CPI discusses the importance of bringing an engineering mindset to collaborate with biologists on pharma development
IN LIGHT of the current coronavirus outbreak, governments are promising that a vaccine will be available within 18 months, but how can engineers and scientists work together to make best use of their combined skillsets to help accelerate this?
A key report, Engineering Biology: A Priority for Growth, published by the Royal Academy of Engineering in December 2019 has highlighted the importance of engineering biology and the need to value people who can work across disciplines to drive progress. Hence there is a need to understand the different approaches adopted by different professions such as engineering and biologists, to understand the challenges of creating focussed, cross-disciplinary and high performing teams.
In the past, there has been a clear distinction between the roles that scientists and engineers contribute to the development of new products and processes. Scientists predominantly focus on the problem, often creating many possible solutions, but they can make decisions that can inadvertently have a negative impact on the final manufacturing process. The scientists’ work is then handed over to engineers who concentrate on translating it into a scalable manufacturing process. The difference in approach between disciplines can create a disconnection in the definition of what success looks like. Scientists are often searching for the best solution, frequently measured in terms of product productivity and yields. Unfortunately, this solution is often inherently unstable, and delivers processes that can be difficult to run at production scale. Engineers value robustness, and they understand that processes must be reliable and provide optimal performance, resulting in stable processes that consistently deliver an output within specified controlled limits.
The current status quo potentially limits the benefits that engineering approaches can contribute to achieving what true success could be. To maximise the value of an engineering mindset, projects would certainly benefit from a collaborative approach through using the skills and knowledge that only truly reside within multidisciplinary teams. Focussing on early utilisation of engineering methodologies, helping to rationalise early decision points and reducing the requirement for information handover between disciplines later in the project are all examples of how this could be achieved.
The need to rapidly identify and manufacture a vaccine for the coronavirus provides a unique opportunity to explore different working strategies
This gap has been identified in relation to the rapid development, scaleup and manufacture of vaccines to combat future pandemic disease outbreaks and has led to the foundation of the Vaccines Manufacturing and Innovation Centre (see p31). The aim of the Centre is to form multi-disciplinary collaborations to rapidly advance the development of new vaccine technologies, and to provide the vaccine manufacturing facilities capable of supporting national responses to future pandemics. Multidisciplinary collaboration will be vital for rapid, successful outcomes.
This renewed interest in vaccines from the public, government and industry – together with the need to rapidly identify and manufacture a vaccine for the coronavirus – provides a unique opportunity to explore different working strategies and review the positive benefits they can offer to enable the fast tracking of medical solutions.
Biopharmaceuticals are complex molecules that are manufactured using living biological sources. They have come to dominate the market with eight of the ten best-selling drugs in 2018 being biopharmaceuticals (BESIG Webinar 2019, The Biopharmaceutical Business, https://bit.ly/3bmajbi). Examples include monoclonal antibodies, insulin, growth factors and vaccines.
Once drug discovery identifies a new biopharmaceutical candidate, the genetic information (DNA) is engineered into a host cell (vector) to produce the product alongside the other molecules that the cell produces to grow and metabolise. After product expression is complete, the target product is purified from a complex, poorly-defined mixture of host cell products such as proteins and DNA to provide a bulk product of a certain purity, suitable typically for intravenous injection (drug substance). This is then formulated into dosage forms suitable for delivery to the patient (drug product).
This creates a different manufacturing challenge compared to chemical-based products. In terms of complexity, the molecules are orders of magnitude larger and can only be characterised using multiple analytical methods. Certain stages of the process are fully defined and understood, but there are significant gaps in underlying knowledge around the cellular processes which manufacture the product and the impact that small changes in the DNA sequence can have on manufacturability and functionality.
For molecules of the same basic type, monoclonal antibodies being the major example, platform manufacturing approaches have been developed. In bioprocessing, a platform manufacturing process (platform process) is a standard process that has been developed to produce a specific class of molecules which have similar structures and molecular properties. The same basic process structure can then be used to manufacture these molecules. It provides significant overall cost of goods (COG) advantages as it avoids unnecessary process development work, avoids manufacturing plant reconfiguration and provides a structure into which the learning from one product can be transferred to other similar products.
