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

Sean Milmo

The 2020–2025 strategy of the European Union’s medicines agencies network (EMRN) (1), covering licensing authorities in 30 states as well as the EU’s own European Medicines Agency (EMA), has been called a ‘living’ document.

EMA and the Heads of Medicines Agencies (HMA), representing national authorities, which published the strategy in early July 2020, warned that after the draft document is finalized in November 2020, following a three-month public consultation, its content and objectives will be subject to regular review. This review status is mainly because the next five years are expected to be a period of rapid advances in science and technology in medicines, particularly in the collection and processing of healthcare data.

The strategy gives unusual prominence to the regulatory response to the development and introduction of innovative production processes, especially for advanced therapy medicinal products (ATMPs) and continuous manufacturing by small production units. Also, the document has been published too early to incorporate all the important lessons to be learned from the shortcomings in the supply and application of drug treatments in the COVID-19 pandemic. Instead, these lessons will need to be inserted into the strategy at a later date.

Another major factor likely to trigger changes in the document is the EU’s Pharmaceutical Strategy for Europe (2), due to be published by the European Commission (EC), the EU executive, by the end of 2020. It will have a much broader and longer-term scope than the EMA/HMA strategy, extending well beyond regulatory matters so that it is more closely aligned with the EU’s current industrial and digital strategies, the European Green Deal (3) and, yet to be finalized, Europe’s Beating Cancer Plan (4).

The medicine’s network strategy, which will be followed by the EU’s 27 member states and three non-EU countries—Iceland, Norway, and Liechtenstein—covers issues such as medicines availability and shortages, supply chain problems, data analytics and digitalization, antimicrobial resistance (AMR), pandemics, and regulatory operational excellence.

The network’s strategy is mainly concerned with issues centred on the quality, safety, and efficacy of medicines, which, because of digitalization, is increasingly being extended to the provision of data of these aspects of pharmaceuticals. An important objective outlined in the strategy is for EMRN to become Europe’s trusted source for healthcare data.

The Pharmaceutical Strategy will ultimately be dealing with matters of policy and potential legislative changes.

To highlight the differences in approach of the network agencies and the commission, the network strategy document gives as an example the issue of new medicines, centrally approved by EMA, being withheld from certain EU national markets. Company-initiated limits on the distribution of centrally approved products for pan-European marketing has been pinpointed by regulators as a major cause of lack of accessibility to new medicines.

It would be the job of EMRN to ensure the marketing authorization holders (MAHs) are fulfilling their regulatory distribution obligations under EU regulations. If a MAH’s actions were for commercial reasons, then the commission may need to be involved because ‘political encouragement’ may have to be applied, as reported in the strategy document.

In a roadmap on the Pharmaceutical Strategy (5), the commission stated that a major objective was to increase the manufacturing competitiveness of the European pharmaceutical sector. The EU needed greater autonomy in the supplies of medicines, particularly in APIs for non-patented medicines in Europe, of which the vast majority come from China and India. The EC is considering proposing expansions in European production capacity, especially for APIs, backed by the development of innovative production processes.

Hence, EMRN has concentrated on the laying of the regulatory groundwork for new manufacturing processes in the EU extensively in its strategy. A big driver is EC initiatives on the possible expansion of European pharmaceutical production capacity. These initiatives could include reshoring of some API manufacturing and the establishment of vaccine production units based on technological platforms for the development and production of vaccines in emergencies.

The network will also be considering the regulatory implications of the introduction of new process technologies, which have been under development over the past few years.

With personalized medicines, such as those based on gene and cell therapies, regulators are preparing for decentralized production in small manufacturing units, which bring the making of the treatment to patients. More drugs will be produced as a result in hospital pharmacies or operating theatres or even at the patient’s bedside. These small machines will be table-top size and mostly based on continuous rather than batch processes.

“At the moment, regulatory barriers or lack of harmonization of regulatory approaches is seen as a significant barrier to industry innovation and the take-up of new models such as continuous manufacturing,” states the strategy document (1).

Another area likely to see legislative changes is Substances of Human Origin (SoHo) because interfaces between tissue and cells and organs could affect the way plasma or tissues as starting materials, are regulated.

Advances in manufacturing processes and the introduction of production models using different types of locations will necessitate changes in good manufacturing practice (GMP) standards and guidelines. “Sustainable harmonized GMP guidance and supervisory procedures (conducted by EMA working groups) will be needed to provide a level playing field and a stable GMP regulatory environment with predictable outcomes,” according to the strategy document (1).

New manufacturing systems could hasten a shake-up in the implementation of good distribution practice (GDP) standards in Europe where the EU is already considering improvements. “The competences between authorities, especially as regards how GDP activities are authorized and supervised locally, are fragmented,” says the strategy document (1). “There should be consistent and comprehensive implementation of current GDP principles in all member states to ensure the integrity of the supply chain.”

Also, there will have to be changes in quality guidelines at the international level. The Geneva-based International Council for Harmonization (ICH) in pharmaceuticals is already planning a new guideline covering continuous manufacturing (1).

EMRN also envisages innovations in treatments and their production in the fight against infectious diseases, such as bacterial phages, monoclonal antibodies, and microbiomes, because of the enormous threat of AMR. AMR is considered to be a bigger danger by the regulators to human health than pandemics like COVID.

