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

Sean Milmo

On 1 Jan. 2021, the United Kingdom formally left the European Union to become a third country and no longer a member of the Union’s single market and customs union. But what the country has lost after more than 40 years of membership, the UK government believes it can make up—at least in life sciences—with the increased competitiveness generated by the country being able to develop its own regulations and drug evaluation methods.

A key objective of the UK government is to use the country’s clout as one of Europe’s biggest research centres for pharmaceuticals and related products to speed up the development and approval of new medicines so that they reach patients more quickly. Giving patients quicker access to innovative drugs is also a key priority for the EU over the next several years.

On 24 Dec. 2020, a few days before the Brexit deadline, the UK and EU agreed to a 1000-page EU-UK Trade Co-operation Agreement, which effectively eliminated tariffs and quotas on their goods. But in principle, it allowed the UK to erect its own non-tariff barriers, although the EU reserved the right to retaliate with its own measures if it considered that the UK was threatening its competitiveness.

The UK has, for example, decided to draw up its own version of the EU chemicals legislation—called REACH (Registration, Evaluation, Authorization, and Restriction of Chemicals)—which sets technical standards for chemical ingredients for medicines (1).

Because the UK is a separate legal entity—a third country—the UK’s excipient producers and their raw material suppliers have started to be concerned about procedures like customs declarations and rules of origin.

An unusual feature of the trade deal, covering the four nations of England, Wales, Scotland, and Northern Ireland on the UK side, was the creation of a customs border within the UK’s boundaries (2). This runs through the Irish Sea to avoid the necessity for a ‘hard’ border between the Irish Republic, an EU member, and Northern Ireland.

Under the agreement, Northern Ireland has to have its own EU-UK border, because it is subject to EU single market and customs union rules, unlike the rest of the UK. By late February 2021, the arrangement was having to be re-negotiated with the EU accused of being ‘legalistic’ in ways the border was being applied. Other sections of the agreement were also already looking likely candidates for re-negotiations as well.

In the first two months of the year, medicines and related products seemed to flow without much disruption between the UK and the EU. This could have been due to the setting up of protected shipping and freight routes for pharmaceuticals and other essential products (3).

Also, the EU-UK trade deal managed to avoid the setting up of major technical barriers to medicinal products (4). There has been, for example, mutual recognition of each other’s good manufacturing practice (GMP) inspections (4).

Meanwhile, UK government officials have been working on a strategy aimed at boosting the competitiveness of its pharmaceuticals sector by making the country a focal point for investment in drug development within Europe.

One means of boosting competitiveness has been ensuring that the country’s regulatory system and drug evaluation procedures provide relatively rapid pathways to the market. This regulatory change is being implemented despite the handicap of no longer being part of the EU’s medicines licensing network with the European Medicines Agency’s (EMA) centralized system for EU-wide authorizations and the decentralized procedure for national approvals. The UK tactic seems to be to exploit gaps and loopholes in existing EU legislation.

Even before the UK formally left the EU when it was obliged to obey EU legislation, the country demonstrated some success with this approach when it surged ahead of its European rivals in the roll-out of the two main COVID-19 vaccines launched by Pfizer and AstraZeneca.

During a transition period ending with Brexit on 1 Jan. 2021, the UK was obliged to obey EU legislation but not non-regulatory initiatives. When the remaining 27 member states voluntarily agreed in June 2020 on a collective arrangement for the joint procurement and approval through EMA of the new COVID-19 vaccines, the UK opted out.

Both regions approved the vaccines under a 2010 EU directive (5), but while the EU-27 chose the longer route of a conditional authorization, the UK selected the quicker alternative of a temporary approval. As a result, by 18 Feb. 2021 the UK had vaccinated 26% of its population versus 8% in Denmark—the leading EU country for vaccines availability—6% in Germany, and 5% in France (6).

Areas being prioritized by the UK government in its post-Brexit plans are those where the country has research advantages and opportunities to adjust its regulations so that they are more in line with the needs of the market. With the continuous manufacturing of pharmaceuticals, for example, the EU and the rest of Europe has been making slow progress on the approval of continuous production processes. This slow progress stems partly from a lack of agreement on issues like the definition of ‘continuous’ and ‘quality management standards’, which will have to be consistent with those for batch processing.

At Strathclyde University, Scotland, CMAC Future Manufacturing Research Hub, which is funded by the UK government and by international drug companies with operations in the country, aims to make personalized products through digitalized supply chains. In February 2021, it held an international conference to push for an integrated approach to the adoption of continuous manufacturing and other advanced manufacturing technologies (7).

“Continuous manufacturing needs to be recognized more as a simplified but sophisticated production technique for solving many of the quality issues with medicines production,” Paul Hodges, chairman of NiTech Solutions, told Pharmaceutical Technology Europe.

Medicines Manufacturing Industry Partnership (MMIP), representing international drug manufacturers with operations in the UK, has been working closely with government ministries and agencies, and the research-orientated Association of the British Pharmaceutical Industry (ABPI), to maintain the UK’s strong position in continuous production and digitalization (8). One of the agencies has been the drug authorization body Medicines and Healthcare products Regulatory Agency (MHRA).

“ABPI and MMIP are supportive of work that shows how advanced digital technologies and continuous manufacturing can improve efficiency in all types of medicines manufacturing, across traditional small molecules, biologics, and complex medicines including cell and gene therapies,” an ABPI spokesperson told Pharmaceutical Technology Europe. “These advances require close collaboration with regulators (i.e., MHRA in the UK) for smooth implementation.”

Other areas of importance—not just to the government but industry and academia as well—in UK research in the post-Brexit era will be genomics, artificial intelligence (AI), early-stage diagnostics, and big data.

Industry believes that the National Institute for Health and Care Excellence (NICE), the government’s health technology assessment (HTA) body, is being too restrictive with its evaluation of digitalization products, which ultimately sets the price paid by the government for them (9).

