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

Sean Milmo

	Europe’s pharmaceutical industry, especially its growing number of companies developing and marketing drug device combinations (DDCs), has been expecting a lot from a draft European Medicines Agency (EMA) guideline (1) on the implementation of a new EU medical devices regulation (MDR).

	The guideline, issued in late May 2019, almost exactly a year before MDR comes into force, was anticipated to fill some major information gaps, particularly about how safety certification organizations, called Notified Bodies (NBs), would assess the quality, safety, and performance of new DDCs.

	More fundamentally, the industry wants a holistic approach to be taken in the evaluation by regulators of the drug and device in DDCs (2,3). This is particularly the case with single, integral products designed for the drug and device to be used exclusively in a specific, non-reusable combination, such as a prefilled syringe or prefilled autoinjector. 

	This approach would necessitate the drug and device, especially their interaction, being assessed together by a regulatory authority-either the EMA for products with EU-wide distribution or national competent authorities (NCAs), usually medicines licensing agencies, in EU member states. There are fears that the NBs involvement in assessment will undermine an integrated approval system (2,3).

	The MDR is replacing the 1993 EU directive on medical devices (MDD), while a separate regulation on 

 diagnostics due to come into force in 2022 will replace a 1998 directive on companion diagnostics. The degree of satisfaction within the industry with the 26-page MDR guideline will become clear after a three-month consultation, which ends 31 August 2019, leading to the finalization of the document before the MDR starts being implemented on 26 May 2020.

	So far, it appears that at least parts of the industry, especially those developing and producing biopharmaceutical device combinations, who are most affected by the regulation, are not happy with the guideline. They are particularly concerned about an absence of detail in the report about how its article 117, requiring certain higher-risk DDCs to be assessed by NBs, will operate.

	“The guideline is not giving us all the information we need,” says Veronique Debaut, regulatory affairs manager at European Biopharmaceutical Enterprises (EBE), part of the Brussels-based European Federation of Pharmaceutical Industries and Associations (EFPIA). “We still need more clarification on certain issues, such as what will the process be for the assessment of DDCs by Notified Bodies,” she told 

	Furthermore, lack of clarity in the guideline is arousing concerns within the pharma industry about whether the regulatory infrastructure for implementing MDR will be sufficiently well prepared for its enforcement next May. As a result, DDC producers may have to postpone market launches of new products.

	A major anxiety is that an inadequate number of NBs will have been designated by the European Union to conduct MDR assessments when the regulation comes into force. Due to stricter criteria being applied when certification organizations are selected as NBs for assessment work under the new regulations covering both medical devices and companion diagnostics, the total of NBs could drop by as much as a third compared with the numbers conducting assessments under the existing legislation.

	While NB numbers are decreasing, more devices and diagnostic products are having to be assessed by NBs because of a widening of the scope of the new legislation. Furthermore, the NBs will have to check whether individual products comply with a much longer list of quality, safety, and performance requirements than those in the existing MDD.

	NBs will be needed not just to certify new products but some classes of existing medical devices already on the market, some containing pharmaceuticals. Those unable to be recertified because of a scarcity of NBs may have to be withdrawn from the market.

	NBs will typically take three to nine months to complete a product recertification, while even more time will be needed to complete a new MDR certification, according to MedTech Europe, the trade association for medical device and diagnostics manufacturers (4).

	“At the current pace of preparation, the new regulatory system will not be ready early enough to absorb this extra workload,” said Serge Bernasconi, MedTech Europe’s chief executive, in an open letter to the European Commission in April 2019 (4). “As of May 2020, thousands of medical devices will become non-compliant and will not be authorized for use by surgeons, doctors, hospitals, and patients.”

	By May 2019, only two NBs-UK-based BSI Assurance and Tuev Sued of Germany-have been designated for MDR work, while the European Commission estimated that by the end of the year a total of 12 would have been designated. “This is way too late (and) insufficient,” Bernasconi protested. “[It] gives no guarantee that Notified Bodies would have enough capacity to ensure continued regulatory approval of devices by May 2020.”

	Ironically, EMA wants to use the guideline to ensure a smoothly operating regulatory system for controlling DDCs at a time when they will be accounting for a growing proportion of new drug approvals, especially at the EU level. Out of 593 marketing authorization applications for medical products approved by EMA between January 2010 and mid-2018, almost a quarter had device components. The majority of these devices were prefilled syringes or pens, inhalers, nasal sprays, tablet delivery systems, and advanced therapy medicinal products (ATMPs), such as autologous cultured chondrocytes embedded in a biodegradable matrix or scaffold. In 2017, DDCs accounted for around a third of EMA drug approvals, a proportion which was about two-thirds higher than in the previous year.

	“[DDCs] will likely become more commonplace as technology develops,” says the guideline (1). “The availability of commercialized devices with automated functions is increasing [which] may benefit patients with regular and long-term dosing requirements in an outpatient setting.”

	Harmonization is a key objective of MDR. It has been introduced as a regulation because EU regulations have to be transposed directly into national legislation without alteration. Directives, which provide the basis for existing EU rules on medical devices and 

 diagnostics, can be modified by EU member states, which has led to inconsistencies in the way they are applied across the EU.

	The numbers of general safety and performance requirements (GSPRs) listed in the MDR’s Annex 1 are considerably higher than in its MDD counterpart due to a need to ensure that the MDR’s rules are more clearly aligned with a broader set of international harmonized standards and guides. These include those of the International Organization for Standardization (ISO) and the International Council for Harmonization (ICH) of pharmaceuticals.

	While the medical device directive has 94 essential requirements divided into 13 clauses, the MDR has 178 GSPRs spread over 23 clauses. The guideline stresses that its “core precept” is that the regulatory authority will have the main responsibility for evaluating “the device-specific aspects of safety and performance relevant to the quality, safety, and efficacy of the medicinal product,” while the NB would, “as applicable, assess the relevant GSPRs.”

	Within the marketing authorization application (MAA) dossier, data on the two aspects would be given separately. One section would contain information on the drug-specific quality and safety attributes related to the device. Another section would comprise relevant information on compliance with the MDR’s Annex 1, including the NB’s opinion of GSPR compliance. 

	A major issue with the interaction between the device and drug, whose assessment will effectively be the responsibility of the regulatory authority, will be the compatibility of the device’s materials with the medicine. The guideline lists incompatibility dangers from materials such as moisture, microbial contamination, vapour phase permeation, and extractable and leachable substances, such as lubricants and label adhesives.

	The guideline does not include advice on how the NBs should make their assessments. “The processes by which a NB derives their opinion are not within the scope of this guideline,” it says. But it does recommend that the results of the NB’s assessment should be presented as a technical summary report on the grounds that this would avoid duplication with evaluations by the regulatory authority.