“If the emergence and spread of AMR spreads without restraint, the annual number of deaths worldwide is expected to increase to millions, making AMR a more common cause of disease than cancer by 2050,” the strategy document says (1).

To combat AMR effectively requires a ‘One Health’ approach combining human and animal health, the network asserts (1). But this necessitates a massive degree of multidisciplinary collaboration between legislators, regulators, physicians, veterinarians, academia, the pharmaceutical and food industries, and agriculture. However, this sort of cooperation is needed to control pandemics as well.

Perhaps in the short term, the biggest challenge facing the EMRN is the digitalization of the network or what it calls a ‘digital transformation’. This will not only require investment in IT infrastructure within and between agencies. It will also mean the building up of new capabilities among regulators and their staffs in data analytics so that they have full command of the potentially huge amounts of data that will be submitted by pharmaceutical companies in support of their marketing authorization applications.

Digitalization is already a major force behind improvements and innovations in pharmaceutical production processes. Furthermore, the network wants to create data storage and processing capacity that will help to make EU regulators the prime reference point for healthcare data. In particular, EMRN wants to make significant use of real-world data—data generated after a medicine has been marketed. These data will help fill some of the information gaps left by the narrow scope of clinical trials.

The EMRN concedes that there could be difficulties ahead with its digitalization programme because of a lack of existing regulatory standards and guidance on the use of patient data and artificial intelligence, already used in pharmaceutical development and production. Data science and its application has progressed far faster than regulations and guidelines.

The strategy document acknowledges that some national agencies are lagging behind with digitalization. Some authorities may have to achieve digital transformation more slowly than others.

A key issue will be the allocation of sufficient resources for digitalization both in term of funds and expert staff. Finance will have to be provided both by the EU and national governments.

EMA’s management board has complained about pressures on resources, although the matter was not specifically highlighted in the strategy document. Instead the strategy emphasizes the huge tasks facing the network as it confronts new scientific, technological, and social trends. “These challenges have never been greater,” the report confirms (1).

A lot will depend on the EC and its Pharmaceutical Strategy, which will be in a position to set the future policy directions of the whole EU medicines licensing network.

HMA and EMA, “European Medicines Agencies Network Strategy to 2025,” (Amsterdam, 3 July 2020).

EC, “Pharmaceutical Strategy for Europe,” 

EC, “Communication on European Green Deal” (Brussels, 11 Dec. 2019).

EC, “Europe’s Beating Cancer Plan—About this Initiative,” 

EC, “Pharmaceuticals—Safe and Affordable Medicines (New EU Strategy)—About this Initiative,” 


Vol. 32, No. 9
September 2020
Pages: 6–8

When referring to this article, please cite it as S. Milmo, “Regulations Under Regular Review,” 

Articles

The 2020–2025 EMRN strategy will be regularly reviewed over the coming five years to accommodate science and technology advances.

Regulations Under Regular Review

-nitrosamines in sartan anti-hypertensive drugs two years ago could ultimately have a much wider impact on pharma manufacturers, as well as regulators, than previously expected. Instead of introducing stricter rules on monitoring only the presence of 

-nitrosamines in medicines, European Union regulators want manufacturers and national regulators to take more effective action in tackling serious impurities in APIs and finished products.

This decision follows a study of the N-nitrosamines cases by a ‘lessons learnt’ group within the EU’s medicines licensing network, which concluded that the presence of the impurities had much broader implications for marketing authorization holders (MAHs) regarding the lack of control of production processes of not only medicines but their ingredients as well (1).

-nitrosamines saga began in mid-2018 when European medicines regulators discovered that Zhejiang Huahai, a Chinese drug manufacturer, was exporting an API containing 

-nitrosamines for an angiotensin II receptor blocker or sartan hypertension treatment, called valsartan, to Europe (2). 

-nitrosamines are classified as being probable human carcinogens.

-nitrosodiethylamine (NDEA)—were found in other sartan medicines, or their APIs, on the European market (2). The first response of the EU’s medicines licensing network, which is headed by the European Medicines Agency (EMA) and covers all the national drug agencies in the EU, was to recall some medicines from pharmacies and ban the use of sartan APIs made by some manufacturers (1).

Further investigation by EMA revealed that the risk from 

-nitrosamines in sartans, despite their carcinogenic classification, was low (1). In the vast majority of sartans, N-nitrosamines were either not present or present at low levels only.

EMA also concluded that the source of the impurities was the use of the solvent dimethylformamide with sodium nitrite in the presence of an acid, which led to the formation of 

-nitrosamines during the manufacture of sartan APIs (1). There was also the potential for the source to be 

-nitrosamine-contaminated solvents, reagents, or manufacturing equipment.

As a result, MAHs of sartans were instructed by EMA in January 2019 to test their products specifically for 

-nitrosamines and, if necessary, to make changes to the production processes for the APIs of the medicines (2). It then became clear that the presence of N-nitrosamines was not just a problem for sartans and their APIs but other medicines and potentially signalled difficulties with the detection of a wide range of impurities.