“Those medicines for rarer conditions—in fact, precisely the sort of medicines that are enabled by developments in genomics, AI, and big data happen to be the medicines that tend to systematically have a harder time getting through (the evaluation process) than many others,” Richard Torbett, ABPI’s chief executive, told a conference in November 2020 on a NICE review of its appraisal methods (9).

“We have to have a system that is fair across all disease areas, and we believe that there’s increasingly strong evidence to suggest that there are certain types of medicines that typically have a harder time than others,” he said. “(We have proposed) some modifications in the methods that will allow particularly rarer diseases to be on a level playing field with diseases in other therapeutic areas.”

In its own proposals for modifications to its appraisal methods, which are subject to consultation until 15 April 2021, NICE acknowledges the need for change (10). NICE has suggested that there should be more opportunities for patients to have access to promising new technologies despite deficiencies in clinical outcome data. These products would be available on the market on condition that their suppliers filled the evidence gaps within a fixed time period.

Linking HTAs with drug licensing procedures shows how Brexit has given a new flexibility to UK drug regulators and medicine evaluators. If the government’s ultimate aim of attracting new investment is successful, the UK’s approach may soon spread to other parts of Europe.

1. EU, Regulation Concerning the Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) and establishing a European Chemicals Agency (Brussels, 18 Dec. 2006).
2. EU and UK Gov., Agreement on the Withdrawal of the United Kingdom of Great Britain and Northern Ireland from the European Union and the European Atomic Energy Community (Brussels 31 Jan. 2020).
3. UK Department of Health & Social Care, “Letter to medicines and medical product suppliers,” 

 (London, 3 Aug. 2020).
4. EU and UK Gov., Trade and Cooperation Agreement between the European Union and the European Atomic Energy Community of the One Part, and the United Kingdom and Northern Ireland of the Other Part (Brussels, 31 Dec. 2020).
5. EU, Directive 2010/84/EU Amending, as Regards Pharmacovigilance, Directive 2001/83/EC on the Community Code Relating to Medicinal Products for Human Use (Brussels, 15 Dec. 2010).
6. Our World in Data, “Cumulative COVID-19 Doses Administered per 100 People—Collected from Official Data” (University of Oxford, 22 Feb. 2021).
7. MIT and CMAC, International Symposium on Continuous Manufacturing of Pharmaceuticals 2021 (Glasgow, 18 Feb. 2021).
8. MMIP, “Representing Voice of Medicine Manufacturing in the UK” (London, 2020).
9. ABPI, “Global Science Superpower; Future of Medicines Valuation,” Presentation, 2 Nov. 2020.
10. NICE, “NICE’s Methods of Technology Evaluation—Presenting a Case for Change,” News Release, 6 Nov. 2020.

When referring to this article, please cite it as S. Milmo, “Adapting Regulations Post-Brexit,” 

Articles

The UK government is taking advantage of the new regulatory flexibility, afforded by Brexit, to boost the country’s competitiveness in pharma.

Adapting Regulations Post-Brexit

Europe will be hoping to see the suppression of the COVID-19 virus in 2021 with a drastic fall in infections, hospital admissions, and deaths. The virus suppression should then trigger an economic recovery, big enough hopefully to save the region from a deep recession.

The ending of the pandemic will enable the European Union and neighbouring countries to move ahead with a legislative agenda aimed at tackling some of the region’s major public health problems. Once COVID-19 has receded to the background, the EU and many national governments in the region will be focusing on how to make sure that they are better prepared for the next pandemic. Now, after the experience of COVID‑19, pandemics are no longer considered to be remote possibilities.

The European Commission (EC), which makes proposals for new legislation and guidelines, has indicated that the EU intends to take a much tougher line on issues like reliability of drug supplies, particularly on essential medicines (1). The new policy could have a major impact on future relations between the EU and national governments, and the industry.

Some of the regulatory initiatives will aim to put right deficiencies that gained prominence during the pandemic. The biggest of these shortfalls is the chronic issue of shortages of medicines, which periodically, even during normal times, become such a serious matter that they can cause local health crises.

The EC is calling it an EU Health Union in which the prevailing ethos will be one of countries working together rather than individually. In fact, the commission will be given much more control than it previously had over EU public health, which traditionally has been overwhelmingly the responsibility of individual member states.

Over the thorny issue of supplies of COVID-19 vaccines, which first became available in late 2020, the EC persuaded 27 EU member states in June 2020 to back a €2 billion joint procurement of sufficient doses to meet the needs of the whole of the EU (2).

The only country not to participate was the United Kingdom, which finally left the EU at the end of the year. Instead, the UK reached its own deals with a number of vaccine manufacturers (3). One of the deals struck by the UK was with AstraZeneca, which was developing a vaccine jointly with Oxford University to be manufactured in the UK (3). Another deal was reached by the UK for a vaccine jointly developed by Pfizer and BioNTech of Germany (3).

In January 2021, AstraZeneca and Pfizer/BioNTech announced that they were having to make production changes. Though denied by the companies, these changes could result in their not fulfilling supply contracts—advance purchase agreements (APA)—with the EU on time (4). The announcements of reduced supply came even after the EU had put up money to ensure the companies had sufficient manufacturing capacity (5).

The EC reacted furiously to the announcements, particularly to the news from AstraZeneca, which Health Commissioner Stella Kyriakides said could result in “considerably” fewer doses being supplied in the first quarter of this year (6). The expected reduction is widely reported to amount to 75 million doses out of the 300 million doses with an option for another 100 million in the EU-AstraZeneca deal.

“Pharmaceutical companies, vaccine developers, have moral, societal, and contractual responsibilities, which they need to uphold,” said Kyriakides in a statement (6).

