Jose-Carlos Gutiérrez-Ramos - Chief Science Officer, Danaher
As many countries lift all their pandemic restrictions, and COVID-19 transitions from a pandemic to an endemic disease, many people are looking back and assessing what aspects of life will go back to normal and what changes will likely never be reversed. Precedents have been set that may have radically reshaped expectations, for instance, those of patients, physicians, and the general public regarding the timeframe for new drug discovery and development. Fault-lines in our global economy and ways of working have been exposed, and conversely, unity around a shared value in the face of a common threat has spurred enormous collaboration worldwide. The biopharma ecosystem underwent many changes to pivot and meet the urgent need for new vaccines and antivirals to combat COVID-19, resulting in the development of many new therapeutics, including mRNA vaccines. These changes have also dramatically altered manufacturing business models and priorities across the sector. We highlight five ways in which biomanufacturing business models have changed and how these changes impact the direction of travel for the industry.
1.Time is Precious
The urgency of the pandemic and the ambition to be first to impact caused many biopharma businesses to change their ways of working, focusing primarily on speed. Remarkably, two of the medicines brought to market in record time belonged to an entirely new class of therapeutic, mRNA vaccines. The question now is how can we sustain these pandemic speeds, productivity, and innovation once the pandemic ends? The answer lies in many directions, with the advances made in biopharma approaches, infrastructure and processes needing to be established for the long term and built on. This includes the digital transformation and integration of the business at multiple levels, resilient biopharmaceutical manufacturing processes that scale rapidly and can be readily deployed at multiple sites, and open innovation and federated risk management founded on secure multistakeholder collaborations and partnerships. Bringing together these critical pieces of the puzzle will help biopharma companies better balance innovation and competition, as well as deliver novel therapeutics as quickly and effectively as possible to the patients that need them.
2. The Center of Gravity is Shifting in Biopharma
Biopharma companies have increasingly turned to external suppliers and vendors for raw materials and services, opting to outsource work rather than performing it in-house. This trend was supercharged during the pandemic and the role of suppliers and vendors has evolved. While companies traditionally conducted all tasks in-house, with their center of gravity located squarely in drug discovery and commercial manufacturing, this focus is shifting. Especially, with the increasingly diverse and rapidly growing therapeutic modality of genomic medicines, much of the disease target identification and discovery phase is increasingly being performed by academic research teams and their spinout biotechnology companies. Manufacturing is frequently outsourced to Contract Manufacturing Organizations (CMOs), some of which have evolved to also perform the drug development as Contract Development and Manufacturing Organizations (CDMOs). And clinical trials are also increasingly being conducted by Clinical Research Organizations (CROs).
So, where does that leave the biopharma companies? They remain responsible for seeing a therapeutic candidate through from bench to bedside but as more functions are outsourced, their center of gravity is shifting. Industry players look to these companies to provide the expertise, experience, and gestalt necessary for critical decisions throughout the drug-making process, most particularly with a view towards anticipating and meeting all the requirements to secure regulatory approval and successfully complete the essential last mile to get a therapy to market and clinic. The critical strengths from biopharma in this value chain are centered on pathobiology expertise, clinical development and regulatory expertise and intimate knowledge of patient management.
This shift in the biopharma center of gravity has been catalyzed by the pandemic, as biotech and biopharma companies increasingly relied on their suppliers and vendors to supply not only raw materials, but their own niche expertise to get critical discovery, development, manufacturing, and distribution projects launched and successfully completed. This shift also means that the biopharma ecosystem is becoming increasingly collaborative. For instance, the Oxford University and AstraZeneca COVID-19 vaccine was developed with vital support from a consortium of brave stakeholders. The consortium included Pall Biotech who not only developed the industrial biomanufacturing process to produce the vaccine at clinical grade but even lent another company the large-scale bioreactor they needed to start manufacturing the vaccine in the Netherlands.1
3. Teamwork Makes the Dream Work
By relying on the expertise of Pall Biotech to develop their vaccine bioprocess, Oxford University and AstraZeneca were provided a scalable manufacturing process for the COVID-19 vaccine in just eight weeks instead of the typical five years.2 This enabled the first commercial batch of the vaccine to be produced by one of Oxford/ AstraZeneca’s CMOs in the UK only 60 days after Pall Biotech started work on designing the bioprocess itself.1
Another example of this evolution of the biopharma ecosystem and the growing role of vendors and suppliers as trusted and linchpin partners is demonstrated by the increasing number of expanded partnerships occurring between biopharma companies and their vendors. For instance, Moderna, the company that developed one of the first two mRNA COVID vaccines to be approved by the US Food and Drug Administration (FDA), has been building a relationship with a vendor, Aldevron, for nearly a decade.3 Aldevron is the leading provider of high-quality plasmid DNA, mRNA and recombinant proteins necessary for vaccines, gene and cell therapy, gene editing and diagnostic applications.3 During the pandemic, Moderna expanded their long-standing partnership with Aldevron, who would supply plasmid DNA that would serve as the genetic template for generating the COVID-19 mRNA vaccine, as well as for other investigational programs in Moderna’s pipeline.3 Aldevron’s deep experience, coupled with their enhanced operational efficiencies and then recent capacity expansion placed them in an excellent position to support Moderna’s efforts to develop their COVID-19 vaccines, especially at such a critical time.3
The involvement of Pall Biotech with the Oxford University research team that co-developed the Vaxrevia COVID-19 vaccine with AstraZeneca was also founded in part on a close relationship with one of the academic research leaders.1 The importance of these collaborative relationships and the knowledge sharing that occurs as part of these partnerships is essential for innovation and ultimately the successful delivery of drug discovery and development projects, helping to accelerate the entire process of getting a therapeutic candidate through to market.