In April 2019, the EU medicines licensing network asked MAHs manufacturing the diabetes medicine pioglitazone to check their processes for NDMA after low levels of the impurity were found in batches of the drug made by an Indian producer (3).

EMA then revealed in September 2019 that it was starting a review of over-the-counter versions of ranitidine after tests had found NDMA in the medicine (4). The agency’s human medicines committee (CHMP), in April 2020, recommended the suspension of all ranitidine medicines due to NDMA in the products (5). Although the NDMA levels were generally low, the impurity had been found in several medicines at levels considered unacceptable. There were also unresolved questions about the source of the impurity in ranitidine. However, a final recommendation on the suspension was postponed in June 2020, after a ranitidine MAH asked for a re-examination of the decision (5).

The ‘lessons learnt’ group, which reported in June 2020 after being set up in May 2019 and hearing evidence from a stakeholder’s workshop in Amsterdam in November 2019, concluded that the underlying issue with all the 

-nitrosamine cases was inadequate control of impurities (1).

Despite the availability of plenty of guidance from the Geneva-based International Council for Harmonization (ICH) on requirements for human pharmaceuticals and from the 

 standards on certificates of suitability (CEPs), the potential for 

-nitrosamines impurities was not recognized during the development, manufacture, and evaluation of medicines found to contain them, the lessons learntgroup said (1). “MAHs, who usually outsource API manufacturing, may not have sufficient oversight of the manufacturing process,” the group added.

Guidelines needed to be clarified and amended to help MAHs but also regulators to better assess the possible presence of impurities, like 

-nitrosamines, the group suggested. The group proposed “further training for regulatory assessors in the network to improve the chances of identifying potential impurities during the evaluation of marketing authorization applications and certificates of suitability.”

The broadening of the range of the group’s recommendations from N-nitrosamines to other impurities has been accepted by EMA and the rest of the network, except they have narrowed the scope to “potentially carcinogenic” substances.

“The network is currently working on the implementation of the recommendations, including timelines for the different recommendations,” an EMA spokesperson told 

EMA sees the recommendations as complementing requirements specific to 

-nitrosamine impurities, which were announced in July 2020 and stipulated by the agency’s human medicines committee (CHMP) (6).

The requirements followed a request in September 2019 by EMA’s Executive Director Guido Rasi under article 5(3) of the EU regulation 726/2004 for the CHMP to give a scientific opinion on the issue of identification of 

-nitrosamine impurities in chemically synthesized APIs as well as in biological products (6).

The opinion would cover all scientific knowledge on 

-nitrosamine impurities in APIs and their impact on the safe use of medicines. In drawing up the opinion, the CHMP would work with the coordination group (CMDh) of the medicine regulatory bodies of the EU member states and Iceland, Liechtenstein, and Norway.

According to CHMP’s article 5(3) report, the presence of 

-nitrosamines in medicinal products should be at or below limits based on principles set out in the ICH M7 guideline on the assessment and control of DNA reactive mutagenic ‘cohort of concern’ compounds, which include 

-nitrosamines, and are derived from a lifetime exposure risk of 1 in 100,000 (6).

The lessons learnt recommendations are extensive in scope, covering not just the prevention of 

-nitrosamines and other impurities but also incident management, market surveillance, communication, and international cooperation.

They focus more on the responsibilities, as laid down in guidelines, of MAHs, finished product and API manufacturers, and active substance master file (ASMF) and CEP holders. A guidance review is, for example, proposed to clarify the responsibilities of these groups in respect of quality management systems, personnel, documentation, supplier qualification, contract and technical agreements, and management of quality defects.

Guidance should raise awareness of the importance of adequate knowledge of products and processes in order to “strengthen oversight of the entire supply chain” (1). According to the lessons learnt proposals, for example, guidelines should be updated on the need for improved exchanges of information between ASMF and CEP holders and MAHs on API product and process materials and the creation of impurities during API production. This would help MAHS “take full responsibility for the quality of their products, including APIs” (1).

The need for more effective audits of API and intermediate manufacturers should be emphasized in guidance. The reliability of the qualified personnel declaration system should be improved to enable MAHs to exercise more authority over API and intermediate manufacturing while supply-chain traceability of APIs and finished products should also be upgraded.

The lessons learnt report proposes that ICH guidelines be revised with the M7 guidance giving more details on the control of impurities and possibly being extended retroactively to older products. The report also recommended additions to the EU’s good manufacturing practice (GMP) guidance on the requirement to retain API and excipient samples, including those of product batches to enable batch-specific supply-chain traceability of APIs and finished products. GMP inspectors should also possibly be given guidance on how to verify during inspections what measures API producers have taken to reduce the risk of unexpected impurities.

The lessons learnt group acknowledges that its recommendations should synchronize well with the proposals put forward by CHMP under the article 5(3) procedure as well as other EU 

-nitrosamine-related initiatives. However, the group stresses that its proposals come from regulators within the EU’s medicines licensing network. “Other stakeholders, such as the pharma industry, are encouraged to conduct their own exercises to consider what additional actions they should take,” the group specified (1).