After Pascal Soriot, AstraZeneca’s chief executive, claimed in an interview (7) in January 2021 with the Italian newspaper 

 that the EU contract only committed his company to make its “best efforts” to deliver the agreed supplies on time, the EC demanded that in the interests of transparency AstraZeneca publish the text of its APA (8). The need for more transparency is likely to be a constant theme in the EU’s future demand for greater reliability of drugs supplies.

The text of the contract published on 29 Jan. 2021, with confidential details on prices, costs, and output redacted, confirmed that AstraZeneca had agreed to use its “Best Reasonable Efforts” to manufacture the contracted doses in its manufacturing sites in the EU. These sites comprised facilities in Belgium and the Netherlands and, since when the deal was signed in August 2020 the UK was considered to be technically part of the EU, plants in Oxford and Staffordshire, UK too.

On the day the contract was published, the European Medicines Agency (EMA) gave conditional approval to the AstraZeneca vaccine for use by all patients over 18 (9). At the same time, the EC published details of a system for authorizing the export of vaccines subject to APAs because of “a risk that vaccines produced in the Union are exported from the Union, in particular to non-vulnerable countries” (10). Such a potential breach of contractual commitments made by pharmaceutical companies could cause shortages and therefore delays in the administration of vaccines to EU patients, according to the commission.

The planned export curbs, together with the information that companies would need to provide to the authorities, were already arousing concern in the industry before their details were published. “It is vital that any measures proposed by the commission do not restrict or have other negative impacts on exports of vaccines or the import of key vaccine manufacturing supplies,” said the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the Vaccines Europe in a joint statement on 27 Jan. 2021 (11). “[This is particularly the case] given the importance of global supply chains in delivering vaccines to citizens in Europe and the world.”

The scheme under which vaccine exports are having to be approved by national authorities in consultation with the EC will be in force only until 31 March 2021 (10). The commission has not ruled out an alternative system of control being introduced after that. “The aim is to provide us immediately with full transparency—transparency that until now has been lacking and which Europeans expect,” commented Valdis Dombrovskis, EU trade commissioner, in a press release (12).

COVID-19 vaccine producers are having to tell national authorities, which in some countries are the government’s health ministries, details of their export plans including amounts, destinations, and dates of delivery. In addition, they are being expected to give information about their vaccine exports over the previous three months (10).

Vaccine exports to certain countries, mainly neighbouring non-EU states, are being exempted from the new rules. Sales to international funds to finance supplies to poorer countries are also being allowed. The major exception among the neighbouring states is the UK, which had a vaccination rate of 12% in late January against 2.5% in the EU (13)—a gap which made the commission the target of much criticism by irate EU citizens.

The EC wants to use the lessons learned from the COVID-19 pandemic as a foundation for a legislative programme aimed at improving healthcare in the EU with dealing with medicine shortages and inadequate access to innovative treatments prioritized.

There are a range of underlying causes of scarcities to be tackled—such as parallel trade, shortages of APIs, supply quotas, levels of prices and reimbursements, and even companies’ marketing strategies. Many of the legislative choices could be directed at stronger obligations on industry to ensure supplies, earlier notification by companies of impending scarcities, and enhanced transparency of stocks along supply chains.

However, the COVID-19 pandemic has made clear that the most urgent health policy requirement in Europe is the creation of a system for dealing with vaccine and medicine supplies during major health crises.

Despite its wealth, Europe has been among the regions that has suffered the most from COVID-19. By early 2021, it had a cumulative total of approximately 20 million cases and 500,000 deaths, with the UK having the highest death total of over 100,000 in January 2021, followed by Italy with 85,000 and France 73,000 (14).

The EC has been looking at ways of extending supply systems during emergencies to cover not just medicines but other essential products, while at the same time ensuring they are highly secure and resilient. It has been considering the feasibility of combining with non-EU members of the World Trade Organization to set up more coherent global supply chains (1).

Without some sort of solution, it will not just be Europe that will be in danger of descending into trade wars over supplies of vaccines.

Building a European Health Union: Stronger Crisis Preparedness and Response for Europe

,” Communication, 11 Nov. 2020.
2. EC, “

Coronavirus: Commission Unveils EU Vaccination Strategy

,” Press Release, 17 June 2020.
3. Department of Health and Social Care, “

, 11 Jan. 2021
4. BioNTech, “Statement on Manufacturing,” Press Release, 1 Feb. 2021.
5. EC, “

Remarks by Commissioner Stella Kyriakides

” (Brussels, 27 Jan. 2021).
7. A. Guerrera, S. Bolzen, and R. de Miguel, “Pascal Soriot: ‘There are a Lot of Emotions on Vaccines in EU. But it’s Complicated’,” 

Vaccines: Contract Between European Commission and AstraZeneca Now Published

,” Press Release, 29 Jan. 2021.
9. EMA, “

EMA Recommends COVID-19 Vaccine of AstraZeneca for Authorisation in the EU

,” Press Release, 29 Jan. 2021.
10. EC, 

Commission Implementing Regulation (EU) 2021/111 Making the Exportation of Certain Products Subject to the Production of an Export Authorisation

 (Brussels, 29 Jan. 2021).
11. EFPIA and Vaccines Europe, “EFPIA-Vaccines Europe Statement on COVID-19 Vaccines Distribution” (Brussels, 27 Jan. 2021).
12. EC, “

Opening Remarks by Executive Vice-President and Trade Commission Valdis Dombrovskis at the Press Conference on Transparency and Authorisation Mechanism for Exports of COVID-19 Vaccines

,” Press Release, 29 Jan. 2021.
13. Our World in Data, “Cumulative COVID-19 Doses Administered per 100 People—Collected from Official Data” (University of Oxford, 29 Jan. 2021).
14. ECDC, “COVID-19 Situation Update for EU/EEA” (Solna, Sweden, 28 Jan. 2021).


Vol. 33, No. 2
February 2021
Pages: 7–8

When referring to this article, please cite it as S. Milmo, “Getting Tough on Supplies,” 

The EC intends to get tougher on issues such as reliability of drug supplies, particularly essential medicines.

