A Project to Develop and Protect

Matthew Duchars and John Challenger describe the plans to design and build a facility that the UK would use for emergency vaccine production

WITH the sudden appearance of the Covid-19 virus and its impact on practically every nation in the world, the planned development of the Vaccines Manufacturing and Innovation Centre (VMIC) has now become a project of immediate national importance for the United Kingdom. Before describing the development of the new facility, which is now at an advanced stage of design, it is perhaps worthwhile providing a little of the recent history which in some respects mirrored VMIC’s formation. During the 1970s, Glaxo and the Wellcome Foundation were two of the major suppliers of vaccines to the NHS but they were increasingly experiencing poor returns on the manufacture of many of the vaccines that formed the backbone of the UK’s national child vaccination programme. This inevitably led to decreasing investment in manufacturing facilities which led to an increasing pressure by the then Medicines Inspectorate (the forerunner of today’s Medicines and Healthcare products Regulatory Agency) to update them, in order to meet their requirements for current good manufacturing practice.

In the mid-1980s, both Wellcome and Glaxo started to explore the possibility of building new facilities, but both companies experienced difficulties in securing cost effective proposals for the design and construction of plant to meet their requirements. Ultimately, both organisations transferred their technology and manufacturing licences for a wide range of vaccines to Evans Medical (Medeva). Part of the transfer of assets included Glaxo’s vaccine manufacturing site at Speke, Liverpool. The newly-formed organisation set about the task of planning a project that would bring together all of their newly-acquired vaccine production under one roof. The project was set to  include the upgrade of existing facilities and the expansion of the Speke site in general. Again, attempts to secure suitably cost-effective tenders failed. It was in 1991 that GRC Consultants, a specialist process design consultancy, was approached to undertake the project on an engineering, procurement and construction management (EPCM) basis. Based on an effective and capable supply chain, which included WHP, the forerunner of the company that has had a deep involvement in the development of the VMIC facilities, the project was successfully completed in a period of two years. Interestingly, the design of the facility was based on a series of manufacturing modules, each handling a specific vaccine, all of which were to operate in cleanrooms suitable to meet the requirements of the Advisory Committee for Dangerous Pathogens (ACDP) for either level 2 or 3 containment. During the development of the main plant, GRC Consultants was requested to incorporate a vaccines development unit within the timescale of the original project. The facility, which was ultimately acquired by Novartis, operated successfully for many years and was eventually decommissioned in the later part of the first decade of 2000.

Initial planning

In 2015 Professor Adrian Hill of the Jenner Institute at the University of Oxford highlighted that if a pandemic were to occur at some stage in the future, the lack of a coordinated approach to vaccine development and preparedness of the UK to respond to such a threat could be a problem. A group of academics from Oxford University, Imperial College and London School of Hygiene and Tropical Medicine formed a partnership and initiated plans to establish a vaccines development and small-scale manufacturing facility. As the plans progressed, the partnership also enlisted the help of Janssen, Merck (MSD) and Cytiva (formally GE Healthcare Life Science). This group approached WH Partnership In 2016 to undertake a feasibility and concept design for a new facility, based on their recently completed initial concept design for a facility at Oxford University. Preliminary plans were developed with some approximate project timescales and costs. At the same time, Innovate UK put out a call for proposals to build a new national vaccine facility, to help support and promote vaccine development in the UK, as well as to provide a level of emergency response for possible localised outbreaks or releases. Prior to funding being awarded, it was necessary for a front-end design study to be completed in order to establish a budget and programme that could be used as a basis for the application of funding.

The emergence of VMIC

In order for such a venture to be successful, it was realised that an organisation needed to be formed that could manage the project and would ultimately be responsible to promote, develop and accelerate the growth of the UK vaccine industry. Thus VMIC was formed as a company, to lead the consortium of academic and commercial partners. The new company would promote collaboration with the academic sector and SMEs, which are rich in new vaccine technologies, and would provide expertise in process development and manufacturing within the new state-of-the-art manufacturing facility. The primary aim was that VMIC would be able to bridge the gap between R&D activities and manufacturing so that new vaccine products could enter clinical development. This is considered a value driver in terms of attracting funding and to enable further opportunities and partnering with the pharmaceutical industry taking new vaccines through their developmental stage up to product launch. A minimal amount of contract manufacturing could also be conducted but this was not the main focus or priority for VMIC, which was established as a not-for-profit company.