1. HMA and EMA, “Lessons Learnt from Presence of 

-Nitrosamine Impurities in Sartan Medicines” (Amsterdam, 23 June 2020).
2. EMA, “Angiotensin-II-Receptor Antagonists (Sartans) Containing a Tetrazole Group” (Amsterdam, 1 Feb. 2019).
3. EMA, “Update on Nitrosamine Impurities: EMA Continues Work on the Prevention of Impurities in Medicines,” 

, Press Release, 26 April 2019.
4. EMA, “EMA to Review Ranitidine Medicine Following Detection of NDMA,” 

, Press Release, 13 Sept. 2019.
5. EMA, “Ranitidine-Containing Medicinal Products” (Amsterdam, 30 April 2020, Updated 26 June 2020).
6. EMA and CHMP, “Assessment Report: Procedure Under Article 5(3) of Regulation EC(No) 726/2004; Nitrosamine Impurities in Human Medicinal Products” (Amsterdam, 25 June 2020).

When referring to this article, please cite it as S. Milmo, “Tackling Serious Impurities,” 

EU regulators are requesting more effective action be taken to tackle serious impurities in APIs and finished products.

Tackling Serious Impurities

	Editor's Note: This article was published in 

	Pharmaceutical companies, groups representing health professionals and care providers, non-governmental organizations (NGOs), and other stakeholders are currently working on their responses to a draft revised guideline by the European Medicines Agency on environmental risk assessment (ERA) for new marketing authorizations of medicines (1).

	The guideline-which will apply to medicinal products authorized at both the centralized and decentralized, mainly national, levels within the European Union-will replace an existing ERA guideline issued in 2006 (2). In fact, this guideline, the first of its kind in the EU, was first drafted almost 20 years ago.

	Now, the new guidance is being introduced at a time of growing demands, especially among some politicians and NGOs, for much tighter controls on the environmental effects of medicines throughout their entire lifecycles. As a result, the contents of the document, which is currently going through a seven-month consultation process, could turn out to be controversial for groups wanting environmental risks of pharmaceuticals to be much more strictly regulated. 

	The 48-page new guideline is much more detailed than the current 12-page version. This is mainly because over the past 12 years the environmental assessment of chemical substances and compounds has become much more sophisticated and complex. As a result, any revised guidance requires a lot more information on how to conduct up-to-date safety profile tests.

	EMA’s guideline gives much more prominence, for example, to endocrine active substances (EAS) in the wake of rising concerns about their dangers to the environment, even in small quantities (1).

	Much of its advice on testing methods comes from guidance laid down by the Helsinki-based European Chemicals Agency (ECHA), which is responsible for administering the Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH), the EU’s chemicals safety regulation. REACH came into force after the existing ERA guideline in June 2007, since then ECHA has issued a mass of guidelines on the testing of substances.

	Another major source for EMA on assessment technologies and systems has been the Paris-based Organization for Economic Co-operation and Development (OECD), a leading provider of international protocols which has been issuing an increasing amount of information on safety test methods.

	The likelihood that the new guideline will generate more detailed information on the environmental impact of medicines will be welcomed by environmental scientists and officials in the industry. This is particularly true among those involved in efforts in the pharmaceutical sector to build up large amounts of data on the behaviour of medicines in the environment so that industry can draw up internationally recognized standards of good practice in environmental management, especially in the control of effluent from pharmaceutical manufacturing plants (3).

	“Important data will be generated about the environmental effects of new medicines mostly when they are excreted by patients during treatment but which can then be used by industry when dealing with effluent from manufacturing facilities,” Bengt Mattson, co-chair of the European industry’s Inter-Association Task Force on pharmaceuticals in the environment, told Pharmaceutical Technology Europe.

	Mattson’s group, which comprises Europe’s main pharmaceutical associations, has also helped to set up the Eco-Pharmaco-Stewardship (EPS) dealing with environmental issues during the entire lifecycles of medicines (4). 

Notable similarities with previous guideline

	While there are big changes in both the depth and coverage of the new ERA guideline, there are also notable similarities with the 2006 document, which are already arousing opposition among NGOs and other organizations campaigning for more environmental regulatory controls on pharmaceuticals. 

	For many of these groups, a priority is that potential environmental damage must be included in the benefit/risk analysis by regulators when deciding to authorize a medicine. But in its revised document, EMA repeats the stipulation in its 2006 guideline that environmental impact should not ‘constitute a criterion for refusal’ of a marketing authorization (1).

	“It is disappointing to see, after more than a decade, that there is no advancement in EMA’s guidelines and no stronger indication that the environmental impact of pharmaceuticals is truly being considered,” Will Clark, executive director of Health Care Without Europe, whose members include hospitals, healthcare professionals, and environmental organizations, told Pharmaceutical Technology Europe. 

	“ERA results should be systematically considered in the risk-benefit analysis of marketing authorization decisions for new human medicinal products,” Clark added.

	NGOs have been pressing for a range of Pharmaceuticals in the Environment (PIE) controls in the EU. In 2018, the European Environmental Bureau (EEB) and Changing Markets Foundation (CMF) put forward eight pages of proposals in a joint position paper on PIE regulations, many of them linked to ERA procedures and outcomes (5).

	Besides authorization of medicines being at least partly conditional on ERA results, other changes supported by NGOs include assessment of drugs authorized before the 2006 guide, incorporating assessments of manufacturing plant effluents in ERAs, and increasing public access to ERA data.