Getting Tough on Supplies

The European Union’s pharmaceutical strategy has finally been issued by the European Commission (EC) to provide an EU policy and legislative framework for medicines over the next several years. The document has been welcomed by industry because it should give a sense of direction to the medicines authorization agencies at both the EU and national levels. This is despite the prospect that it will lead to more legislation and to bring regulations into relatively new areas.

“The pharmaceutical strategy is absolutely critical, not just for our industry but other industries as well [since] it is the first time we have a pharmaceutical strategy,” said Nathalie Moll, director general of European Federation of Pharmaceutical Industries and Associations (EFPIA), in an internal interview for an EFPIA blog in November 2020 (1).

The strategy is seen by the EC as providing an opportunity for the EU and its 27 member states to deal with the weaknesses in the pharmaceutical controls system revealed by the COVID-19 outbreak.

“Though Europe’s response has demonstrated strengths,” the strategy document reports, “existing vulnerabilities have been thrown into sharp focus, including those related to data availability, the supply of medicines, or the availability of manufacturing capacities to adapt and support the production of medicines” (2).

However, the broad objective behind the strategy is to bring the pharmaceuticals sector in Europe, the world’s second largest medicines market and a powerhouse in pharmaceuticals innovation, into line with changes aimed at transforming the region into a low carbon economy. Under the 2015 Paris Agreement on limiting global warming (3), the EU is committed to reducing carbon emissions by 55% by 2030 and to achieve net zero emissions by 2050.

As a result, a lot of the strategy’s proposals stem from the European Green Deal, published in late 2019 (4), from which has emanated last year’s EU industrial strategy (5). This Industrial Strategy focuses on the development of ‘enabling’ technologies such as pharmaceuticals, particularly biomedicines. Emerging biopharmaceutical companies account for more than 70% of the European pharmaceutical sector’s research pipeline.

An important element of the industrial strategy is ways of achieving ‘strategic autonomy’ by reducing the region’s dependence on others for critical products and their raw materials—such as pharmaceuticals. With medicines, this means ensuring the availability and security of supplies, which the COVID-19 pandemic has shown—at least initially—to be a major weakness in Europe’s healthcare system.

The solution to the problem—proposed in the pharmaceutical strategy—is for the EC to take a more active coordinating role in protecting health during emergencies. The objective would be to create more solidarity between states as an alternative to unilateral action by individual EU countries.

The commission is aiming to build a strong European Health Union in the public health field, enabling EU countries to prepare for and to respond together to health crises, as well as to combat diseases like cancer.

Among the commission’s proposals are the declaration of emergencies at EU-level combined with EU measures and harmonization of EU national and regional preparedness plans, which would be regularly audited.

With the greater centralization of preparedness and responses, bigger roles will be given to two main EU agencies—European Centre for Disease Prevention and Control (ECDC) responsible for epidemiology and dealing with communicable disease and the European Medicines Agency (EMA).

ECDC will monitor infectious disease outbreaks using common standards and definitions. It will also carry out risk analysis, modelling, and assessment of healthcare capacities for specialized treatments. It will also have the task of deploying an EU Health Task Force to help local response in EU countries.

EMA’s role in crisis management will be to monitor and mitigate shortages of medicines as well as medical devices. It will also advise on medicines that can treat, prevent, or diagnose diseases that can cause emergency crises.

In addition to giving the extra responsibilities to ECDC and EMA for dealing with health emergencies, the commission is planning to set up a health emergency preparedness and response authority (HERA), details on which were published in a communication two weeks before the pharmaceutical strategy was issued (6).

The new authority will support the development of crosscutting technologies and solutions on multiple potential future threats, such as vaccine platform technologies, the application of digital tools and artificial intelligence as well as the development of specific countermeasures, including through clinical trials designs and data infrastructure. One of HERA’s tasks will be ensuring that sufficient production capacity will be available for new medicines, and that there are proper arrangements for stockpiling and distribution.

The commission has proposed that various existing ad hoc and advisory groups dealing with medicines shortages and availability should be made part of EMA’s permanent structure under new legislation because of the agency’s extra responsibilities for tackling shortages.

The groups include two separate expert steering bodies on medicines and medical devices shortages and scientific groups on new medical treatments. Their permanent transfer to EMA could blur the dividing line between the agency and HERA.

The transfer of the medical devices steering group into the EMA is a significant expansion of the agency’s jurisdiction because currently it has only limited regulatory competence with devices. Furthermore, EMA will also host medical devices expert panels on a permanent basis, which can play an essential part in clinical preparedness and crisis management during emergencies.

EMA’s job will be to monitor medicines supply in advance of a possible crisis in availability. “To support such work, obligations will be placed on marketing authorization holders and member states to provide the necessary data through streamlined IT tools,” according to the commission.

Among the legislative proposals in the pharmaceutical strategy for dealing with shortages are stronger obligations on industry to ensure the supply of medicines, earlier notification of shortages and withdrawals, and enhanced transparency of stocks across the supply chain. In addition, member states would have to improve their procurement strategies and do more joint procurement of critical medicines.

The commission is considering measures to help the possible reshoring from Asia to Europe of the production of critical medicines, APIs, and their raw materials and intermediates. This is because [medicines] supply chains have become increasingly unreliable and fragmented with several different companies with varying levels of competence involved in the manufacture of the same product.

But setting up critical medicines production capacity in the EU would have to be compliant with the Union’s competition rules and those of the World Trade Organization, the commission warned (2).

More transparency among companies features prominently in the commission’s proposals for pharmaceuticals in the environment (PIE) and on the continuous oversight of medicines during their entire life cycles through to disposal.

Last year’s discovery of contamination of several drugs by nitrosamines showed the need for a strengthened oversight of global pharmaceuticals manufacturing with more transparency across supply chains. “The accountability of all actors for the quality of the medicines is essential, but especially that of the marketing authorization holders,” said the commission (2). “Compliance with good manufacturing and distribution practices should be enhanced.”