	EBE and EFPIA have suggested in three papers, the first of which was issued in January 2018, various ways in which certain DDCs may not need specific NB assessments, especially if a risk-based approach is adopted by regulators (2,3,5). These could include combinations based on platform technologies or wellâknown technologies.

	“Where a device is also a component of an already marketed medicinal product, there is opportunity to leverage prior knowledge and previous NB opinion without the need for further oversight,” the two organizations said in a joint reflection paper on MDR’s Article 117, issued July 2018 (2).        

	In a reflection paper on quality control strategies for DDCs issued in June 2019 but before publication of the MDR guideline, EBE argued that existing global harmonized guidelines such as those of ISO and ICH are sufficient for operating an adequate quality control strategy for combination products (5).   

	“The fundamental principles underpinning drug product component and device component guidance are broadly aligned,” EBE said. “Since the building blocks for product development are already in place, adapting and clarifying Module 3 (MAA quality) content for DDC products should be possible with minimal disruption to existing ‘best practice’.”

	Discussions between industry and EMA on the finalization of the MDR guideline are likely to centre on how much current quality principles and processes used by DDC manufacturers need to be changed to deal with the likely longer-term growth in DDC products.

Draft Guidance 259165/2019, Guideline on Quality Requirements for Drug-Device Combinations

 (Amsterdam, 29 May 2019).
	2. EBE and EFPIA, Reflection paper. An Industry Perspective on Article 117 of the EU Medical Devices Regulation and the Impact on how Medicines are Assessed (Brussels, 12 July 2018).
	3. EBE, Reflection paper. Medicinal Product Incorporating a Drug Delivery Device Component: An Industry Perspective on the EU Marketing Application Technical Requirements, Regulatory Review Process and Post-Approval Device Related Change Assessment (Brussels, 15 January 2018).
	4. MedTech Europe, “Open Letter on the Implementation and Readiness Status of the New Medical Devices Regulation,’’ Letter to Jyrki Katainen, Vice-President, Jobs, Growth, Investment and Competitiveness, European Commission, 15 April 2019.
	5. EBE, Reflection paper, Medicinal Product Incorporating a Drug Delivery Device Component: An Industry Perspective on Delivery of an Efficient, ‘End to End’ Control Strategy (Brussels, 12 June 2019).


	Vol. 31, No. 7
	July 2019
	Pages: 10–12

	When referring to this article, please cite it as S. Milmo, “Clarifying Industry’s Concerns Over Regulation of Drug Device Combinations,” 

Articles

Will EMA’s draft guideline clarify questions about the assessment of drug device combinations in relation to the EU medical devices regulation?


Clarifying Industry’s Concerns Over Regulation of Drug Device Combinations

	After a radical shift in public, medical, and scientific opinion about the effectiveness of cannabis-based medicines in the treatment of certain conditions, most European countries have legalized the use of these drugs. But European states, particularly in the European Union, have adopted a range of different regulatory policies for dealing with the medicines, particularly with regard to the quality standards in the cultivation of the cannabis crops and the manufacture and distribution of their medicinal products.

	The vast majority of countries have approved cannabis medicines after they have gone through the standardized authorization process based on good manufacturing practice (GMP) and positive clinical trials. Also, many have stipulated that they should only be available by prescription.

	A growing number of countries, however, have begun to allow access to the medicines through unconventional regulatory schemes with less quality controls on cultivation and manufacture and less importance given to evidence from clinical trials. The result has been a fragmented regulatory approach across the region to cannabis medicines, which will be a challenge for regulators to harmonize.

	Although the Cannabis sativa plant has a long history as a source of medicines, its use as a means of treatment of illnesses had declined by the past century. In 1961, the United Nations’ Single Convention on Narcotics Drugs (CND) categorized it as a drug with no medical use, effectively ending its availability as a legal medicine in the many European and other countries that signed the treaty (1).

	Its revival as a medical treatment over the past 20 years followed mounting scientific evidence that cannabinoids-substances found in the cannabis plant that act on specific receptors in the human brain and body-could effectively treat conditions like chronic pain and neurological disorders such a multiple sclerosis and epilepsy. Scientists also discovered that the human body has its own cannabinoids-endocannabinoids-and that synthetic cannabinoids could be made in the laboratory.

	In certain countries, there has been a sharp rise in consumption of cannabis medicines after they were allowed to be prescribed or even made available without prescription. In the Netherlands, the medical use of cannabis-mainly for the treatment of chronic pain prescribed by pharmacists-went up from 6.9 per 100,000 patients in 2010 to 24.6 per 100,000 patients in 2016 (2).

	Even countries with a relatively relaxed policy on the use of cannabis as a medicine broadly followed a regulatory framework laid down by an amended version of the 1961 CND.

	Compliance with the treaty’s requirements on medical use of cannabis is monitored by the Vienna-based International Narcotics Control Board (INCB), which is responsible for the implementation of the UN drug control conventions, including the CND. The CND requires that governments establish a national cannabis agency to control the production and regulation of the supply of cannabis for medical use, according to the INCB’s latest annual report (3).

	“The national agency is required to license producers, purchase and take possession of stocks, and maintain a monopoly on wholesale trading and stocks,” says the INCB (3). “All programmes for the medical use of cannabinoids must be developed and implemented under the full authority of the state concerned.”

	The INCB is critical of what it regards as “poorly regulated” medical cannabis programmes. These programmes include allowing the use of cannabis for a wide variety of medical conditions in the absence of evidence of efficacy and safety from controlled clinical trials, the provision of nonâstandardized cannabis products under minimal medical supervision, and the cultivation of cannabis by patients themselves or the purchase of it from commercial outlets that produce cannabis illicitly.

	The Netherlands, the first European country to relax rules restricting use of medical cannabis, introduced a law in 2003 allowing doctors to prescribe it for a wide range of conditions, leaving the doctor to judge whether it would be an effective treatment (1).

	In compliance with the 1961 CND but also to ensure quality control, a single, private Dutch company, Bedrocan, has been granted a monopoly to produce cannabis, with its products mainly comprising the cannabinoids cannabidiol (CBD) and tetrahydrocannabinol (THC), the compound that gives cannabis a euphoric effect. Bedrocan’s products are not only sold in the Netherlands but exported to several other European countries. 

	After Germany changed its legislation two years ago to allow doctors to officially prescribe medicinal cannabis products, the country’s Federal Institute for Drugs and Medical Devices (BfArM), its medicines licensing as well narcotics control body, set up a German Cannabis Agency.

	“The functions of the Cannabis Agency are based on the requirements set out by the (amended 1961) Convention,” explained Prof. Dr. Werner Knoess, head of the new agency, in an interview in BfArM’s latest annual report (4). “We monitor the cultivation, harvest, quality assurance, storage, packaging, and distribution of cannabis to wholesalers and chemists or manufacturers.”