	Currently, only a relatively small number of medicines have been found to pose any significant environmental risks, under the present ERA system. Out of 478 new environmental risk assessments by industry published in 2017 on the website fass.se, a Swedish medicines information portal, 10 substances were considered to pose risks or be hazardous. Two were classified as posing high-risk, seven moderate-risk, and one as being hazardous, according to a review of the assessments conducted annually by the Swedish Environmental Research Institute (IVL) (6).

	Under the new guideline, more medicines may be assessed across Europe as being a potential environmental risk or hazard than under the existing guidance because of the requirement for the use of more up-to-date and in-depth test methods.

	As in the 2006 document, EMA continues to advise a tiered approach to assessments of medicines with some products needing more thorough investigation than others (1).  

	For each medicine, both risk and hazard assessments for persistent, bioaccumulative, and toxic (PBT) substances have to be performed because harm can occur regardless of the level of exposure. But with products found not to be readily biodegradable, for example, further testing is considered necessary.

	The assessment methods used with PBTs are identical to those methods that ECHA requires to be applied to chemicals under REACH (1).

	A prime objective behind the more detailed guideline is the creation of more consistency on environmental risk issues between national licensing agencies. “[We are] looking for harmonization in the future, based on the implementation of the revised guideline,” Adrian van den Hoven, director general of Medicines for Europe, the generics trade association, told Pharmaceutical Technology Europe.

	But harmonization may turn out to be more difficult to achieve due to the more up-to-date assessment methods advised by the guideline. The additional ERA data give more opportunities for differing interpretation of assessment information by national agency specialists. Some agencies employ their own ecotoxicologists for ERA evaluations. 

	NGOs are expecting that, after the consultation process on the guideline, its scope might be extended to include medicines authorized before 2006, revealing more products with environmental risks. A German report on aquatic pollution found that no ERAs on the top 10 human medicinal products found in the country’s surface water were available, according to the EEB/CMF position paper (5).

	However, as part of the EPS initiative, the industry is supporting both an extension of the scope of ERA to pre-2006 products and to updating existing environmental risk assessments. 

	“We are investigating the methodology to prioritize legacy (pre-2006) compounds with little or no data for future ERAs,” said Mattson. “The pharmaceutical industry believes that among the large number of incompletely tested compounds for their environmental risks, only a limited number are of real environmental concern. For this (prioritization) process, no legislative initiative is foreseen yet. Therefore, a voluntary approach is more likely to go forward.”

	Updates of existing ERAs would be particularly useful for companies seeking marketing authorizations of products with the same active ingredient, according to Mattson. “The oversight of this process needs to be with regulators in co-operation with industry,” he explained. “Industry is open to any non-legislative approaches (on this issue).”

	Easier access to the ERA’s data of a medicine’s originator is desired, in particular, by generic-drug manufacturers. “We don’t believe that it makes sense to replicate the same studies over and over again-which would massively affect the cost and availability of generic approvals,” said van den Hoven. “No arrangement is foreseen in the current draft guideline (on data sharing), only the suggestion that sharing of information is to be considered.”

	The revised guideline is likely to be changed as a result of the consultation process due to end on 30 June 2019. Also, it may have to be altered after the imminent publication of a longâawaited PIE strategy by the European Commission (7).  

	“If (the strategy) is released prior to the finalization of the guideline following the consultation period, (our) drafting group will attempt to align the guideline as much as possible with the Commission’s strategy,” an EMA spokesperson told Pharmaceutical Technology Europe. However, she pointed out the objectives of the two documents are different with the PIE strategy covering the full lifecycle of pharmaceuticals and the ERA guideline mainly consumption.

	Nonetheless NGOs and some politicians want a much bigger overlap between the two. The 2006 document went through three consultations before being adopted. The new guideline may have to undergo at least a similar number before being finalized.

	1.    EMA, “Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use” (London, 15 November 2018).

	2.    EMA, “Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use” (London, 1 June 2006).

	3.    Innovative Medicines Initiative, “Intelligence-led Assessment of Pharmaceuticals in the Environment” (Brussels, 2017).

	4.    EFPIA and other pharmaceutical organizations, “Inter-Association Initiative (IAI), Eco-Pharmaco-Stewardship” (Brussels, April 2016).

	5.    European Environmental Bureau (EEB) and Changing Markets Foundation, “Policy Options for Regulating Pharmaceuticals in the Environment” (Brussels, February 2018).

	6.    Swedish Environmental Research Institute (IVL), “Self-Declarations on Environmental Classifications at fass.se-Experiences from Reviewing Process during 2017” (Stockholm, June 2018).

	7.    European Commission, “Roadmap-Strategic Approach to Pharmaceuticals in the Environment” (Brussels, 28 April 2017).  

	When referring to this article, please cite it as S. Milmo, “Spotlight on Assessing the Environmental Impact of Medicines," 

Various groups and stakeholders from pharma, healthcare, and government are responding to a new draft environmental risk assessment guidance from EMA.


