Regulating with Flexibility: The Pandemic Effect

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.

Challenges with checking compliance

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.

Accelerating vaccine development

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).

The biggest difference in approaches in European countries—both inside and outside the EU—is on the issue of genetically modified organisms (GMOs), which could become a major obstacle to regulatory uniformity on COVID-19 vaccines across the region. In July 2020, the EU introduced a regulation exempting clinical trials of COVID-19 vaccines and treatments from EU GMO legislation (8).

However, after a vaccine has completed trials and been approved, it could run into problems with rules at a national level in the EU like limits on scaled-up manufacture and obligatory environmental risk assessments. In fact, once COVID-19 is no longer categorized as a health emergency, many exemptions and relaxations of rules could be withdrawn. Even the manufacture of vaccines at new facilities, which have been temporarily subject to remote inspections will have to be given full on-site GMP assessments. Regulators seem unlikely to reverse approvals, but they may demand significant numbers of alleged deficiencies to be put right.

References

1. PIC/S, GMP Inspection Reliance (Geneva, June 2018).
2. C. O’Sullivan, P. Rutten, and C. Schatz, “Why Tech Transfer May be Critical to Beating COVID-19,” McKinsey & Company, 23 July 2020.
3. T. Thanh Le, et al., Nat. Rev. Drug Discov., 19, 667–668 (2020).
4. T. Thanh Le, et al., Nat. Rev. Drug Discov., 19, 305–306 (2020).
5. EC, “Coronavirus: Commission Continues Expanding Future Vaccine Portfolio with New Talks,” ec.europa.eu, Press Release, 20 Aug. 2020.
6. EC, “Coronavirus: Commission Unveil EU Vaccines Strategy,” ec.europa.eu, Press Release, 17 June 2020.
7. UK Gov., “Consultation Document: Changes to Human Medicine Regulations to Support Roll-Out of COVID-19 Vaccines,” gov.uk, 28 Aug. 2020.
8. EU, Regulation (EU) 2020/1043 on the Conduct of Clinical Trials with and Supply of Medicinal Products for Human Use Containing or Consisting of Genetically Modified Organisms Intended to Treat or Prevent COVID-19 (Brussels, 15 July 2020).

About the Author

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

Article Details

Pharmaceutical Technology Europe
Vol. 32, No. 10
October 2020
Pages: 6–8

Citation

When referring to this article, please cite it as S. Milmo, “Regulating with Flexibility: The Pandemic Effect,” Pharmaceutical Technology Europe 32 (10) 2020.