In monoclonal antibody manufacture this platform approach comprises the following steps. An upstream process based around mammalian cell culture (CHO - Chinese Hamster Ovary cells) using high yielding cell lines produces the required antibody. These are then combined with a highly selective affinity chromatography purification based on affinity capture using immobilised protein A, which only binds monoclonal antibodies. This results in an integrated, templated development and manufacturing platform, that together with standard analytical methods, has resulted in streamlined development and manufacture with significant COG reductions.
This platform approach for monoclonal antibody (mAb) manufacture has delivered significant benefits in terms of speed-to-market and COG reduction over the last 20 years. To help accelerate and de-risk the acceptance of next generation advanced therapy medical products (ATMP) such as gene and cell-based therapies, we need to draw on the experience of the commoditisation of mAb. Manufacturing large molecule therapies is complex and requires multi-stage manufacturing processes. The therapy choices and manufacturing options are continually changing, and decisions taken early in the product development lifecycle can have significant impacts on the manufacturability of the final product. Historically, it can take more than ten years for a product to come to market.
...new possibilities to redefine the traditional roles and responsibilities that scientists and engineers play in the development of new products and processes
Several other manufacturing trends have impacted the development approach. The first of these is the need for manufacturing flexibility, with facilities being designed that incorporate only critical fixed equipment in the original design (ie air handling, high quality water systems). Another emerging trend consists of basing processing equipment on single use, off-the-shelf packages. This gives facilities the flexibility to increase their capacity (install more key equipment such as bioreactors) or produce multiple products (single-use equipment allows rapid product change over). Increased titre of products with higher-yielding expression systems based on scientific understanding means that facility scales are reducing further, supporting the move to single-use equipment supplied as packaged units by multiple vendors. For example, bioreactors up to 2,000 L scale are being widely installed in new facilities and all the main unit operations (chromatography, tangential flow filtration etc) are available in single use formats. The move towards focussed therapeutic products (stratified or personalised medicines) and the desire for localised manufacture is further pressure to reduce batch sizes and manufacturing complexity.
All these changes open new possibilities to redefine the traditional roles and responsibilities that scientists and engineers play in the development of new products and processes.
Vaccines illustrate some of the complexity of process selection for biopharmaceuticals, with several different approaches available for producing a vaccine to an antigen such as the coronavirus. Each vaccine type has different development complexities, different timelines and different manufacturing requirements as summarised in Table 1. Additionally, there are two fundamentally different approaches: delivering the antigen in its final form (higher therapeutic dose), or supplying the genetic information direct to the patient’s own cells, enabling them to effectively manufacture their own vaccine (lower therapeutic dose).
There is a clear strategic need to develop an effective, safe vaccine to dampen down the devastating impact of coronavirus. The chances of success are significantly higher by parallel tracking the process development of multiple vaccine candidates. Using a structured and risk-based criteria for prioritising possible approaches will allow the most appropriate routes to be selected early and increase the chance of achieving a successful outcome. This criteria should be based on the understanding of a range of aspects such as the capability of available facilities, the likely production requirements, and process efficiency. Applying an engineering mindset early enables evaluation of these aspects to guide the early discussions, helping to ensure that decisions are made that enable the best outcome within the constraints presented.
Government funding can help encourage the adoption of new manufacturing approaches and working practices. Continuous manufacturing has been a mainstay of the chemical industry for many decades but has had limited uptake within the biopharmaceutical sector due, in part, to the complexity of the processes and the multidisciplinary teams needed for successful project delivery.
There is a great example where Innovate UK funding has enabled a UK-based consortium to explore the challenges of converting established batch purification processes to continuous. The demonstration system was established at CPI’s facility in Darlington, which is a £38m (US$47m) investment by the UK Government to help support the biologics industry.
The project developed a fully automated and flexible continuous manufacturing system that integrated multi-step process systems together with control and in-process monitoring for a range of monoclonal-like molecules. CPI was able to utilise its experienced engineering team, whose industry experience includes pharmaceutical, biotech upstream, downstream, fill/finish and facility design, and also included expertise in automation and software control to deliver this project alongside CPI’s scientific team.
This project was made possible by splitting the challenge into mini projects, enabling tasks to be parallel tracked, using regular review meetings to enable critical decisions to be taken to ensure challenges were addressed in the best way for the whole project. A holistic project management approach enabled necessary compromises to be made and agreed between all team members within the constraints of time, budget and quality. This approach will support the rapid development of robust and GMP compatible processes.