Spotlight on Assessing the Environmental Impact of Medicines

	Pharmaceutical companies in Europe involved in the development of integral drug-device combinations (DDCs) were left on tenterhooks in August 2018 after the European Medicines Agency (EMA) revealed it would be cutting back work on guidelines on the authorization of certain unspecified groups of medicines (1). The announcement raised fears among companies that they would have to postpone plans for the commercialization of new combination products because of delays in obtaining marketing authorizations due to a lack of clarity about approval rules.

	Developers of integral DDCs, which range from pre-filled syringes to complex electro-mechanical devices, have been waiting for a crucial guideline for more than a year on procedures for the assessment of device components in combination products under the European Union’s Medical Devices Regulation (MDR), which is replacing the 1993 Medical Devices Directive (MDD).

	When it comes into effect in May 2020, the MDR will require, for the first time, integral DDCs to have their drug device components evaluated by specialist organizations, called notified bodies (NBs), for certifying device standards. The legislation contains large gaps in information about the process for the assessment of DDCs by NBs, which can be filled only by an EMA guideline. The agency started preparing a draft of the guideline in early 2017.

	“There is currently no understanding of how the process to support this new requirement (for an NB opinion on a device) would work,” stated the Brussels-based European Biopharmaceutical Enterprises (EBE) in a reflection paper published in July 2018 (2). “In turn, concerns are being raised that this [information gap] could impact approval timelines and unduly delay important medicines getting to market.”

	Biopharmaceuticals producers, of which EBE is a leading European representative, are particularly worried about problems with approvals of combination products under MDR because of the growing number of biologicals, such as monoclonal antibodies (mAbs), being delivered through DDCs.

	The views expressed by EBE, which is a branch of the European Federation of Pharmaceutical Industries and Associations (EFPIA), are also being echoed by other associations, such as Medicines for Europe, representing generic-drug producers, and MedTech Europe, the medical device manufacturers’ association.

	Unfortunately for the pharma and medical device sectors anxious about uncertainties regarding requirements under the MDR, EMA is facing a period of upheaval due to the United Kingdom’s departure from the European Union in March 2019. The agency is currently having to complete the relocation of its headquarters from London to Amsterdam, Netherlands, over the next five months and also cope with an expected 35% reduction of staff. As a result, it is temporarily reducing its activities, including the drawing up of guidelines, between November 2018 and June next year.

	The agency, however, disclosed in early October 2018 that it would carry on preparing the guideline on MDR, as well as a number of other guidelines on issues such as pharmacovigilance, anticancer medicinal products, and GMP guidance on manufacture of sterile products (3).

	“EMA is aware of the concerns raised by the industry that came with the introduction of the new MDR, and in particular with Article 117 (requiring an NB opinion on combination products),” an agency spokesperson told 

	“Work on seven guidelines which address either an urgent public/animal health need or are necessary to support and facilitate preparation for Brexit or the implementation of new or revised legislation will continue beyond 1 Nov. 2018. This includes the guideline on quality requirements of medicinal products containing a device component for delivery or use of the medical product.”

	There have been other signs that the regulatory authorities are increasing their efforts to eliminate uncertainties on MDR. EMA now has a dedicated task force on MDR implementation as it affects the agency’s responsibilities for the centralized licensing of medicines, including DDCs, in the EU. There have also been informal talks on MDR between industry representatives and officials of the European Commission, the EU executive that has overall responsibility for the regulation’s implementation.

	“We are still hoping to make more progress than this,” Barbara Freischem, EBE’s executive director, told 

	Other obstacles remain once the draft of the EMA guideline has been completed, possibly by the end of this year. The draft has to go through a consultation process with stakeholders and other interested parties, whose comments will have to be considered when the guideline is finalized, probably well into 2019, two years after the adoption of MDR.

	It is unclear what impact the guideline will have on national agencies or competent authorities (CAs) in EU member states, which approve combination products in their own markets, and to what degree of urgency they will be moved forward with the implementation of MDR.

	Competent Authorities for Medical Devices (CAMD)-an association representing national medical device licensing agencies, many of whom also approve medicines-has given a “low” priority to guidance for combination products on the “appropriate level of interaction with relevant authorities” (4).

	Industry believes that there needs to be a clear relationship between regulatory authorities, NBs, and combination product manufacturers for the approval procedure to work properly.

	Most of the more than 30 objectives listed in a CAMD roadmap, which also covers companion diagnostics, have been allocated a “medium” or “high” priority.

	There have also been delays in an EU-wide procedure for raising the efficiency of NBs by requiring that each one be certified according to new, tougher standards. This process is likely to result in fewer notified bodies being accredited to do MDR assessment work, particularly on DDCs and other combination products.

	“We don’t know whether there will be sufficient NBs and whether those that are available will have the capability to evaluate combination products like DDCs,” said Freischem.

	Accredited NBs will have to have been designated to conduct conformity assessments on drug device combinations. DDC manufacturers will then be free to choose one of these designated notified bodies to evaluate their products.

	The EBE has suggested that the process of NB evaluation could be made easier for both the medicine and device manufacturers, as well as the notified bodies, by basing the EMA guideline on an already existing guideline, issued by the agency in 2011 (5). This guideline is for combination products comprising advanced therapy medicinal products (ATMPs), such as gene and cell therapies.