	The agency has been selecting suitable companies to cultivate cannabis, which will then be purchased by the agency for distribution through third parties to medicine producers and pharmacists. The BfArM had to draw up its own pharmacopoeia monograph to ensure that the cannabis meets pharmaceutical-grade standards.

	Because of what it regards as limited knowledge of the effectiveness and safety of cannabis medicines, the BfArM’s narcotics control branch is conducting a five-year survey on their application, due to be completed in 2022.

	An increasing number of European states are now permitting access to unlicensed cannabis-based medicines through individualized schemes like named-patient systems and compassionate or exceptional use.

	Under a law in Italy allowing any doctor to prescribe plant extracts, cannabis preparations for medical use can be provided by any pharmacy as long as it complies with the specifications on the prescriptions.

	After a review by its Home Office (interior ministry) concluded that there was ‘conclusive’ or ‘reasonable’ evidence of the therapeutic benefits of cannabis-based medicines in the treatment of certain medical conditions, the UK government announced in October 2018 plans to change its Misuse of Drugs Regulations to allow doctors to prescribe unlicensed cannabis medicines (5). The doctors would have to be specialist physicians with knowledge of cannabis medicines and the conditions for which they have therapeutic value. They would be able to specify the formulation of the medicines to the manufacturer, which will have to meet GMP standards.

	The United Kingdom is the home base of GW Pharmaceuticals, which over the past 20 years has been pioneering the development of cannabis-based medicines through the standard authorization procedure for pharmaceuticals including GMP quality assurance and controlled clinical trials.

	The company’s lead product is Epidiolex, a CBD treatment for two childhood-onset drug-resistant epilepsy syndromes, Lennox-Gastaut and Draver. The drug was approved by the US Food and Drug Administration (FDA) in June 2018 and was due to complete the European Medicines Agency’s authorization process for marketing in the EU in the second quarter of 2019.

	GW’s first cannabis medicinal product-Sativex, a mouth spray comprising 50/50 CBD and THC for relief of multiple sclerosis symptoms-was approved in the UK in 2010 and is now available in numerous countries across the world under marketing agreements with international pharma companies such as Bayer and Almirall.

	The strategy being followed by GW is to maintain a world-leading position in cannabinoid medicines through its proprietary cannabinoid product platform. This includes the building-up of a library of internally generated novel cannabis types, development of in-house extraction, processing and analytical techniques, and in-house formulation and manufacturing capabilities.

	Despite following the standardized route to the development and authorization of its products, GW is still subject in the UK and elsewhere to national regulations on controlled substances like cannabis. The company’s cultivation, manufacture, distribution, exporting, and importing of cannabis and its medical derivatives has to be regularly licensed by national narcotics agencies.

	However, international monitoring organizations such as INCB are complaining that changes to national regulations to lift restrictions on medicinal cannabis are undermining controls on the recreational use of the plant’s extracts, particularly THCs.

	The long-established system, backed by international treaties, of strict curbs on cannabis consumption is also being weakened by the spread of applications of cannabis-based substances to skin-care cosmetics and toiletries. CBD oils are even being made available as a food in Europe, although they have to be given approval as a novel food product to be marketed.

	In November 2018, the expert committee on drug dependence at the UN’s World Health Organization (WHO) in Geneva recommended a relaxation of restrictions on cannabis and cannabis-related substances. The deregulation of the cannabis market may work against pharmaceutical companies focused on the development of high-quality but highly regulated cannabis-derived medicines. 

	CBD and THC are the only cannabinoids that have been researched in depth for their possible medical properties, but there are at least 70 others that may be effective medical treatments.

	“We are at the forefront of [a] new area of science,” says GW (6). But the potential of that science may be more difficult to achieve with a decriminalized cannabis market in which the divide between recreational and medical use will become blurred.

	1. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), “Medical Use of Cannabis and Cannabinoids,” Rapid Communication (Lisbon, December 2018).
	2. B. de Hoop, E.R. Heerdink, and A. Hazekamp, 

, 2018 3(1) 54–55.
	3. INCB, “Chapter I: Cannabis and Cannabinoids for Medical, Scientific, and ‘Recreational’ Use: Risks and Benefits,” 

 (Vienna, 5 March 2019).
	4. BfArM, 2017–2018 Annual Report (Bonn, June 2018).
	5. MHRA, “The Supply, Manufacture, Importation, and Distribution of Unlicensed Cannabis-Based Products for Medicinal Use in Human ‘Specials’,” Guidance Document (London, November 2018).
	6. GW Pharmaceuticals, 


	Vol. 31, No. 6
	June 2019
	Pages: 6–8

	When referring to this article, please cite it as S. Milmo, “Regulating Cannabis-Based Medicines in Europe,” 

The current fragmented regulatory approach to cannabis medicines across Europe is challenging to harmonize.

Regulating Cannabis-Based Medicines in Europe

	The European Union has a lengthening queue of revisions and other changes to good manufacturing practice (GMP) guidelines, which is worrying industry because of the impact the delays are having on pharmaceutical businesses, particularly investment decisions. The guidelines comprise key sections of the EU’s GMP guide, which also includes good distribution practice (GDP).

	Among the areas covered by the revised or new guidelines are sterile products, imported medicines, data integrity, drug device combinations (DDCs), investigational medicinal products, and streamlining of information on the GMP responsibilities of marketing authorization holders (MAHs). In a joint letter to the European Medicines Agency (EMA), sent in October 2018 on behalf of 13 trade associations and professional associations, Sini Eskola, regulatory, drug development, and manufacturing director at the European Federation of Pharmaceutical Industries and Associations (EFPIA), said the topics covered by the guidelines were ‘urgent’ (1).

	The delays have been exacerbated by the disruption to the operations of the EMA’s expert committees, particularly the GMP/GDP inspectors working group (GMDP IWG) as a result of Brexit. The planned withdrawal of the United Kingdom from the EU has forced EMA to move its headquarters from London to Amsterdam to ensure it was based in an EU member state.

	The IWG and other specialist committees have had to confine their work on revisions to four guidelines on the manufacture of sterile medicinal products, guidances for medicine importers, a reflection paper on GMP and MAHs, and on quality requirements for DDCs. Scheduled activities on other guidelines were temporarily suspended in October 2018, and are anticipated to last for at least a year according to EMA. Even with those guidelines on which revision work is continuing, activities have been slowed down without any new target dates for completion or meetings with industry representatives being announced.

	“More transparency on the actual status of these few projects shortlisted (for continued work) would be more than welcome as currently industry has no idea when the IWG would communicate back or when it foresees further actions,” Koen Laenen told 

. Laenen is regulatory affairs and quality manager at Medicines for Europe, which represents generics and biosimilars producers and was one of the signatories of the joint letter to EMA. “For 2019, no stakeholder meetings with industry are foreseen by IWG,” he continued. “This is a long period for no official meetings with different stakeholders.” 

