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As vaccines for COVID-19 dash towards the finish line, companies have in parallel had to work at break-neck speed to scale up at-risk manufacturing of the candidates to ensure that they can be delivered quickly once approved.

Dr Anissa Boumlic-Courtade

Dr Anissa Boumlic-Courtade

Vaccine manufacturing can be extremely complex and German multinational Merck KGaA has been collaborating on various fronts, including on process development approaches, to accelerate production of COVID-19 candidates, including with prominent participants such as The Jenner Institute.

AstraZeneca PLC is collaborating with the institute and the Oxford Vaccine Group at the University of Oxford to advance its contender AZD1222 (also known as ChAdOx1 nCoV-19), aimed at preventing COVID-19 disease from the SARS-CoV-2 virus. Global clinical trials for AZD1222, which were voluntarily paused on 6 September, recently resumed in Japan follows other restarts in the UK, Brazil, South Africa and India. (Also see "Coronavirus Update: Trump Tests Positive, US Pause Remains On AstraZeneca Vaccine" - Scrip, 2 Oct, 2020.) 

Dr Anissa Boumlic-Courtade, head of global vaccine and plasma segments, bioprocessing, within the life science business at Merck KGaA, emphasized in a recent webinar that the traditional vaccine paradigm does not allow “adequate response” to tackle outbreaks. Besides, existing manufacturing capacity, in the context of COVID-19, is not necessarily adapted from a process and scale perspective, and building new facilities is also not really feasible amid a raging pandemic.

 

In an interview with Scrip, Boumlic-Courtade shared some of the lessons from past outbreaks that could improve vaccine manufacturing processes and response speed, highlighting the value of pre-existing platforms and deploying single-use technologies across the production workflow.

 

Merck's collaboration with The Jenner Institute, initiated in 2017, saw the development of a rapid, scalable platform following good manufacturing practices and using disposable technologies for the institute's adenovirus platform. While initial work was conducted with a rabies vaccine candidate, the platform was then validated with different adenovirus constructs to accelerate future development and manufacturing.

As a result, the partners could crunch process development time to two months from a year – a critical step to manufacturing the COVID-19 vaccine at scale, they said in April this year.

Merck is collaborating with over 45 vaccine developers globally, including the Baylor College of Medicine in Houston, Texas to advance its vaccine manufacturing platform for COVID-19. (Also see "How Merck KgaA’s Life Science Unit Is Riding The Crest Of The Gene Therapy Wave" - Scrip, 2 Mar, 2018.) 

 

Are there any lessons learned from previous outbreaks such H1N1 influenza, Ebola, MERS or Zika that can facilitate faster scale-up and improve manufacturing timelines for a COVID-19 vaccine?

Past outbreaks and influenza pandemics have taught us a number of lessons, including that pre-existing manufacturing platforms should be used to reduce process development work and accelerate the scale-up process. In addition, flexible manufacturing either through integration of single-use technologies in the manufacturing process or using complete single-use platforms should be increased. During the influenza pandemic, switching to single-use technologies for the filling of vaccines vials increased capacity by 40% for a major vaccine company. Innovating technologies both on the vaccine design and manufacturing sides should also be introduced. Nucleic acids, for example, are now emerging; their manufacturing is less complex than other modalities. Innovation in adjuvants, expression systems and purification methodologies have and will continue to allow for better and faster response. While we have all of these lessons from past experiences, the difference with the novel coronavirus is how much faster can we come out with an effective vaccine.

You mentioned how flexible manufacturing/facility design will be required to accelerate and de-risk vaccine manufacturing preparedness, including for a COVID-19 vaccine, and that single-use processing can be vital. What kind of benefits does such next-generation production provide in general and specifically in terms of cost competitiveness, and is Merck deploying single-use technologies for the COVID-19 vaccine projects it is engaged in?

 

Flexible manufacturing can start from introducing single-use technologies in the manufacturing process to designing a facility that can accommodate multiple vaccines, and scale to adapt faster to the needs and potential unanticipated demand due to a pandemic. Single-use technologies are already used by several companies and in the major commercial vaccines, with varying degrees. Typically, these technologies allow faster turnaround since cleaning processes are eliminated and reduce cross-contamination risk. Future vaccine facilities are expected to integrate more the notion of evolving layouts and processing trains. Flexible manufacturing of vaccines can be competitive from a cost perspective, depending on the volume and the type of vaccines to manufacture. Merck is supplying various critical raw materials and technologies to vaccine developers and manufacturers including single-use technologies.

Merck’s 2017 collaboration with The Jenner Institute led to the development of a rapid, scalable platform for the institute's adenovirus platform using a rabies vaccine and that’s now being leveraged for their COVID-19 vaccine. What did this mean in terms of a head-start for the vaccine and other efficiencies, time and cost savings? Is the platform deployed at other contract manufacturing sites for AZD1222/ChAdOx1 nCoV-19?

The work performed at the Jenner Institute with Merck’s support has allowed the institute to reduce process development in key unit operations to produce a COVID-19 vaccine candidate. This is the key benefit of having a pre-established platform upon which variations can be minimized for any new vaccine candidate. In addition, Jenner was able to build upon the work and optimize further steps to reduce the cost of goods. The vaccine candidate and its platform has since been transferred to multiple locations and partners.

Experts say that the current challenges of virus vector-based vaccines are essentially around manufacturing that can effectively balance high recovery yield and impurity clearance and keep costs low. Are these aspects adequately addressed for COVID-19 vaccines currently?

What we’re witnessing is that for COVID-19, manufacturers have been able to apply past learnings and improvements of their platforms to increase efficiency, i.e., yields, and manage the cost of goods. These are typically a small fraction of the total cost of vaccines.

COVID-19 could see the first RNA vaccine to emerge, which is exciting but comes with a host of uncertainties/complexities both around the platform itself and the immunity the vaccine can provide. What are the potential challenges for manufacturers to demonstrate scalability and robustness of operations?

Indeed, mRNA vaccines are promising and could drive a number of changes in this industry. Manufacturers need to prove that the platforms can be scaled up in different areas. For example, the synthesis of mRNA and the complexion with lipid nanoparticles — a key delivery vehicle — need to be reproducible when moving to larger volumes. In addition, the purification process of mRNA vaccines can be tedious and its simplification is needed to ensure better scale-up and industrial long-term viability.

How are manufacturers poised to deal with regulatory complexities around the manufacturing process for a COVID-19 vaccine, since plant and equipment will need to be qualified and processes validated by multiple regulators from various jurisdictions where the vaccine will be used?

It will depend on whether the vaccine needs to be produced in multiple places and where it will be marketed. Indeed, manufacturers that are planning to produce in multiple locations will have to go through different regulatory and licensing pathways. That was a pain point raised by MSD [Merck & Co., Inc.] in its journey to market its Ebola vaccine. There are multiple strategies that manufacturers are adopting to alleviate some of the complexity associated with vaccine manufacturing approval: technology transfer to existing plants or contract manufacturing organizations; co-operation with governments such as in the execution of local clinical trials; partnerships with other vaccine companies that have the existing infrastructure and; setting up a network of regulatory laboratories to facilitate and expedite release - this is an initiative that CEPI [the Coalition for Epidemic Preparedness Innovations] is overseeing and could be a good example of co-operation as part of any pandemic resilience plan. In any case, close collaboration with regulatory and local authorities is key.
 

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