The European Green Deal with its ambition for zero pollution will be putting pressure on the industry to reduce resource use, emissions, and levels of pharmaceutical residues during medicines’ life cycles.

In a proposed review of current pharmaceutical legislation, the commission aims to look at rules on environmental risk assessments (ERAs) for the authorization of medicines so that sustainability and climate neutrality becomes the ‘driver’ in the industry.

Also, through international cooperation, the EC will be urging action on combating environmental risks posed by waste discharges from pharmaceutical plants, particularly in the spread of antimicrobial resistance. It will be suggesting that the use of good manufacturing practices (GMP) should be assessed as a means of addressing this problem.

ERAs and the extension of GMP to plant discharge controls have been two areas in which the commission has previously been reluctant to press for changes. The pharmaceutical strategy indicates a new willingness to shift medicines regulation into new territories.

1. EFPIA, “Will EU Pharmaceutical Strategy help Europe to Become a World Leader in Medical Innovation Once Again?” Press statement and podcast, 25 Nov. 2020.
2. EC, “Pharmaceutical Strategy for Europe,” 

, Communication, 25 Nov. 2020.
3. United Nations Framework Convention on Climate Change, “Paris Agreement” (Paris, 12 Dec. 2015).
4. EC, “The European Green Deal,” 

, Communication, 11 Dec. 2019.
5. EC, “A New Industrial Strategy for Europe,” 

, Communication, 3 March 2020.
6. EC, “Building a European Health Union: Reinforcing EU’s Resilience for Crossborder Health Threats,” 


Vol. 33, No. 1
January 2021
Pages: 8–9

When referring to this article, please cite it as S. Milmo, “Strategizing for Strength in EU Pharma,” 

The recently published European pharmaceutical strategy is being seen as an opportunity to strengthen medicines regulation in the region.

Strategizing for Strength in EU Pharma 

A temporary system, under which good manufacturing practice (GMP) inspections have been performed virtually or remotely during COVID‑19, appeared to have been seen as such a success among pharmaceutical companies that they want it to become a permanent alternative. The Brussels-based European Federation of Pharmaceutical Industries and Associations (EFPIA) said in a recent reflection paper that there could be ‘added value’ in retaining a ‘virtual’ inspection system beyond the pandemic (1).

Virtual inspections combine the use of paper and digital documentation, such as reports on previous GMP inspections, and electronic IT technologies, such as video conferencing. “We think the pandemic situation has demonstrated the effectiveness of using virtual inspections as one potential tool to support the determination of (GMP) compliance,” Pär Tellner, EFPIA’s director, regulatory, drug development, and manufacturing told 

. “The technology is now fit for purpose and therefore can be implemented,” he added.

The principle of virtual inspections is also supported by the Geneva-based International Federation of Pharmaceutical Manufacturers and Associations (IFPMA). “The term ‘virtual inspection’ applies to inspections that are performed off-site through the use of enhanced communication and information technology to fulfil legal requirements of on-site inspections,” IFMPA said in an updated document on virtual inspections in July (2).

However, the regulators in Europe are generally being cautious about virtual inspections. The International Coalition of Medicines Regulatory Authorities (ICMRA) has set up a working group on ‘office-based’ GMP inspections led by the UK’s Medicines and Healthcare products Regulatory Agency (MHRA). The Pharmaceutical Inspection Co-operation Scheme (PIC/S), a regulatory authorities’ organization headquartered in Geneva, is holding an appropriately virtual seminar in Finland in December 2020 on the subject.

The current policy of agencies—at least in Europe—is that the results of remote, desktop inspections should be confirmed by on-site inspections once GMP inspectors can travel freely again. There are doubts among regulators about whether distant inspections can be sufficiently reliable, even with the help of e-technologies.

The European Medicines Agency (EMA), Heads of Medicines Agencies (HMA), representing national authorities, together with the European Commission have introduced a system during the pandemic under which the validity of GMP certificates for European manufacturing and importing sites for finished products and active substances will be extended to the end of 2021 (3). But it leaves open the question of how the certificates could then be renewed.

For new sites and facilities in Europe that do not have documentation on previous inspections, GMP certificates can be issued on the basis of distant assessments. But on-site inspections should take place once COVID-19 restrictions are lifted, according to EMA (3).

There may be opportunities for a different approach to facilities with a history of a high level of GMP compliance with which a brief site visit may only be necessary. Regulatory authorities are reported to have introduced some flexibility into inspection schemes by combining virtual inspections with short, targeted on-site visits, according to Tellner.

Changes to some local GMP guidance documents may be necessary to bring them up to date with the new e-technologies and then use of virtual methods.“We think there is no need to change intentions in GMP guidance as virtual inspections can be a tool in addition to on-site and paper-based inspections,” added Tellner. “We understand agencies can issue GMP-certificates (along the lines required by the European Union) legislation if the inspector can ensure compliance.”

On-site inspections by foreign inspectorates could become unnecessary or at least be required “only in exceptional circumstances,” EFPIA reported in a reflection paper on GMP and good distribution practice (GDP) inspections, published in May 2020 (1). Instead desktop assessments could be complemented by “an on-site inspection by an acknowledged local supervisory inspectorate,” the paper specified.

“The advantage of an assessment/inspection/certification by a local inspectorate includes knowledge of the site-specific history, insight into culture, optimization of (regulatory agency) resources, and benefits from improved inspection logistics (e.g., no language barriers, less travel),” the EFPIA paper explained.

Inspectors performing desktop GMP assessments already have advisory tools available, mainly provided by PIC/S through its 2018 Guidance on 

 (4). This guidance was originally drawn up by ICMRA, which then transferred it to the care of PIC/S.