	Despite the hold-up in the IWG’s operations, the industry is pressing for a continued dialogue with the group, preferably through face-to-face meetings on some issues. The need for consultations with stakeholders, especially industry representatives, is a major reason for the length of time it can take to revise or draw up new versions of GMP guidelines. A consultation period after the publication of a draft, the processing of comments and then the finalization of the guideline, can extend to one-to-two years.

	Once a guideline is completed, there can be further delays while the industry and EMA or the European Commission-the EU executive to which the agency is accountable-sort out how the new or modified guideline should be implemented.

	This is what has happened on a new, lengthy guideline on the manufacture of sterile medicinal products, work on which started in 2014 with a draft being published late in 2017, and a consultation period being completed in March 2018. However, its finalization has been held up because of disagreement of how it should be implemented, which is unlikely to be resolved until the IWG is fully operational again.

	The new guideline, which comprises Annex 1 of the EU GMP guide, has tripled in size from its 16-page original document, which was introduced in 1971, to a 50-page document. The enlargement contains the principles of quality risk management to “ensure that microbial, particulate, and pyrogen contamination associated with microbes is prevented in the final product” (2).

	Other additions include details on the use of new technologies, also mainly to provide protection against particulates and microbes. Another expanded area is the training and skills required of personnel to ensure they have the appropriate engineering and microbiological knowledge.

	The complexity and detail of the guideline is expected to lead to the closure of sterile capacity serving the European market in anticipation of its extra costs. “[On the basis of] the current draft, we expect that for several sterile manufacturing sites, the capacity for some products will be reduced by 50% during the [guideline’s] implementation phase,” Laenen explained. “This implementation phase could be lengthy, amounting to several years. Hence, reduced sterile production capacity could occur for products that are already on [the World Health Organization’s] WHO’s shortage list. It’s important also that once the new Annex 1 is adopted, inspectorates are treating and interpreting it in a uniform way to prevent differences in audit findings and outcomes.”

	The additional work the industry is wanting EMA to perform on the guideline could postpone its full implementation even further. In their joint letter to the agency, the trade associations and professional organizations have asked for the opportunity to provide further feedback to the IWG before the document is finalized. This is because of the large number of comments submitted during the first consultation round.

	The industry wants workshops, seminars, and training sessions to be held to achieve a clearer understanding between the pharmaceutical sector and the inspectorate on the purpose, scope, and expectations of the guideline’s risk-based approaches. There is a need to understand more clearly how the risk control measures in the guideline help to enhance levels of sterility, according to the joint letter. To enable a “harmonized understanding and implementation” of the new guideline, industry suggests in the letter that training materials be developed for both pharmaceutical companies and regulators.

	Finally, industry wants at least parts of the guideline to be implemented gradually over a period of up to five years because of risk assessment requirements and the complexity of the changes. One area likely to cause complications, for example, is the risks created by poor quality control of filters, which may necessitate pre-use, post-sterilization integrity testing.

	A large proportion of guideline revisions have been triggered by the establishment of new technologies, which indicates that there will be an increasing number of new versions of guidelines over the next several years. Much of the impetus behind the drawing up of the new guideline on sterile manufacturing has come from the use of new technologies, particularly in dealing with microbial contamination.

	EMA published in November 2018, with a consultation period due to end in May 2019, a draft guideline on the quality of water for pharmaceutical use because the two existing guidelines on the subject, issued in 2001 and 2002, were out of date (3). The existing guidelines allowed only distillation for purification of water for injection. The new guideline permits the use of new technologies such as reverse osmosis coupled with techniques like electrodeionization, ultrafiltration, and nanofiltration. 

	In a draft document on EMA Regulatory Science to 2025, published in December 2018, the agency outlines how it is aiming to keep pace with technological advances (4). “The pace of innovation has accelerated dramatically in recent years,” said Guido Rasi, EMA executive director, in the document. “Regulators need to be ready to support the development of increasingly complex medicines.”

	Among the agency’s strategic goals will be the facilitation of the introduction of novel manufacturing technologies by taking a ‘flexible approach’ in the application of GMP. This policy has already run into difficulties with controls of advanced therapy medicinal products (ATMPs). Instead of issuing new up-to-date guidelines on the manufacture of active biological substances, the EC adopted, in November 2017, a standalone regulation of GMP for ATMPs (5).

	This action raised accusations of a lowering of GMP standards. The Geneva-based Pharmaceutical Inspection Co-operation Scheme (PIC/S), which aims to develop common GMP standards among inspectorates worldwide, claimed that the EU guideline risked leading to divergencies in GMP internationally, particularly with ATMPs.

	Participants in PIC/S include EMA, FDA, and WHO. EMA’s guideline on sterile manufacturing was, for example, drawn up in close collaboration with PIC/S and the WHO. PIC/S now comprises 52 authorities mainly in Europe and North America but also including Asia-Pacific, South America, and Africa so that it provides a global network of inspectorates.

	The primary aim behind efforts to achieve harmonization of GMP standards is to make efficient use of inspection resources by avoiding the necessity for duplicate inspections of pharmaceutical plants across the world, especially those exporting their products into the global pharmaceuticals market. A joint report last year on an international inspection program of API plants in 2011–2016, involving EMA, FDA, WHO, and approximately 10 other authorities, mainly in Europe, concluded that more work was needed to be done to avoid duplication. National legislation requiring unnecessary inspections was, for example, still to be left unamended.

	The dispute between the EU and PIC/S over the ATMP guidance underlines the challenges facing the EMA and other regulators in both keeping in step with new technologies while also ensuring that guideline revisions and changes remain consistent with international GMP standards.

	1. EFPIA and other organizations, “Letter to Brendan Cuddy, EMA’s Head of Manufacturing and Quality Compliance, from Sini Eskola, EFPIA’s Director of Regulatory, Drug Development and Manufacturing” (Brussels, October 31, 2018).
	2. European Commission, EU GMP Annex 1 Revision: Manufacture of Sterile Medicinal Products (Draft) (Brussels, December 20, 2017).
	3. EMA, Guideline on the Quality of Water for Pharmaceutical Use EMA/CHMP/CVMP/QWP/4986873/2018 (London, November 13, 2018).
	4. EMA, EMA Regulatory Science to 2025-Strategic Ref lection (Draft) EMA/872479/2018 (London, December 2018).
	5. European Commission, Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products (Brussels, November 22, 2017).


	Volume 31, No. 5
	May 2019
	Pages: 6–8

	When referring to this article, please cite it as S. Milmo, "Playing the Waiting Game with GMP Guideline Revisions,"

Delays in revisions to guidelines by the European Union are impeding the pharmaceutical industry.