The VMIC will be a centre of excellence and innovation for the development of novel vaccines, vaccine-like medicines and manufacturing processes. It will carry out training in GMP manufacture, run vaccine bio-manufacturing symposia and provide expertise in vaccine manufacturing. VMIC will work closely with its founding members and partners, all of whom have strong track records in vaccine research and development, including the development of novel viral vector vaccine platforms, nucleic acid based vaccines, vaccine GMP manufacture, and clinical evaluation of vaccines. It is anticipated that in addition to providing their expertise, the founding members will also make available intellectual property (IP) and cell lines to VMIC. It is important to note that the founding institutions are members of other vaccine development and manufacturing hubs, ensuring access to a wider network of vaccine innovation. Academic institutions and SMEs have expressed support in engaging with the VMIC; many potential users, including founding partners, are in receipt of grants from UK funding bodies supporting development of novel vaccines. In particular, VMIC’s partners Janssen and Merck are global leaders in vaccine development and manufacture and can provide access to their expertise, IP and technological base. Cytiva will also provide an option to access its disposable manufacturing equipment on a favourable basis. One of VMIC’s main aims is to also enhance UK preparedness and response capabilities for producing vaccines against emerging infectious diseases. In the event of an emergency, VMIC will work with the UK Government to develop and scale up manufacturing processes, and then produce vaccine, for use during an outbreak identified as a public health emergency of international concern. This of course was a prophetic concept, given the current global threat of Covid-19.

VMIC will work with the UK government to develop and scale up manufacturing processes, and then produce vaccine, for use during an outbreak identified as a public health emergency of international concern... a prophetic concept, given the current global threat of Covid-19

In addition to funding and cell lines, VMIC’s partners will also provide state-of-the-art equipment and training. The facility is designed to be technology agnostic, enabling it to be used for different platforms such as virally vectored vaccines, or nucleic acid based vaccines. It is expected that having this capability available in the UK will help to anchor new vaccine or existing vaccine companies in the UK, thus contributing to the regeneration of the vaccine development and manufacturing capabilities and infrastructure in the UK.  The centre will be constructed at the Harwell Science and Innovation Campus outside Oxford .

The project

The initial basis of design for the facility required that it should have multiple cleanrooms each capable of independent GMP manufacture, allowing different manufacturing campaigns to be carried out simultaneously. The cleanrooms have been designed to handle Biosafety Level 2 (BSL 2) material, suitable for production of non-replicating viral vectors and live attenuated viral vaccines. The operating scale of the various GMP cleanrooms have been divided into three different ranges of scale. Smaller operations up to 10 L upstream and hand-operated fill and finish (up to 500 dosage units); medium-scale operations of 10-200 L scales upstream with semi-automatic fill and finish (500–5,000 dosage units); and larger operations of 200–2,000 L scale upstream with automated fill and finish (with batch sizes of up to 72,000 dosage units). Studies have been carried out to establish whether BSL 3 materials could be handled in the new facility – these will not be incorporated in the initial phase of construction but could be retro-fitted if it were deemed necessary. Manufacturing processes will need to be highly efficient and fully scalable, in preparation for potential product licensing. Vaccine projects will range from pilot scale, for experimental vaccines and for early-phase clinical studies (including first in human trials), to medium-scale through to Phase II clinical trials. The facility will also be capable of producing Phase III clinical material, as part of its emergency response capability. This has been designed to be capable of manufacturing 3m doses of vaccine over a short period of 3 months. However, since the advent of Covid-19, strenuous efforts have been made to ensure the design could be adjusted to enable full-scale vaccine production to meet the UK’s response to a pandemic.

Clearly, there are many challenges that the design team has had to face, particularly with regard to the uncertain nature of the vaccines and processes that may be adopted in the future. The scale and hence the space requirement in each area of the plant are particularly challenging but there are a number of recently completed facilities in the UK and mainland Europe on which practical design options can be based. As mentioned, a flexible approach to plant and equipment layout has been taken, with the adoption of highly serviced space in which various equipment arrangements can be established to meet the requirements of specific processes. This approach applies primarily to the development laboratories, the primary bulk vaccine production and downstream processing areas. The position is a little more predictable in areas such as buffer preparation, formulation, filling and packaging where, at the manufacturing scale, proven technology will be adopted in the interests of reliability.

In its role of vaccine development, VMIC will continue to monitor novel equipment and systems development in order to apply the most appropriate solutions to any new vaccine processes that might arise. For example, consideration has been given to the research into various means of stabilising vaccines for extended shelf life. Research is underway both in the UK and abroad on this critical issue but many of these processes are at an early stage of development and as a result lyophilisation (or freeze drying), which for all its difficulties, is also being considered since it has proven to be a reasonably reliable approach in the past. The use of robotic technology is also being considered, for example, in the filling of pre-sterilised and sealed vials. 