The guidance was issued in response to the growing complexity of pharmaceutical global supply chains, which made inspection of overseas sites beyond the capacity of national regulatory authorities. The guidance helped authorities use inspection reports on sites by other agencies as a basis for providing GMP certificates without a new inspection.

The guidance suggested ways of vetting the regulatory authorities doing the original inspections. It also recommended examining the original GMP certificates or, when not available, the inspection reports themselves, which were often held by the pharmaceutical companies whose products were being made at the sites.

PIC/S has been reviewing the guidance’s implementation based on desktop assessments made in 2019, after which it set up a working group on inspection reliance. “This new working group will investigate how to further facilitate reliance and how any barriers which may exist can be removed,” explained a PIC/S spokesperson to 

At the same time, a clear distinction between inspection reliance and distant assessment of GMP reliance is emerging. While the former is a system for relying on another inspection report from another inspectorate to avoid a duplicate on-site inspection, the latter is much broader in scope, covering a range of information sources whose assessment is considered to be equivalent to an inspection. The real-time communication of confidential data in virtual inspections also requires its own security measures.

The planning stage in remote and virtual inspections is the time when it becomes clear what data and documents are required to make a distant assessment. A major requirement should be details of the history of GMP/GDP compliance and the occurrence of major deficiencies, according to the EFPIA reflection paper (1).

Risks should be assessed taking into account the complexity of a site, processes and products produced, consistency of output levels, and reported events and deficiencies since the last GMP inspection. A key to the success of remote or virtual inspection systems is the willingness between national regulatory agencies to share information with each other and between agencies and pharmaceutical companies.

Politics could also intervene in the exchange of information between national authorities from documents. The UK’s regulatory agencies have been facing the prospect of having access to information from EU regulatory authorities restricted from the beginning of January 2021 as the transition period for the country’s departure from the EU ends.

Gaining similar access to data from EU countries as it had when it was a member of the Union would have to be covered by an EU-UK free trade agreement, which was still being negotiated in November with a distinct prospect of no deal. Or it would have to be provided by a mutual recognition agreement embracing GMP/GDP standards and inspections, which would take time to finalize.

MHRA claimed that any EU restrictions on exchange of data would not be a major problem. “[We] will accept imports from EU and EEA [European Economic Area] countries, which are on an approved country for import list, so it is anticipated that relatively limited information will be required from these countries,” an MHRA spokesman told 

Creating a smoothly operating remote or virtual international inspection system with unimpeded exchange of information on an agency-to-agency and company-agency basis could turn out to be a lengthy process.

EFPIA, “Alternative GMP/GDP Inspection Practices in a Pandemic Situation (COVID-19) and Beyond,” Reflection Paper (Brussels, 28 May 2020).

IFPMA, “Points to Consider for Virtual GMP Inspections—an Industry Perspective,” Living Document (Geneva, Last Updated 23 July 2020).

EMA, HMA, EC, “Questions and Answers on Regulatory Expectations for Medicinal Products for Human Use During the COVID-19 Pandemic” (Brussels, 10 April 2020, revised 1–3 July 2020)


Vol. 32, No. 12
December 2020
Pages: 6–8

When referring to this article, please cite it as S. Milmo, “Inspecting GMP at a Distance,” 

The success of virtual GMP inspections performed during the pandemic may lead to more flexible opportunities in the future. 

Inspecting GMP at a Distance

For Europe’s regulatory authorities, particularly the European Medicines Agency (EMA) which coordinates the European Union’s medicines licensing network, COVID-19 has necessitated a massive diversion of resources.

EMA pointed out in its mid-year report, issued in September 2020 (1), that due to the additional work of dealing with the pandemic it has had to shelve plans for returning its operations to normality this year following the completion of its relocation to Amsterdam from London in 2019. The move, which was prompted by the United Kingdom’s exodus from the European Union following a referendum in 2016, had caused a severe disruption of EMA’s activities.

The pandemic had altered the agency’s role—as well as that of the national medicines authorities in the EU’s 27 member states. “The COVID-19 crisis has changed the landscape in which the agency operates,” the report said (1).

With the rest of the European Medicines Regulatory Network (EMRN), the agency now had the task, for example, of creating the right regulatory conditions for the rapid development of pioneering vaccines that will be administered to unprecedented numbers of people across Europe and the rest of the world.

But these new responsibilities are stretching its resources to an extent that the full resumption of its operations to levels before its relocation could be even more difficult. EMA has pleaded with the European Commission (EC) for more funds to finance the costs of its increased duties (2).

“It is critical that extra resources are urgently made available to EMA to allow the agency to fulfil its public health mandate and respond to patient needs in all disease areas,” according to a statement by EMA’s management board after its October meeting (2).

Perhaps one of the biggest new jobs being undertaken by EMA is a pharmacovigilance scheme for monitoring a range of COVID-19 vaccines likely to be launched across Europe in 2021.

EMA will be in charge of the scheme in the EU as it seeks to ensure the quality, safety, and efficacy of vaccines among millions of Europeans. But the agency will be involved in the surveillance of COVID-19 vaccines elsewhere in Europe and the world through a special pharmacovigilance network being set up through the International Coalition of Medicines Regulatory Authorities (ICMRA), in which EMA is a leading player.

EMA, which acts as the contact point for ICMRA, co-chaired in October 2020 an ICMRA meeting on surveillance of COVID-19 vaccines and sharing of experience on observational studies. The organization currently has a membership of authorities from around 25 different countries, most of them European but also the US Food and Drug Administration (FDA) and agencies in Canada, Japan, Australia, and South Korea.

A consensus has emerged in the ICMRA membership that with COVID-19 vaccines and treatments, post-authorization data from real-world evidence and observational studies data should be collected centrally and pooled internationally. Even the analysis of the data could be done on an international level.