Playing the Waiting Game with GMP Guideline Revisions

	After several years of consultations with stakeholders followed by periods of prevarication, the European Commission has finally published a strategy (1) that will provide a basis for the European Union’s policy on pharmaceuticals in the environment (PIE). The commission has been obliged to draw up the strategy under two pieces of EU legislation-one introduced more than eight years ago on pharmacovigilance (2) and the other approved in 2013 on water pollution (3). It had also pledged to issue a PIE policy under agreements with the United Nations and other international bodies.

	The publication and contents of the strategy were welcomed by a joint PIE task force of the three main European pharmaceutical trade associations. The strategy covers several areas on which the task force itself and other industry initiatives are working, such as the identification and prioritization of medicines likely to present environmental risks, more effective monitoring of environmental impacts, and greater data transparency with environmental risk assessment (4).

	The industry is broadly supporting the strategy despite the likelihood that it could result in tougher PIE regulations. “There are many things in the strategy that are good, although there are others that we are concerned about,” Bengt Mattson, co-chair of the joint task force, told 

. “On the whole, it is a positive document that will allow us to be closely involved in continuous discussion among stakeholders about the best way forward on the PIE issue.”

	The strategy was issued by the commission as a ‘communication’ so that it did not have to be a vehicle for presenting specific proposals for legislation. Instead it pinpoints six areas for possible regulatory and other measures to tackle what it calls the ‘emerging problem’ of pollution by pharmaceuticals and their residues.

	The six areas listed in the strategy are increasing awareness of the PIE issue, filling knowledge gaps about the problem, promoting greener manufacturing, and the development of medicine less environmentally harmful, improving environmental risk assessment, expanding environmental monitoring, and more efficient waste management (1).

	Any new PIE regulations-in the form of new legislation or amendments to existing regulations-may not come into force for several years because of the necessity for further consultations and other preparatory work, such as social and economic impact assessments necessary for legislative changes. Any legislative action would have to be put forward by a new commission, which is due to take office in November 2019 (5). Also, there will be uncertainties about the environmental stance of a new European Parliament, which is scheduled to be inaugurated in July 2019.

	Until the two arms of the legislature are actually presented with draft regulations by the commission, the arguments about the most effective ways of dealing with pharmaceutical pollution will continue to rage among the major stakeholders-such as the pharma industry, regulators, healthcare professionals, and providers and non-governmental organizations (NGOs).

	However, as a result of the publication of the strategy, the scope of the discussions will be much narrower-at least in terms of what steps can be taken with the strong support of the EU at the regional and national levels. “At least we know what will now be the focus of the discussions as laid down by the range of options selected in the Commission’s strategy,” said Mattson.

	A priority will be the creation of research projects to help fill, through the EU-funded research programme, a variety of knowledge gaps. The EU has already financed in recent years at least 10 research projects on pharmaceutical pollution and waste treatment processes.

	“More information is still needed to understand and evaluate certain pharmaceuticals [regarding] their environmental concentrations and the resulting levels of risks,” said the commission in the document (1). It admits that ‘no clear link’ has been established between pharmaceuticals in the environment and direct impacts on human health. But it points to a World Health Organization study showing possible effects of long-term exposure to vulnerable populations that dictate a need for a precautionary approach to the PIE problem (6). 

	Also, there are worries about the role of the environment in antimicrobial resistance (AMR), on which the commission has already launched an action plan (7). The PIE strategy highlights the ‘particular concern’ that emissions from some antimicrobials manufacturing plants in third countries, some of which export products to the EU, could be contributing to AMR’s global spread.

	Research, including that in areas like AMR, will be a major objective of the strategy through EU-funded programmes and organizations like the Brussels-based Innovate Medicines Initiative (IMI), which has a €5-billion (approximately $5.6 billion) budget provided jointly by the EU and the pharma industry. Among the IMI’s projects is a scheme called Intelligent Assessment of Pharmaceuticals in the Environment (iPIE), which conducts research to help support regulatory initiatives.

	“The industry has a lot to contribute because we should know more about our substances than others,” explained Mattson. But he also pointed out that the other stakeholders would be heavily involved in discussions on future measures, covering the whole lifecycle of pharmaceuticals.

	Among the research mentioned in the strategy are schemes to support the development of ‘greener’ pharmaceuticals, which degrade more readily in wastewater treatment plants and in the environment. Also, research can be used to manage risk more effectively by increasing knowledge, for example, on the eco-toxicity and environmental fate of pharmaceuticals. Another research aim would be to find out more about the effects on humans of chronic exposure to low levels of pharmaceuticals in the environment, taking into account mixtures of multiple pharmaceutical substances.

	A combination of regulatory pressures and incentives could be used to persuade pharmaceutical companies to switch to more environmentally benign medicines. For example, procurement policies could be more widely applied to encourage greener pharmaceutical design and production processes.

	A more fundamental move would be “to explore how extended producer responsibility could play a role in supporting action to improve the efficacy of water treatment,” according to the commission.

	As pharmaceuticals and their production processes become greener, regulations could be changed to target more pharmaceutical substances considered to be an environmental risk. Under the Water Framework Directive (WFD) (8), the EU’s main legislation on preventing water pollution, pharmaceuticals with similar effects could be put into risk categories limiting their water concentrations.

	Under the Industrial Emissions Directive (9), the primary legislation for applying pollution controls on pharmaceutical manufacturing plants, state-of-the-art production processes may have to be employed in the production of certain medicines and active ingredients. 

	The strategy document even suggests that the EU exert its influence through ‘dialogue and co-operation’ to encourage non-EU countries to take action on pharmaceutical emissions from plants suspected of contributing to global AMR.

	Among other key strategy options is raising the efficiency of environmental monitoring of pharmaceuticals and improving their risk assessment. It suggests increasing environmental expertise among regulators involved in environmental risk assessment of medicines. Ways should be examined of giving the public more access to information from environmental risk assessments and relevant toxicological thresholds, while taking into account dataâprotection rules.

	To expand monitoring, the commission will consider adding more pharmaceuticals to the WFD’s ‘watch list’. Also, it will support studies on the monitoring of pharmaceutical substances not only in fresh and marine waters but also in soils, sediments, and wildlife.   

	The feasibility of monitoring of AMR microorganisms and genes could be considered, including their inclusion in the EU’s Europeâwide survey of soil conditions with observations being made at 250,000 sample points.

	As the EU prepares to become much more active in controlling pharmaceuticals in the environment, industry is warning that regulatory and other initiatives must be based on science and risk. “We are worried that general limits on concentrations of pharmaceutical substances will be imposed, which are not justified on the basis of science or risk,” Mattson explained. “We don’t want pharmaceutical substances to be banned or restricted just because they are hazardous without taking into account risks of exposure. Medicines are intrinsically hazardous, otherwise they would not have beneficial effects on patients.”

