecycle management protocols for manufacturing and other changes. It aims to facilitate greater predictability and efficiency in the management of post-approval CMC changes, particularly through the use of increased product and process knowledge. The established condition concept is “the single most important element of the Q12 guideline,” says Beata Stepniewska, deputy director general and head of regulatory affairs at Medicines for Europe, representing generics and biosimilars producers.

	In the draft guideline (1), established conditions are divided into two categories-“implicit,” derived from existing regional regulation or guidance without being proposed by the MAH and “explicit,” which are specifically identified and proposed voluntarily by the MAH itself. The explicit approach gives the MAH, with the agreement of the regulator, the freedom to focus on process performance by using automation tools such as in-line continuous monitoring. The PLCM system in the guideline provides for documentary back-up for a product-specific approach covering key elements of an MAH’s quality control strategy and any post-approval CMC commitments that have been put forward by the authorization holder and then approved by the regulator. Under the ICH guideline, however, the two concepts may not be brought into effect fully-at least for a while-because regulators would be able to stick to their own existing non-compatible regulations.

	“Flexibility to deviate from a harmonized and agreed guideline and to allow some exceptions to not implementing the guideline fully at the regional level would undermine the whole principle of harmonization,” says Stepniewska. “Non-acceptance of the established conditions would have a big impact on companies trying to get a harmonized dossier across several regions.”

	The European Federation of Pharmaceutical Industries and Associations (EFPIA), representing Europe’s research-based pharmaceutical companies and a founding ICH member, has also been critical of the flexibility allowed in the draft guideline. “[We are] disappointed that stakeholders within the European Union will not be able to benefit fully from the efficiency gains that were hoped to be achieved through full implementation of ICH Q12,” says an EFPIA spokesperson. It sees the main benefit of the Q12 guideline as bringing greater efficiency in the lifecycle management of product manufacturing, which should reduce drug shortages and ensure patient access to medicines.

	“EFPIA is keen to work with the European Commission and the European Medicines Agency (EMA) to assess more closely which parts [of the ICH Q12 guideline] might be implemented now and at what point it might be appropriate to address the others,” the spokesperson adds. EFPIA echoed the views of Medicines for Europe that the flexibility allowed in the guideline could affect all pharmaceutical companies in Europe and elsewhere with international operations in medicines subject to manufacturing changes during their lifecycles. “Even if the ICH guideline will be implemented by the majority of ICH [regulatory] members, companies would not benefit fully from it [because their] standard practice is to release products first when the changes in the manufacturing process is accepted by all regulatory authorities,” the EFPIA official explains.

	The restructured ICH, now called ICH Association, generally aims to reach consensus with industry and other stakeholders by the end of a guideline finalization process. But that may be difficult in the case of Q12 because of a deep divide over the issue of regulatory flexibility. Nor would a more powerful industry presence in the new ICH have made much difference. “The ICH Q12 is a very specific case, as the Commission found out at a late stage that the draft ICH guideline cannot be implemented without a change in EU legislation,” says the EFPIA spokesperson. “A stronger industry voice or representation would, therefore, not have addressed this issue.”

	The industry itself could also take some of the blame. “The conclusion is, however, that both the Commission and the European industry need to make a proper legal analysis earlier in the process for topics that risk being in conflict with EU legislation,” admitted the spokesperson. Nonetheless, the issue of representation at the top level of decision-making on global regulations and standards remains a matter of concern for the pharmaceutical industry.

	“[The industry’s worries about the guideline] does not mean that we challenge the [regulators’] dominant role in the ICH and the possibility for them to endorse the guideline even if the industry is against it,” says Stepniewska. “If we want to achieve progress in science and in implementing an outcome of scientific discussion, previously established regulatory frameworks shall not be a barrier to achieving progress.”

Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management

, Draft version (ICH, Geneva, 16 Nov. 2017).
	2. ICH, E17 

General Principles for Planning and Design of Multi-Regional Clinical Trials-E17

, Final version (ICH, Geneva, 16 Nov. 2017). 


	Vol. 30, No. 4
	April 2018
	Pages: 6–8


	When referring to this article, please cite it as S. Milmo, “ICH Q12 Guidelines Spark Controversies,” 

The flexibility and incompatibility of ICH Q12 guidelines with current EU legislations raise complications.

ICH Q12 Guidelines Spark Controversies

	The European pharmaceutical industry and regulators are worried about an imminent worsening of the persistent problem of shortages of medicines in the region. Although both agree that regulations are partly to be blamed for a likely rise in the number of incidents of drug scarcities, they have different views on the issue of how regulations are reducing the availability of medicines.