Pharmacovigilance of COVID-19 vaccines is likely to be different from that of other products because of the high probability of links between adverse reactions and defects in vaccine manufacture. Thirty-three COVID vaccines are currently in clinical trials out of 321 under development, according to the latest study by the journal 

The relationship between adverse effects and production deficiencies is a characteristic of vaccines in general. “Variability and small changes in the manufacturing process, new components, new production and administration technologies may impact safety and these may require specific pharmacovigilance systems,” warns EMA’s guideline for good pharmacovigilance practices (GVP) on prophylactic vaccines (4).

In addition, like with the majority of modern vaccines, COVID-19 vaccines will be mostly biologicals, which carry the risk of unpredictable variabilities even within the same production process.

“As with other biological products, the safety, quality, and efficacy of vaccines are as dependent on product-specific manufacturing process as on the inherent profile of active antigens and excipients,” says the GVP vaccines guideline (4).

With COVID-19 vaccines, post-authorization problems with production processes could be more prevalent, because with some of the leading candidates for mass deployment, particularly those based on RNA/DNA particles, they employ new technologies.

In addition, the scale of vaccination programmes covering ultimately billions of people is unparalleled in scale, requiring networks of sub-contracted manufacturers, which may lead to inconsistencies in quality. A major challenge is the surveillance of quality standards in the production of sterile vaccine vials and the maintenance of sterility levels during filling and distribution. Vials design and production have also been benefitting from new technologies, such as the use of plastic on the vial exteriors and glass linings inside as a barrier against gases and other potential contaminants.

“The GMP standards will be applied to the manufacture of sterile vials for the vaccines as per standard requirements, regardless of location,” said a spokesman for the Medicines and Healthcare products Regulatory Agency (MHRA) of the UK, where a COVID-19 vaccine being jointly developed by AstraZeneca and Oxford University is considered likely to be among the first to gain authorization for mass distribution.

“All sites that produce sterile vaccines would be subject to [good manufacturing practice] GMP inspection procedures and require valid GMP authorizations to be in place,” the spokesman told 

. However, other agencies may have to resort to remote GMP certification of sub-contracted vial filling sites.

Manufacturers of vaccines and their containers could be subject to two waves of standards-checking inspections—one for GMP and the other for pharmacovigilance. Because the latter will be the most extensive covering, for example, requiring surveillance quality systems in all the operations of a business, a manufacturer that is considered to be compliant with pharmacovigilance standards is unlikely to be breaching GMP rules. Non-compliance with GMP standards would be considered to be a pharmacovigilance failure.

The extra work being taken on by EMA and the other EMRN agencies to prepare the pharmacovigilance scheme and to deal with other COVID-19-related responsibilities is requiring staff to be transferred from normal regulatory tasks. In EMA, personnel amounting to 40 full-time equivalents (FTEs) have been switched to new roles.

At the same time, the agency’s usual activities are expanding. Requests that medicine under development be classified as advanced therapy medicinal products (ATMP) has doubled in the past three years, EMA’s management board was told at its October 2020 meeting (2). One of the biggest tasks facing the agency is the implementation of plans for its Big Data project, DARWIN EU or Data Analytics Real World Interrogation Network. EMA is having to negotiate with the EC for help in funding what will be the EU platform for accessing healthcare data from across the EU.

Due to the pressures on its operations, the agency has had to prioritize its activities with the highest importance being attached to core business activities, especially those that ensure a stable income for the agency, carrying out of legal obligations, and IT applications for corporate communication for enabling EMA to continue operations.

Other priorities include the work of key working parties and groups, drawing up of certain guidelines, the fight against anti-microbial resistance (AMR), co-operation with health technology assessment (HTA) bodies, innovation (especially in emerging therapies), clinical data publication, and international co-operation.

But not all aspects of priority areas are being given preferential treatment. Some innovation activities are being reduced or suspended. These include innovation workshops and science collaborations with HTAs. Some work on the issue of pharmaceuticals in the environment has been delayed, which affects action on AMR.

International co-operation has been cut back, with EMA contributions to guideline work at the Geneva-based International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use being reduced.

Yet the agency points out that with more funds from the EC there could be a better balance between performing EMA’s core work in public health, the expansion of normal tasks such as ATMP classification, and the additional burdens stemming from COVID-19.

“EMA has informed the EC that it needs additional staff with specialized scientific and technical competencies to respond to the COVID-19 crisis,” an agency spokesperson told 

This includes personnel for additional scientific evaluation work, increased safety monitoring, support on medicine shortages, increased transparency and publication of clinical data, public health information, and communication.

“The agency also needs additional staff to manage the non-COVID-19 application-driven workload, which has increased by 35% since 2014, and for the work on the implementation of new pieces of legislation,” the spokesperson added.

EMA expects to receive an answer on its requests for extra money before the end of December 2020. The future scope of its activities could well depend on it.

EMA, “Mid-Year Report 2020” (Amsterdam, 25 Sept. 2020).

EMA. “Highlights of Management Board: October 20 Meeting,” (Brussels, 5 Oct. 2020).

Guideline on Good Pharmacovigilance Practice—Vaccines for Prophylaxis Against Infectious Diseases


Vol. 32, No. 11
November 2020
Pages: 8–9

When referring to this article, please cite it as S. Milmo, “COVID-19 Stresses EMA Resources,” 

The agency is balancing a variety of important issues including the review of COVID-19 vaccines. 

COVID-19 Stresses EMA Resources

The building, expansion, and even acquisition of plants for the manufacture of COVID-19 vaccines have been accelerating in Europe as the vaccine candidate frontrunners—those most likely to emerge as approved in 2021—become clearer. However, for European regulators the task of approving the production processes and facilities for manufacturing the vaccines is requiring a lot of flexibility.

Inspectors checking compliance with current good manufacturing practice (CGMP) have not been able to visit sites because of travel controls, social distancing rules, and other safety regulations. Even inspectors vetting clinical trials to ensure compliance with good clinical practice have had to keep away from trial locations.