	Nonetheless the commission says in the strategy document that it will foster exchange of information between EU states on best practices in taking environmental considerations into account in ‘the choice of therapy’.

	Also, it will consider the findings of recent evaluations of chemicals under the EU’s Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) legislation (10) on chemicals safety “as regards links with medicinal products legislation in relation to environmental protection.” Currently, pharmaceutical substances, except intermediates used in production, are exempt from REACH regulations.

	There is a danger that as the EU subjects medicines to more environmental controls, the long-established divide between medicines and environmental regulations will start to become blurred and there could be a conflict of interests between the two.

	1. European Commission, “Communication: European Union Strategic Approach to Pharmaceuticals in the Environment” (Brussels, 11 March 2019).
	2. European Union, “Directive (and) Amendment No. 2010/84 on Community Code Relating to Medicinal Products for Human Use” (Brussels, 15 December 2010). “Regulation (and) Amendment No 1235/2010 laying down Community procedure for the authorization and supervision of medicinal products for human and veterinary use” (Brussels, 15 December 2010).
	3. European Union, “Directive No. 2013/39 on priority substances in the field of water pollution” (Brussels, 12 August 2013).
	4. Inter Associations Initiative Pharmaceuticals in the Environment Task Force, “Joint Press Statement on European Union Strategic Approach to Pharmaceuticals in the Environment” (Brussels, 12 March 2019).
	5. European Commission, “

,” accessed 14 March 2019.
	6. WHO, “

,” accessed 12 March 2019. 
	7. European Commission, “EU One Health Action Plan against Antimicrobial Resistance (AMR)” (Brussels, June 2017).
	8. European Union, “Directive No 2000/60 Establishing Framework for Community Action in the Field of Water Pollution” (Brussels, 23 October 2000).
	9. European Union, “Directive No. 2010/75 on Industrial Emissions (Integrated Pollution Prevention Control)” (Brussels, Belgium, 24 Nov. 2010).
	10. European Union, “Regulation No 1907/2006 Concerning the Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH)” (Brussels, Belgium, 18 Dec. 2006). 


	Vol. 31, No. 4
	April 2019
	Pages: 8–9

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

The European Commission has published a strategy that will form the basis for the European Union’s policy on pharmaceuticals in the environment.


Regulating Pharmaceuticals in the Environment

	The European generics and biosimilars sector has been endeavouring, with the close support of its United States counterpart, to accelerate the creation of a single pathway for the global development of its products so that these treatments can be introduced more quickly both in the European market and elsewhere in the world. Although there has been progress in establishing a global regulatory system for generics and biosimilars, this progress remains fragmented with overburdened national licensing agencies doing much of the assessment work for the approval of off-patent products.

	Among the major obstacles still to be overcome is the coolness among governments and their regulators-and even within parts of the industry-to the concept of global comparator products, which could act as references for marketing authorizations. Governments are worried that reliance on global comparators would result in a loss of control of a class of medicines, which in most countries account for the vast majority of drugs on their markets.  

	“Using a global comparator product for different regions around the world is mainly a political question,” Gerard Beuerle, senior director, global generic R&D, Teva Pharmaceuticals, told Medicines for Europe’s regulatory and scientific affairs conference in London on 1 February 2019 (1). Medicines for Europe is the region’s trade association for generic medicines and biosimilars producers.

	Strong political support for change is needed in the EU member states and other European countries because legislation may have to be amended to allow international harmonization. At the same time, there will have to be close collaboration between regulators including a willingness to exchange information on existing comparators being used by agencies. 

	However, global regulatory initiatives such as single pathways in the development of generics and biosimilars would give patients greater access to affordable quality medicines. Hard pressed regulators would be able to process more quickly authorization applications because of less duplication and more efficient use of agency resources.

	Closer co-operation between governments, regulators, and the industry is generating an international climate favourable to advances in the setting-up of a single development pathway.

	The Geneva-based International Council for Harmonization (ICH), the main world body responsible for establishing uniform pharmaceutical standards, no longer exclusively deals with new drugs. During the past three years, ICH has broadened its scope to cover generics. It has also widened a membership predominantly consisting of representatives from Europe, North America, and Japan to include those from emerging economies in Latin America and Asia.   

	At its last assembly meeting at Charlotte, North Carolina, USA, in November 2018, ICH adopted a reflection paper on harmonizing of generic drugs standards (2). “Harmonization may allow developers to use data submitted in support of a generic drug marketing application to meet multiple jurisdictions’ regulatory requirements for marketing authorizations,” the paper says. “Harmonization may increase the size of the genericâdrugs markets and thereby attract more competition from (drug) developers.”

	As a result of the adoption of the reflection paper, ICH is planning to set up in 2019 an informal generic drug discussion group (IGDG) that will recommend areas for harmonization. But the group will operate for only a year, after which ICH’s management committee will decide ‘whether additional work merits its continuation’.

	Another source of collaboration is the International Pharmaceutical Regulators Programme (IPRP). This was created from the merger of the International Generic Drug Regulators Programme (IGDRP), which fostered collaboration among generic-drug regulators, and the International Pharmaceutical Regulators Forum (IPRF) that dealt mainly with patented medicines. 

	The World Health Organization (WHO) now exercises more influence over the international regulation of generics through its programme for assessing finished medicines and APIs, and quality control laboratories to qualify products for governments’ essential medicine procurement schemes around the world. The pre-qualification programme includes an appraisal of the competency of pharmaceutical regulatory agencies with those that are classified as meeting ‘stringent’ standards being entitled to take part in the project (3).

	The use of stringent regulatory authorities (SRAs) provides a useful platform for ensuring that comparators are quality products, Deusdedit Mubangizi, co-ordinator of the WHO prequalification team, told the London meeting. One drawback was that SRAs accounted for only around a third of the world’s regulatory agencies and approximately 25–30% of the global population, he said.

	The EU and US are among the global leaders in single pathway development. The EU has long experience in the use of reference products to harmonize procedures for the approval of generic medicines among its member states. The US Food and Drug Administration (FDA) was a major contributor to the ICH reflection paper by proposing means for harmonizing guidelines on scientific and technical standards for generic drugs.

	The EU and US have now both built up a lot of experience in biosimilar medicines. “Sourcing of foreign reference products is in place without changing respective legislations (in the EU and US),” said Suzette Kox, secretary general of the Geneva-based International Generic and Biosimilars Medicines Association, at the conference (4). “Using a foreign comparator for biosimilar development is no limiting factor anymore for global development of biosimilar medicines.”

	Barriers to the introduction of global comparators remain the biggest hurdle to harmonization of generic medicines regulations because they are so closely linked to uniformity in bioequivalence standards. 