	The industry contends that regulations, particularly those relating to pricing policies, are being applied too strictly so that it has become uneconomic to retain low-priced drugs on the market. The regulators reckon that shortages are occurring when regulations are not being used effectively enough to ensure that medicines remain available.

The Falsified Medicines Directive and Brexit

	The first half of 2019 could be a crunch time for medicines supplies in Europe as a result of a new packaging regulation coming into effect, which is aimed at combating counterfeit drugs, and the United Kingdom’s official departure from the European Union triggering legal changes that will have a big impact on pharmaceutical supply chains. The implementation of rules on the identification of individual medicine packs under the EU’s Falsified Medicines Directive (FMD) will be followed by Brexit, where the UK will no longer be a member of the EU’s single market. Supply bottlenecks could start to form before the two events through to their aftermath.

	“Both FMD and Brexit will come into operation within a couple of months,” Adrian van den Hoven, director general of Medicines for Europe, representing generic medicines and biosimilars producers, said at the 17

 Regulatory and Scientific Affairs Conference, which took place in London on 25–26 Jan. 2018. “Are we going to risk a total regulatory overload within a six-month period from the end of this year to the spring of 2019 during which the supplies system could become clogged up?” he asked.

	A large part of the conference focused on the issue of shortages of medicines and the impact of the FMD packaging legislation and Brexit on their availability.

	“The evidence that the root causes of medicines shortages are economic, including unsustainable pricing and reference pricing policies, is overwhelming,” Marc-Alexander Mahl, head of the generic-drug business of Fresenius Kabi and president of Medicines for Europe, told the meeting. He noted that claw- and pay-back measures used by governments to limit public sector overspending on pharmaceuticals were also partly to blame. A claw- or pay-back is a tax imposed when there is overspending within a budget so that the total net expenditure is kept within the budget’s limit.

Challenges faced by generic-drug companies

	In Romania, 2000 medicines had been withdrawn because of reference pricing and a claw-back tax, while in Portugal, there had been a “drastic reduction” in the number of hospital drug suppliers due to the impact of a pay-back scheme, according to Mahl. He cited the conclusion of a 2016 report (1) by the European Commission on the fiscal sustainability of funding healthcare. “While overspending is recovered via the claw-back tax, it has led to withdrawals of generic medicines from the market,” the report said (1).

	Not only have generic-drug companies struggled to cope with the downward pressures on their profits and sales revenues, but they also have to cope with the expense of running complex supply chains in a high-volume, low-margin business, Mahl highlighted at the meeting. He pointed out that a large generic-drug company in Europe may have as many as 25,000 marketing authorizations, with more than 800 supply-chain employees working with more than 2000 partners and shipping products to up to 50,000 locations. At the same time, generic-drug companies have to invest in R&D to launch new products, formularies, and biosimilars to ensure competition and wider pharmaceutical access in the market, he said.

	Meanwhile, the regulatory demands on generic-medicine producers at the EU and national levels are increasing, particularly with requirements to keep marketing authorizations up to date. Typically, 75% of the EU regulatory fee budget of a generic-drug company is taken up by the maintenance costs of marketing authorizations. Partly as a result of the number of variation approvals nearly doubling in four years, maintenance fees had risen by an average of 45% annually per marketing authorization in 2011–2014, Mahl said. He explained that one way to prevent medicine shortages would be to improve regulatory efficiency so that the administrative and cost burdens of keeping products on the market can be reduced. There should be a flat fee structure for the approval of variations. He also suggested that there should be a lower authorization and maintenance fees for older molecules that still serve a medical need.

	A study in 2017 (2), cited at the conference, showed that national competent authorities (NCAs), which license medicines under the EU decentralized approval procedure, were making more flexible use of regulations to deal with shortages. But the report (2), carried out by the heads of medicines agencies (HMA) representing NCAs, indicated also that often, rules being applied by national authorities were aiming to be even more restrictive.

	Governments have introduced procedures for banning exports of essential medicines at times of acute shortages. Regulatory authorities are also wanting to monitor more closely pharmaceutical plants liable to production disruptions, through measures such as risk-management plans. Finland, for example, has legislation that obliges manufacturers and wholesalers to store additional life-savings medicines for periods of three to 10 months (2). On the other hand, national authorities are being flexible with the enforcement of regulations when dealing with shortages. They are, for example, relaxing language rules on labels and patient leaflets in order to import replacement medicines from other countries. They are also giving emergency authorizations to bring in medicines from abroad.