When built, the new facility will exhibit many of the characteristics of other vaccines development and manufacturing sites, incorporating the latest state-of-the-art technologies. In order to operate several R&D programmes simultaneously, the facility has been designed so that each production cleanroom is contained and supported by dedicated HVAC systems, in order to prevent cross-contamination. In addition, each area is served by a range of process utilities arranged to enable the reconfiguration of plant and equipment to meet the needs of any specific development or manufacturing requirement. The main production and R&D laboratories are located on the ground floor of the facility.

The facility will adopt disposable technology wherever possible for all elements of its manufacturing. This is following a logical trend that was first adopted in the UK in the 1990s by a number of emerging biotechnology companies and has now been refined to cover not only bio-reactors  and associated fluid handling systems (see Figure 3) but extends to all elements of the manufacturing cycle in which direct product contact occurs. VMIC’s partner Cytiva has been particularly helpful in supporting the design primary production area based on operating experience with its equipment. A similar approach has been adopted for the vaccine filling line specification in which all product contact parts are single use.

As is common with all modern vaccine manufacturing operations, the design of the equipment and systems will be based on primary containment but where product exposure can occur, for example in vial-filling operations, isolator technology has been adopted. 

It should also be noted that the output from the plant has been designed around the use of pre-sterilised vials, although the filling equipment that has been purchased would be capable of handling both syringes and cartridges. In addition, consideration has been given to allow filling a range of doses from a single dose to multidose vials, depending on the output required. Whilst the initial production filling equipment is based on highly proven technology, VMIC is also investigating the potential use of more novel techniques such as robotics and the filling of pre-sealed/pre-sterilised vials principally for use in product development and clinical trials.

In addition to the core R&D and manufacturing facilities, a number of other technologies have been considered. The issues surrounding vaccine stability and the potential need for stabilising technologies such as lyophilisation, have been considered. It is planned to incorporate lyophilisation into process capabilities; however, it is more likely that this capability will be used for development purposes, rather than being incorporated into the larger-scale production suites.

The facility has a full range of quality control laboratories, which are housed on the ground and first floor. An advanced rail-based conveyor system is being considered as an option to transfer samples from various areas of the production facilities to the quality control laboratories.

Due to the highly serviced nature of the R&D and manufacturing plant and cleanrooms, the majority of the first floor of the facility is devoted to a full range of required utility generation and distribution plant, including air handling, purified water, water for injection and compressed air generation.

Project status

The current pandemic emergency has injected an even greater level of urgency into the project programme. A proposal has been made to significantly reduce the timescale for construction, commissioning and qualification of the facility and includes the early purchase of long delivery items. This could see the facility coming online in 2021 rather than 2022. Moreover, the proposal includes the potential to expand the facility’s capabilities to enable it to respond to pandemic situations such as the crisis we are currently experiencing. Clearly, much will depend on the ability both of contractors and suppliers to maintain their operations whilst still being alert to the need to protect their staff.

Once operational, VMIC will develop new manufacturing processes in collaboration with industrial and academic users, and will carry out GMP manufacture of experimental vaccines for clinical use, vaccines for public health vaccination campaigns, and some contract manufacture. However, the vast majority of work conducted in the VMIC facility is expected to be research and development collaborations. Importantly, access to the centre, via research collaborations or GMP manufacturing contracts, will be determined according to a range of criteria, to ensure access for both academia and industry. In addition, the facility will be available for emergency response, and will work closely with the Government in pandemic situations such as we are now experiencing, as well as more localised epidemic outbreaks.

This new venture is undoubtedly necessary if the UK is to retain a strategic capability in the field of vaccine development and manufacturing.

Moreover, the facility will form part of a fully-integrated response to pandemic threats. This is particularly important in order to avoid a dependence on imports of critical plant and materials during a crisis. This of course extends to issues wider than just manufacturing, and includes issues such as the provision of testing, the availability of medical equipment and the necessary protective equipment required by the frontline medical staff and other essential workers. At the heart of these issues is the need for sovereign resilience and security in the knowledge that the UK will have both the expertise and technology as a means of avoiding reliance on the global economy to deliver strategically essential supplies to the NHS, and the country as a whole should the UK population require protection. Let us hope that the current circumstances and public investment in the UK’s national science infrastructure will act as a catalyst to supercharge this strategic approach to retaining and growing essential science, technology and manufacturing capabilities.