Traditionally, in successful collaborative R&D projects, scientists designed and executed experiments to generate the important data, which engineers then used to develop and test mechanistic or statistical models. Biostatisticians also played a critical role in data analysis and developing statistical models to support validation of models and confirm experimental design space.
This integrated approach is being demonstrated in the fight against coronavirus where a multi-disciplinary consortium has been assembled...to rapidly develop, scale up and produce the potential adenoviral vaccine candidate
In the future – as highlighted by the coronavirus outbreak – speed is likely to be an additional key measure of success alongside the currently more established criteria. As previously highlighted, this will require the expertise and knowledge of a multidisciplinary approach, clear project goals and agreed success criteria. Using a single multidisciplinary project team will increase mobilisation and a right-first-time approach. Different options can be identified efficiently, and processing challenges addressed in the best way rather than just passed between disciplines without the full appreciation and understanding of the other teams’ key challenges and requirements. But as previously discussed, this is not easy to achieve. Figure 1 shows how the interaction may need to change.
This integrated approach is being demonstrated in the fight against coronavirus where a multi-disciplinary consortium has been assembled, led by Oxford University’s Jenner Institute, to rapidly develop, scale up and produce the potential adenoviral vaccine candidate, ChAdOx1 nCov-19, for fast-tracked clinical trials. The consortium includes University of Oxford Jenner Institute, University of Oxford Clinical Biomanufacturing Facility, the Vaccines Manufacturing and Innovation Centre, Advent Srl, Pall Life Sciences, Cobra Biologics and Halix BV. ChAdOx nCov-19 is one of five frontrunner vaccines in development around the world and is expected to be the UK’s first COVID-19 vaccine.
Another promising vaccine candidate, based on mRNA, is under development at Imperial College London. The rapid scaleup and manufacture is being supported by the mRNA workstream, which is part of the BioIndustries Association-led Vaccine Manufacturing Group. CPI will play a key role in this initiative which is a collaboration of the public sector, industry and academia that builds on the UK’s world-leading science base.
Today, most chemical engineering university programmes include course modules on biochemistry, biochemical engineering and biotechnology that will help engineers understand the unique challenges of working with biological systems. But it needs to be accepted that all areas of specialist expertise are likely to have a different definition of what success will look like. Based on CPI’s experience, these differences can be accommodated within project teams. Project teams need experts across all areas: cross training is useful but unlikely to be the complete solution. Breaking a project into many smaller, time-limited goals allows each specialist the opportunity to add value to the project but within controlled limits.
During these challenging times, it’s apparent now more than ever that we need to use different ways of working to ensure products important to society move from the lab to successful commercial-scale production, and to the public that need them, as efficiently as possible.
1. Classical vaccine (polio) – Thomassen et al, “Next Generation Inactivated Polio Vaccine Manufacturing to Support Post Polio-Eradication Biosafety Goals” PLOS One 8 (2013) e833744.
2. Conjugate vaccine (Prevnar 13) – Dose of 30.8 µg from Prevnar 13 package insert available from FDA website, scale based on CRM197 carrier protein data from US 8,530,171 assuming reductive amine conjugation of glycans having an overall yield of 10%.
3. VLP (Gardasil) – Clendinen et al, “Manufacturing costs of HPV vaccines for developing countries”, Vaccine 34 (2016) 5984-5989.
4. Subunit vaccine (Flublok) – Dose based on Flublok package insert available from FDA website. Scale based on assumption of 200 mg/L expression and 20% overall recovery.
5. Neutralising antibodies – Dose based on Inflectra prescribing information available from FDA website of 3 mg/kg and 70 kg average wt. Scale based on assumption of 2 g/L expression and 75% recovery.
6. RNA vaccine (saRNA) – Tregoning et al, “Self-Amplifying RNA Vaccines Give Equivalent Protection against Influenza to mRNA Vaccines but at Much Lower Doses”, Molecular Therapies 26 (2018) 446-455.
7. DNA vaccine (Adenovirus) – SC Gilbert, “Adenovirus-vectored Ebola vaccines”, Expert Review of Vaccines 14 (2015) 1347-1357.
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