	Within the EU regulatory network for medicines, extending from the European Commission and European Medicines Agency to the HMA and the Co-ordination Group for Mutual Recognition and Decentralized procedures for human medicinal products (CMDh) at the national level, there are moves to adopt more uniform approaches to medicines availability. An HMA/EMA Task Force on medicines availability, which was set up in late 2016, has started meeting regularly since the middle of 2017. It comprises representatives of the HMA, EMA, the European Commission, and the chairs of the CMDh and its veterinary equivalent.

	Kristin Raudsepp, co-chair of the task force, told the conference that it would be addressing issues such as the detection of potential supply disruptions and ways of avoiding shortages. Among the actions planned by the task force was the development of a definition of medicine shortage. The task force also wanted to “develop a concept of reportable shortage and agree on a common set of reporting requirements [as well as] develop metrics that could be used to measure a shortage,” Ruadsepp said.

	Currently, among the major factors influencing the availability of medicines, is the number of authorized medicines that are either not being marketed or are no longer marketed in the EU. In addition, supply chain disruptions are affecting availability. These disruptions could result from difficulties with failed approvals of GMP-standard manufacturing or other safety or quality problems and the effects of parallel trade. Raudsepp, who is director-general of Estonia’s State Agency of Medicines, said that in her own country’s market, 60% of authorized medicines are not available. With those that are being marketed in Estonia, there are approximately 100 medicines experiencing shortages each year, with an average shortage period of 100 days in 2016. “Every [type] of medicine may be in shortage,” she said. “We have had cases of shortages for vaccines in the national vaccination scheme, for cancer treatment, and life-saving hospital medicines.”

	Among the options for dealing with the issue of authorized medicines not being placed on the market was the use of regulations to require companies to make authorized products available, Raudsepp said. The European Commission is planning to send out a questionnaire to stakeholders on the implementation of article 81 of the 2001 EU directive on medicinal products (3).
	Article 81 stipulates that the holder of a marketing authorization for a medicine and its distributors “shall, within the limits of their responsibilities, ensure appropriate and continued supplies of that medicinal product to pharmacies and persons authorized to supply medicinal products.”

	Some participants at the conference pointed out that authorized medicines may not have been put on the market for economic reasons. There may not be the production capacity for manufacturing them. Also, with the FMD packaging regulation and Brexit looming on the horizon, it was not the time for considering the use of regulations to force companies to make products available.

	The conference was warned that there was a danger, which due to its cost and complexity, pharmaceutical companies may not be able to meet the deadline for the implementation of the FMD packaging legislation. The regulation introduces pack identification of medicines involving the use of individual pack barcodes and anti-tamper devices within an “end-to-end” system under which the serialization and other data on each pack can be verified by a pharmacist with a scanner at a dispensing point connected to a central data bank. According to Philippe Drechsle, chair of Medicines for Europe’s FMD task force, a recent survey of the readiness of Medicines of Europe members for the legislation found that the most compliant company reached only a 55% state of readiness while other companies are at a level of 30% or even less (4).

	Moreover, Brexit could result in a number of medicines no longer being available in the EU because of the need to obtain UK-based authorizations or because the UK was the original reference member state (RMS) under the mutual recognition procedure. These authorizations will have to be transferred to an EU state to remain valid after the UK’s departure. Both the FMD regulation and Brexit look highly likely to divert for awhile efforts to tackle the underlying causes of medicine shortages in the EU.

	1. European Commission’s Directorate General for Economic and Financial Affairs and Economic Policy Committee, “Joint Report on Health Care and Long-term Care Systems & Fiscal Sustainability” (Brussels, October 2016).
	2. Heads of Medicines Agencies, “Availability of Medicinal Products for Human Use” (Brussels, 29 May 2017).
	3. European Union Directive, “Community Code Relating to Medicinal Products for Human Use,” 2001/83/EC (Brussels, 6 Nov. 2001).
	4. Philippe Drechsle, “Falsified Medicines: Practical Implementation of the Falsified Medicines Directive in a Nutshell-How is the System Set Up to Detect Falsified Medicines in the Supply Chain?” presentation at the 17

 Regulatory and Scientific Affairs Conference (London, United Kingdom, 25–26 Jan. 2018). 

	When referring to this article, please cite it as S. Milmo, “Tackling Medicine Shortages in Europe,” 

The upcoming serialization deadline and the United Kingdom's departure from the European Union could result in supply bottlenecks. 