4. The Race to Scale
Another important challenge that is increasingly being met by manufacturing business models that incorporate expanded outsourcing to partners is that of scale. With cell and gene therapies, which are currently being directed to the treatment of mainly individuals with rare disease, the scale is typically small. Autologous therapies are as personalized as medicine can get, with the raw material being cells sourced from the patient for whom the final drug product is destined to treat. Gene therapies are mainly effective for only a small population of patients. Therefore, there is no need for large-scale manufacturing of these medicines. However, the medicine manufacturing still needs to comply with very stringent current Good Manufacturing Practice (cGMP) regulations. With such small markets, profitability and even breaking even can be a challenge. One solution is to shift from focusing on realizing value through economies of scale to also realizing value through economies of scope. This means being able to apply the apparatus and expertise developed for producing one cell or gene therapy to the production of another. Thus, by scaling out rather than up to produce multiple cell and gene therapies, the production of personalized or stratified medicines can be economically viable.
The advent of mRNA vaccines amply demonstrated that genetic-based therapeutics or “genomic medicines” need not be restricted to small-scale production. This new therapeutic modality introduced new challenges unique to the modality of genomic medicines, as drug manufacturers now need to be able to scale both up and out. The way that this was achieved for Vaxrevia during the pandemic was through the application of standardized platforms and equipment, coupled with in-depth expertise available from a vendor company that had spent years innovating to meet similar biomanufacturing needs. The remarkable eight-week turnaround time achieved by Pall Biotech was as much due to the know-how of the Pall team as to the incorporation of an automated, end-to-end integrated, platform with single-use technologies. This translated into standardized yet flexible solutions that were relatively easy to implement to produce the vaccine, in compliance with cGMP regulations.4
In a similar way, the adoption of standardized platform approaches, with automation and integration throughout the production process, and single-use technologies could support the small-scale manufacture of genomic medicines, such as genetically modified cell therapies and gene therapies. Along with the support of vendors who have dedicated expertise in the development of bioprocesses for genomic medicines.
5. Biomanufacturing at the Edge
These intellectual, digital, and technological advances will also be crucial for distributed and decentralized biomanufacturing. The need for COVID-19 vaccines worldwide highlighted how the industry needs to change to better prepare for the next pandemic. Pall’s development of a rapidly scalable and deployable bioproduction process was crucial to produce billions of doses of the mRNA COVID-19 vaccine in multiple facilities across the globe. But the supply of any of the vaccines did not meet demand as quickly as was needed.
The supply chain vulnerabilities revealed during the pandemic and the need for better pandemic preparedness including sustainable surge capacity in-country means that biomanufacturing is likely to transition from using global supply chains to local ones. There will be more vertical integration nationally and locally to better ensure the security of supply for times when there is global disruption. However, this does not necessarily mean that biopharma companies are retrenching on the manufacturing business model that relies on outsourcing. Rather, vendors are moving to expand their capabilities alongside their evolving role in the biopharma ecosystem, to supply their partners where they are.
Akin to edge computing, decentralized biomanufacturing models are emerging, requiring new ways to retain integration and manage geographically and temporally disparate facilities. A potential solution could involve increased transparency and trust in practice between partners, where data is shared automatically between biopharma companies and their vendors. This would include biopharma companies revealing more about their needs and demand issues in real-time, and vendors revealing more about their supply operations and ability to meet their partners’ demands. Such mutual openness could lead to improved real-time risk and business continuity management. Computer systems could then be used to apply the data to map and track the supply and demand in real-time, and train machine learning programs to model and predict any changes, enabling rapid response for seamless troubleshooting and problem-solving.
The Brave New World of Biomanufacturing
As the world begins to get back to normal or the “new normal,” the pandemic has left us with many lasting changes. We must continue working together and sustain the new compressed timeframes for biopharmaceutical research and development (R&D) and commercial manufacture, so that we can collectively deliver many more new therapies to patients as quickly, safely, and effectively as possible.
References
- Pike H. The Oxford miracle: making enough COVID-19 vaccine to supply the world. The Pharmaceutical Journal. April 15, 2021. Available at: https://pharmaceutical-journal.com/ article/feature/the-oxford-miracle-making-enough-covid-19-vaccine-to-supply-the-world. Accessed April 19, 2022.
- D’Agata C. Drugmaker ramping up production of potential coronavirus vaccine in record time. CBS News. August 25, 2020. Available at: https://www.cbsnews.com/news/ coronavirus-vaccine-astrazeneca-ramping-up-production/. Accessed April 19, 2022.
- Moderna. Moderna and Aldevron announce expanded partnership for mRNA vaccine and therapeutic pipeline. Moderna. News. May 24, 2021. Available at: https://investors. modernatx.com/news/news-details/2021/Moderna-and-Aldevron-Announce-Expanded-Partnership-for-mRNA-Vaccine-and-Therapeutic-Pipeline-05-24-2021/default.aspx. Accessed April 19, 2022.
- Ligner E. The race to scale. Pharma Manufacturing. August 25, 2021. Available at: https:// www.pharmamanufacturing.com/articles/2021/the-race-to-scale-covid-19-vaccines/. Accessed April 19, 2022.
Jose-Carlos Gutiérrez-Ramos, PhD, is Chief Science Officer of Danaher. He sets Danaher’s science and technology strategy, and leads Danaher’s Innovation Centers and Corporate Science and Technology Teams. Prior to Danaher, he was Global Head of Drug Discovery at AbbVie, Group SVP Biotherapeutics R&D at Pfizer, SVP and CEDD Head of Immuno-inflammation at GlaxoSmithKline, founding CEO and President at Repertoire Immune Medicine and President and CEO of Synlogic.
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