	The seven-year-old guideline would provide, according to EBE, a framework for a tiered, risk-based approach within MDR to combination products. Those using existing, well-known technologies might not, for example, be required to undertake an NB assessment. More complex and innovative products may not only need an NB evaluation but also an opinion of a group of experts.

	Swissmedic, the medicines and devices licensing agency of Switzerland, a non-EU country that aligns its regulations with those of the EU, has already been preparing its own MDR-compliant legislation, which allows for an evaluation by experts.

	With integral complex and innovative combination products, the suitability of the device component would be assessed by the Swiss equivalent of an NB or “some other type of expert opinion,” according to the agency (6).

	EBE stresses the need for NBs to be clear about their responsibilities in the evaluation of DDCs, so the EMA guideline must be unambiguous about what data have to be provided by the medicine manufacturer. This requirement is particularly the case with information related to the compatibility of the drug to features of device components, especially materials.

	The complications in drawing up a coherent procedure for assessing DDCs and other combination products under MDR are being blamed on the usual teething problems with new legislation but also on the fragmented nature of the EU’s system for certifying device component quality standards.

	“You tend to get difficulties with gaps in information with most new legislation,” explains Freischem. “But with MDR, there is the added complexity of having a lot more NBs than there are competent authorities for approving medicines.”

	Also, the MDR quality and related rules for devices have become more numerous and stricter. In an annex to the regulation, they stretch to more than 20 sections with multiple sub-sections.

	DDCs are a fast-growing market with rapid advances in technologies that are inevitably causing regulatory difficulties when medicines and devices are covered by different quality standards and approaches.

	While the quality of medicines is governed by good manufacturing practice (GMP) rules, quality of medical devices is mainly controlled by standards of the International Organization for Standardization (ISO) and sector bodies such as the International Electrotechnical Commission (IEC), which lays down standards for electrical and electronic products.

	Digitalized or electrical devices often have to be assessed against several different standards. An electro-mechanical infuser, for example, can be covered by as many as six different ISO and IEC standards.

	Bringing together different regulatory systems for approving as medicines DDCs and other increasingly complex combination products is likely to become a major challenge for regulatory authorities for some time to come.

	1. EMA, “Brexit Preparedness: EMA to Further Temporarily Scale Back and Suspend Activities,’’ Press Release, 1 August 2018.

	2. European Biopharmaceutical Enterprises (EBE) and European Federation of Pharmaceutical Industries and Associations (EFPIA), “An Industry Perspective on Article 117 of the EU Medical Devices Regulation and Impact on How Medicines are Assessed,’’ Reflection Paper (Brussels, 12 July 2018).

	3. EMA, “Update on EMA’s Brexit Preparedness,’’ Press Release, 9 October 2018.

	4. Competent Authorities for Medical Devices (CAMD), “CAMD Implementation Taskforce: Medical Devices Regulation/In-vitro Diagnostics Regulation (MDR/IVDR) Roadmap,’’ (17 Nov.

	5. EMA, Procedural Advice on the Evaluation of Combined Advanced Therapy Medicinal Products and the Consultation of Notified Bodies in Accordance with Article 9 of Regulation (EC) No. 1394/2007. EMA/354785/2010 (London, 11 Feb. 2011).

	6. Swiss Agency for Therapeutic Products (Swissmedic), “Requirements and Information Relating to Combination Products (Medicinal Products With a Medical Device Component) in the Form Application for Authorisation/Variation, Human Medicinal Products,’’ Press Release, 10 July 2017.


	Vol. 30, No. 11
	November 2018
	Pages: 8-9

	When referring to this article, please cite it as S. Milmo, "Guidelines on Integral Drug-Device Combinations," 

Pharma companies are concerned they may have to postpone plans for the commercialization of new combination products because of delays in obtaining marketing authorizations because of a lack of clarity about approval rules.

Guidelines on Integral Drug-Device Combinations

	Editor's Note: This article was published in

	The European Union is stepping up its efforts to sort out the chronic problem of drug shortages, which has now been a priority for the EU’s medicines agencies for several years. In late August 2018, a joint EU task force on the issue of unavailability of authorized medicines published its work programme for the next two years. The task force was set up in December 2016 by the European Medicines Agency (EMA)-responsible for centrally approved drugs-and the Heads of Medicines Agencies (HMA), which deals with authorizations at the national level.

	The programme shows that if all goes to plan, by 2020 the task force will have laid a foundation for a regulatory and supplies management framework that could curb the increasing number of incidents of drugs shortages across Europe. The sudden acceleration in activity on the issue comes as two events loom on the horizon that could cause-temporarily at least-major disruptions to drug supplies.

	The biggest of these is Brexit, under which the United Kingdom is due to depart from the EU on 30 March 2019 with the status of a third country independent of the Union’s regulations, including those covering medicines. The UK government revealed in August that it is working with the country’s pharmaceutical sector to stockpile next spring an additional six weeks supply of medicine if the UK exits the EU without a withdrawal agreement. A ‘no-deal’ Brexit with customs barriers being erected between the UK and the remaining 27 EU member states would also impact not only medicines imports from mainland Europe but also the considerable number of medicine exports from the UK to its European neighbours.