Instead of making physical inspections, inspectors are doing their job remotely through online exchanges of information and, if necessary, video conferences. They have even been using guidance on desktop reviews issued by the Geneva-based Pharmaceutical Inspection Co-operation Scheme (PIC/S) (1). The guidance has previously been mainly applied by European agencies for GMP checks on sites outside Europe.

After the easing of restrictions in July following full lockdown across much of Europe, the inspection system was starting to return to normality. But when a second wave of the pandemic loomed in August, governments began to tighten rules on social distancing and to reintroduce travel curbs. Physical inspections had to be reined in once again.

GMP is a key means for checking the safety and quality standards of new processes, and plant alterations and expansions, particularly on existing manufacturing sites. The other main aspect of regulation of new processes and alterations of plants is the system of approval of variations. This approval can also be a challenge because of the complexities of the processes for making COVID-19 vaccines. Also, a large amount of documentation can be required, with GMP files being used as a source of data.

The main technology platforms for the vaccine at present include protein recombinants, live attenuated viruses, replicating and non-replicating viral vectors, and inactivated viruses. The platforms also include RNA and DNA particles of viruses, which are new to the sector and have never previously been approved.

Most vaccine candidates currently in clinical trials are targeting, as the primary antigen, the coronavirus’s spike protein and its variants. The technologies are a mix of novel and relatively mature processes but, being vaccines, particularly to combat a pandemic quickly and on a global scale, means the manufacturing and regulatory approval processes are particularly difficult.

“Producing complex pharmaceuticals (such as vaccines) is not just a matter of building the required production line or hardware,” reported McKinsey & Co in a study on COVID-19 vaccines (2). “[Production] also involves a complex—and often finicky—manufacturing process, a large team of experts, a lot of time, many detailed steps, and the right regulatory registrations—and all of this against the highest quality standards.”

In addition, vaccines are mainly biopharmaceuticals, with bigger problems than usual in terms of scalability, stability, and purification. The vaccines production “requires a complicated dance of multiple experts in manufacturing, quality, regulation, engineering, and logistics—also, trainers, lab technicians, smart builders, maintenance crews, scientists, and capable leaders,” reported McKinsey (2).

The McKinsey report warns that a big problem will be the technology transfer necessary for worldwide production by the vaccine producers/or their contract manufacturers. The consultancy estimates with each of the 10–20 vaccine candidates likely to be eventually approved with a need for four to six plants for their international distribution, a total of 2000–6000 multidisciplinary professionals will be involved (2).

A technology transfer procedure should include time for preparing the regulatory approval of the vaccine production process. Of the eight steps in the procedure recommended by McKinsey, three involve work on the variation registration.

First, technology transfers should be planned to ensure that they are in line with local regulations, including those for validation of batches and for stability studies. A variation pack should be put together for submission to competent authorities. Responses to claims by the authorities about deficiencies should be prepared in advance to avoid delays that could be costly due to the need to launch vaccines as quickly as possible after approval.

By early September 2020, there was a total of 321 COVID-19 vaccine candidates, according to the latest study by the journal Nature Reviews Drug Discovery (3). This number was more than 2.5-fold higher than the number recorded in the publication’s previous survey in April (4). Thirty-three vaccine candidates were in clinical trials, which were planned to have more than 280,000 participants in 470 sites in 34 different countries (3). Some of the companies with candidates still in Phase lll trials had already started large-scale manufacturing of their vaccines, the journal reported.

Manufacturing accounts for a high proportion of the total cost of achieving full-scale production of COVID-19 vaccines. Figures from the Coalition for Epidemic Preparedness Innovations (CEPI), a Norway-based vaccine development partnership that is sponsoring eight leading COVID-19 vaccine candidates, show that manufacturing will make up around one third of total R&D costs. But that proportion does not include full scale-up costs and extra expenditures caused by hold-ups and write-offs of costs of plants, which are not used because vaccines fail in the final clinical trials.

In Europe, governments, particularly in Germany and the United Kingdom, have been helping to accelerate vaccine developments by providing generous grants for the building or conversion of production facilities. The European Union, as well as governments, have been making vaccine purchasing deals in advance of their approvals. With all this activity, regulators are under pressure not to cause unnecessary delays with confirmations of GMP compliance and other process technology approvals.

To help speed up vaccine development, the European Commission has adopted a policy of using advance purchase agreements to enable vaccine producers to meet their development costs. The EC has, for example, been negotiating a purchasing deal for more than 200 million doses of vaccine with CureVac of Germany at a time when the company’s RNA vaccine has been still only in Phase l/ll trials (5).

In return for the right to buy a specified number of vaccine doses, the EC will be financing part of a developer’s upfront costs in the form of advance purchase deals, which will be considered as down-payments on vaccines that will actually be bought through the commission by EU member states.

The funding will come from a €2.7 billion (US $3.1 billion) EU emergency COVID-19 support scheme, with additional backing available through loans from the EU’s European Investment (6). Producers entitled to the deals will have to meet certain criteria such as speed of product delivery at scale, reasonable cost, and ability to supply vaccines from an EU-based GMP plant.

In addition, the commission is ensuring flexibility in the regulation of vaccines with, for example, the allowing of remote GMP inspections of production facilities and the relaxation of labelling and packaging rules (6). Authorization procedures are also being sped up with the use of a rolling review system, which can shorten the timeframe by around a third.

At the national level in Europe, controls on COVID-19 vaccines development and distribution are in danger of fragmenting as governments pursue their own methods for speeding up R&D and for providing access to specific groups of patients. Some are considering applying legislation that would allow access to vaccines on compassionate grounds. The government in the UK, which is due to complete its departure from the EU at the end of 2020, has already drawn up legislation to enable the country to manufacture and distribute vaccines under rules slightly different from those in the EU (7).

Regulatory bodies are adapting to new ways of working to cope with the impact of COVID-19.