	“Harmonizing the requirement for performing bioequivalence studies (would be ineffective) if the study has to be repeated for every single country simply because the reference has to be a local comparator,” Alfredo Arieta, head of pharmacokinetics and generic medicines at the Spanish Agency of Medicines and Medical Devices (AEMPS), told the meeting, which devoted a whole session to the global comparator issue (5). 

	Arieta cited a study on comparators published in December in the Journal of Pharmacy & Pharmaceutical Sciences performed by himself and a team of regulators from 13 other agencies comprising FDA, Health Canada, Japan’s Pharmaceuticals and Medical Devices Agency, and agencies in Australia, New Zealand, Taiwan, Singapore, South Korea, South Africa, Brazil, Colombia, Mexico, and Switzerland (6).

	“The acceptance of foreign comparator products is the most limiting factor for the development and regulatory assessment of generic medicines marketed globally,” the study said. But it concluded that “there is currently no consensus amongst regulators on the acceptability of foreign comparators.”

	Most of the agencies are members of the Bioequivalence Working Group for Generics (BEWGG), which also includes the European Medicines Agency (EMA) and aims to promote, within the IPRP, greater collaboration and regulatory convergence. Currently, the agencies follow rules inconsistent with an internationally uniform approach to generics regulation. Some, for example, require bioequivalence studies to be performed with a local comparator while others accept studies based on foreign comparators but only under certain conditions.

	“How can the comparators be different in each country if they were approved (as new drugs) in all the countries based on the same clinical development (evidence)?” Arieta asked at the meeting. He put much of the blame for the problem on restraints on exchange of information among regulators.  

	Due to the absence of legal agreements on information sharing, “regulatory agencies are unaware if the comparator product from other countries is the same product as their own comparator,” he said at the conference. In many cases, a potential flow of information between regulators is blocked by legislation. “Agencies are unable to use (exchanged) information for reasons of confidentiality and/or legal restrictions,” he explained.

	Difficulties with exchanging scientific evidence between regulators is also considered to be a major barrier to harmonization of bioequivalence standards, said Beuerle. Lack of awareness about the scientific data on foreign comparators led at the local level to a lack of confidence in their bioavailability.

	When bioequivalence studies are based on a foreign comparator, the “generics might (be considered) not to be switchable with the local comparator or the local generics in case of products of chronic use,” explained Arieta at the meeting, adding that they might also be thought to be less efficacious or less safe. One result could be an inadvertent protection of local industry with governments thinking that they do not have to accept generics based on references from countries that do not accept their references.

	Among the possible solutions Arieta proposed could be a mutual recognition of a generic medicine by regulators from different countries when the drug involves the same marketing authorization holder, has the same qualitative and quantitative compositions and specifications, and is manufactured in the same plant or with the same production processes. 

	Such a solution would gradually become more viable if consolidation in the generics industry continues with manufacturing taking place in large, centralized plants. “Increased capacity building facilitates standards harmonization,” Guido Rasi, EMA executive director, told the meeting (7). 

	However, the consolidation trend is also being accompanied by a growing number of small suppliers entering the market. It would provide only a partial solution to the difficulties with regulatory convergence.  

	1. G. Beuerle, “Bioequivalence Studies in the Context of Global Development: Challenges and Current Initiatives,” presentation at Regulatory and Scientific Affairs Conference, Medicines for Europe (London, UK 2019).
	2. ICH, Further Opportunities for Harmonization of Standards for Generic Drugs, Reflection paper (Geneva, Switzerland 13 November 2018).
	3. WHO, “

,” accessed February 2019.
	4. S.Kox, “Global Development for Generics/Complex Generics-Catching up with the Biosimilars Framework and Beyond,” presentation at Regulatory and Scientific Affairs Conference, Medicines for Europe (London, UK 2019).
	5. A.G.Arieta, “Global Harmonization of Comparator Products,” presentation at Regulatory and Scientific Affairs Conference, Medicines for Europe (London, UK 2019).
	6. A.G.Arieta et al., 

 22 (1) 28–36 (2019).
	7. G. Rasi, “Globalization: European Medicines Agency’s Vision for the Next Five Years,” presentation at Regulatory and Scientific Affairs Conference, Medicines for Europe (London, UK 2019).  


	Vol. 31, No. 3
	March 2019
	Pages: 6Â­–8

	When referring to this article, please cite it as S. Milmo, "Europe Pushes for Global Easing of Generics Approvals," 

The European generics and biosimilars sector is working on the creation of a single pathway to accelerate development of and access to medicines.

Europe Pushes for Global Easing of Generics Approvals

	The main factor will be the United Kingdom’s departure from the existing 28-member state European Union, due to take place on 29 March 2019, almost three years after the country’s voters backed Brexit by a 52/48% margin in a referendum. 

	Nearly two months before the Brexit deadline day, an EU regulation on the mandatory serialization of drug packaging is scheduled to come into force with a large proportion of pharmaceutical producers and distributors currently looking unlikely to be able to comply with the new rules.

	Both events may require the introduction of emergency regulations at the national and EU levels to ensure that patients have continued access to their medicines. This possible rush of temporary rules to protect medicine supplies could be accompanied by a slowdown in activities on more permanent regulatory initiatives.

	The European Medicines Agency (EMA), which is not only responsible for the centralized licensing of medicines in the EU but also for providing guidance on existing legislation, will not be working at full capacity for much of next year (1). This is due to its relocation from London to the Dutch city of Amsterdam to ensure that the agency remains based in an EU member state. The move of its offices is forcing the agency to suspend or reduce some operations on preparing the ground for new legislation or improving existing regulations (1).

	At the same time, the existing European Commission is completing its five-year term in mid-2019 to be replaced by a new one that could have different regulatory priorities.

	Also, in May voters from the 27 remaining member states will be choosing members of a new European parliament (2) who will take their time sorting out alliances and coalition deals before taking on the task of discussing new legislation. 

	The biggest disruptions are likely to stem from the uncertainties of Brexit, both before it is scheduled to take place and afterwards. In December 2018, four months before the planned departure, it looked possible that the UK could crash out without a withdrawal deal with the EU (3). This would mean that on 30 March 2019 the UK would be considered a third country under the EU’s law without any regulatory ties except those based on the basic trading rules of the World Trade Organization (WTO) (4). 

	In mid-December 2018, the ruling Conservative party and UK parliament were still split over whether to approve a UK–EU withdrawal deal negotiated by prime minister Theresa May. This deal would allow a transition period until the end of 2020 for the negotiation of a free trade agreement and the implementation of a full Brexit (5).

	In a confidence vote on 12 December 2018 among the Conservative party’s 317 members of parliament, close to 40% strongly hostile to the deal opposed the prime minister. This confirmed that the withdrawal agreement would not be supported by a majority in parliament unless May gained further concessions from Brussels.