	The UK and the EU 27 countries seem likely, however, to avoid a no-deal by reaching an agreement this November on measures to soften the regulatory effects of Brexit, including allowing a transition period for a full implementation of the departure by the end of 2020.

	Nonetheless, since the country will still legally become a third country at the end of next March, pharmaceutical companies in the UK will have to make regulatory changes, such as transferring quality control activities and the marketing authorization holder (MAH) status of their medicines to a EU state. Small and medium-sized enterprises (SMEs) in the UK are already admitting they may not be able to meet these obligations on time so that the post-Brexit marketing of their drugs in the EU next spring would be illegal.

	The other event threatening medicines supplies-although to a lesser extent than Brexit-is the implementation on 9 Feb. 2019 of an EU mandatory scheme for the serialization or barcode identification of individual packs of medicine. The new regulation is being introduced to combat counterfeiting of drugs under the EU’s Falsified Medicines Directive.

	There are dangers that the IT infrastructure necessary for the operation of the scheme across the EU may not be fully in place by the deadline. Also, SMEs throughout the EU may have failed to upgrade their packaging lines or arranged to have access to modernized equipment on time.

	The EMA–HMA task force, whose members represent the agencies in the EU’s medicines regulating network, is planning to provide a co-ordination and communications platform to deal with any medicine supplies difficulties next spring, particularly relating to Brexit. It is already drawing up its own guidance on the implementation of post-Brexit regulatory changes like MAH transfers.

	But the main impetus behind its work programme for the next two years is the need to fulfil the objectives of the five-year year strategy, launched in 2015, of the medicines’ agencies network. Dealing with the lack of availability of authorized medicines is a prime aim of the strategy.

	The task force will be guided by a reflection paper of the network, also issued in August 2018, on medicines availability. The paper aims to “provide an oversight of initiatives (and to) propose and explore intended actions to be considered by the network” (1).

	The work programme, which is mainly focused on putting into effect actions agreed by the task force in early 2017, covers three main areas: facilitating the authorization and marketing of medicines to minimize shortages, the prevention and management of supply chain disruptions, and the communication of information on availability issues.

	The task force’s purpose is to put forward long-term solutions. But what happens to medicines supplies next spring after Brexit and the introduction of the serialization regulation could show that other aspects of the whole issue of drug availability may need to be given equal or even greater importance.

	In its new work programme, the task force’s first major job is to complete by the end of 2018 the drawing up of EU-wide common definitions of medicine shortages and what types of specific shortages should be considered to be reportable.

	“Until (uniform) definitions are in place we cannot compare shortages/supply disruptions across the EU,” says the reflection paper (1). The paper shows that there is no harmonized definition or approach to the management of shortages in the EU, particularly at the national level. “There is a lack of clarity of what, when, and to whom reports of shortage/unavailability/supply chain disruption should be made,” according to the paper.

	The timeframes laid down by the national regulatory authorities for reporting shortages or supply chain disruptions ranges from up to 12 months in some EU states to 96 hours in Belgium and 72 hours in France. At the same time, there are approximately 20 different definitions of shortages in use across the EU, says the paper.

	One difficulty facing the task force is that stakeholder groups have different views on what constitutes a shortage. For healthcare professionals and patient representatives, the definition should be determined by how much the lack of availability of a medicine impacts patients. Industry representatives want a distinction between shortages that affect patients and supply disruptions that could be managed with or without regulatory action, according to the paper.

	A joint report issued in 2018 by manufacturers, distributors, and health professional associations stressed the importance of a common definition of a suspected medicine shortage (2). This definition would then be used to establish a simple mechanism for assessing a ‘signal’ of a suspected shortage and for deciding whether it is an actual medicine shortage.

	It suggested the definition of a suspected shortage as being “the inability for a community or hospital pharmacy, as a result of factors beyond their control, to supply a medicinal product to a patient within a defined period.”

	The report emphasized the importance of all suspected shortages being recorded, whether they are single or multisource products.

	The reflection paper advises that definitions should consider “availability in a wider sense,” with distinctions, for example, between worldwide non-availability and shortages of a medicine which is available in some EU states but not in others.

	By the end of this year, the task force is also due to provide metrics for measuring the extent of shortages so that they can be more easily managed and monitored. Metrics would enable benchmarking of shortages due to causes such as manufacturing problems and distribution difficulties.

	Over the next few months, the task force is scheduled to review existing guidance to network agencies on managing shortages, including those that may arise as a result of Brexit. It is also investigating-possibly in preparation for any supply disruptions in the spring-existing ways regulatory agencies communicate to the public information on medicines availability.

	Work on other issues in the task force’s programme, scheduled to be finished between next summer and the end of 2020, include matters such as sharing information within the network and setting up single contact points.

	In 2019, the task force is tackling potentially thorny questions involving interaction with industry. Guidance for companies on reporting shortages will be completed by mid-2019 and ways of encouraging best practices by industry in preventing shortages will be finalized by the end of next year.

	It will be considering ways of introducing authorized medicines into certain national markets that some pharmaceutical companies avoid often because of costs or low returns.

	By the end of 2020, it is due to complete work on an initiative on the use of multilingual packages so that medicines with the appropriate translated patient information can be distributed in countries experiencing shortages.

A European task force outlines its upcoming efforts to combat drug shortages.