	With approximately 80 million medicines packages a month being traded between the UK-a major centre of drugs production in Europe-and the rest of the EU, pharmaceutical supplies not only in the UK itself but also across Europe would be severely impeded without a withdrawal agreement covering the export and imports of medicines (3). It could also impact wide areas of pharmaceuticals regulation in addition to supplies.

	“A ‘no-deal’ Brexit would mean the biggest disintegration of the complex regulated medicines market across Europe in terms of regulation, cross border movement of goods, comparative pricing, and intellectual property,” said Steve Bates, chief executive of the UK Bioindustry Association, representing biopharmaceutical producers, in a blog on 10 December 2018 (6).

	Only a few days before, Matt Hancock, the government’s health secretary, had announced more ‘no-deal’ contingency plans. In addition to a previous instruction to pharmaceutical companies to stockpile six weeks supplies, extra storage space would be made available, and shipping routes would be opened specifically for transporting medicines (3).

	Amidst fears in the industry about the pan-European effects of a Brexit without a deal, the European Federation of Pharmaceutical Industries and Associations (EFPIA) urged in December the European Commission and the UK to take emergency steps in preparation for a ‘no-deal’ scenario. 

	“We ask that the European Commission and member states consider every possible measure they can take collectively and with the UK to avoid disruption in the movement of medicines and clinical trial materials across the UK and EU borders,” said EFPIA (7).

	Among its suggestions were that medicines and clinical trial materials be temporarily exempted from any new customs and borders checks and the creation of fast-track lanes or priority routes for medicines into ports. Also, it proposed recognition by the EU’s European Air Safety Authority (EASA) of UK air safety certificates to ensure that planes, particularly those carrying medicines, can continue to fly, and the possible exemption of active pharmaceutical ingredients (APIs) as well as other medicines raw materials from border checks (7). 

	The European Commission may have to relax medicines regulations even before Brexit to remove any unnecessary obstacles to drug supplies. One of these is an EU regulation for the serialization or identification of individual medicine packs, due to be implemented on 9 February 2019 (8).

	The regulation, introduced under the EU’s Falsified Medicines Directive (FMD) of 2011 to combat counterfeiting of drugs, stipulates that each medicine should carry specific identification and safety features by the February deadline (8). These include a two-dimensional barcode with a machine-readable data matrix that can be accurately decoded using common scanning equipment.

	In preparation for the legislation, medicine manufacturers are having to modernize their packaging lines and adopt new software and communications systems for transferring labelling information to data repositories at national and European hubs. These hubs are connected to a network of wholesalers and pharmacies and other dispensing points across the 32 EU and non-EU states taking part in the scheme (9). 

	By December 2018, it was evident that while all countries in the scheme would have repositories and hubs with connections to the European hub up and running by the deadline, there will be large numbers of pharmaceutical companies, mainly small-to-medium enterprises (SMEs), which will not be ready by February. 

	“Pharmaceutical producers, especially SMEs, are running out of time,” explained Bart Vansteenkiste, global life-sciences business development manager at Domino Printing, a UK-based serialization specialist in printing and coding, when speaking with 

in December. “Only around 30–40% of packaging production lines in the European pharmaceuticals sector are currently ready for the legislation.”

	“According to the text of the legislation, if a medicine pack does not have a compliant label by 9 February 2019, it can’t be dispensed by the pharmacist,” he continued. “It seems unlikely that the European Commission will allow serious shortages to occur because of non-compliance by pharmaceutical manufacturers. Something like a system of fines may have to be introduced to make medicine producers gradually compliant.”

	Medicines for Europe, the Brussels-based trade association for generic and biosimilars manufacturers, has called for emergency action to help SMEs struggling with the high costs of updating packaging lines. 

	“We urgently ask the member states to communicate clear guidance on how they will deal with any actor that would not be able to comply with the FMD as of the deadline,” an association spokesperson told 

	Meanwhile, the relocation of the EMA has forced the agency to reorganize its activities so that it can focus on the core areas of authorization of new and existing medicines and their variations and safety monitoring during their life cycles. The agency has warned that it could lose as much as 30% of its 900 staff as a result of its move to Amsterdam, where initially it will be accommodated in temporary offices (1).

	Well before its relocation, due to be completed by 29 March 2019, the agency has cut back on work in areas such as international activities, guidelines, working party activities, and stakeholder interaction (1). 

	EMA had estimated that it would be able to resume full operations in mid-2019. But now this resumption may have to be extended well into the second half of the year. “In the latter half of 2019, EMA will gradually reintroduce previously suspended/reduced activities in line with priorities in the (European medicines regulatory) Network’s strategy to 2020,” an EMA spokesperson told 

. “We aim to fully resume our international activities by the end of 2019.”

	The EU’s regulatory activities in pharmaceuticals should return to a level of normalcy in 2020, but it may take longer to make up for the ground lost in 2019.

	1. EMA, “EMA Brexit Preparedness Business Continuity Plan-Phase 3 Implementation Plan,” EMA/701082/2018 (London, 9 October 2018).
	2. European Parliament, “Facts and Figures on European Parliament Elections” (Brussels, 20 August 2018).
	3. UK Department of Health & Social Care, “EU Exit-Human Medicines Supply in a March 2019 ‘No-Deal’ Scenario: An Update” (London, 7 December 2018).
	4. European Commission, “Brexit: European Commission Implements ‘No Deal’ Contingency Action Plan in Specific Sectors,” Press Release (Brussels, 19 December 2018).
	5. European Commission, “Draft Agreement on the Withdrawal of the United Kingdom of Great Britain and Northern Ireland from the European Union,” TF50(2018)55 (Brussels, 14 November 2018).
	6. BIA, “CEO Update,” BIA Blog (London, 10 December 2018).
	7. EFPIA, “Brexit: Protecting Medicines Supply in Europe in a ‘NoâDeal’ scenario. The Need for Urgent Action by the European Union,” Position Paper (Brussels, 10 December 2012).
	8. European Commission, “Delegated Regulation (EU) 2016/161 Laying Down Detailed Rules on the Packaging of Medicinal Products for Human use,” (Brussels, 2 October 2015).
	9. European Commission, European Medicines Agency, Heads of Medicines Agencies (HMA), “Letter to Stakeholders Regarding the Implementation of Safety Features under the Falsified Medicines Directive 2011/62/EU” (Brussels, October 2018).  


	Volume 31, Number 1
	January 2019
	Pages: 6–8

	When referring to this article, please cite it as S. Milmo, "A Year of Possible Regulatory Upheaval and Paralysis," 

This coming year could see a combination of regulatory uncertainty and inactivity for the pharma industry, mainly as a result of Brexit.