2022 ISPE Biotechnology Conference: Ongoing Growth & Development

The conference focused on the ongoing development and growth in these technologies, and featured speakers on a broad range of topics, including advanced manufacturing and how lessons learned from COVID-19 vaccine development can apply to biologics development. Highlights from several plenary sessions and keynotes are provided here; the sidebar addresses a panel discussion about addressing risk management as biopharmaceuticals continue to move forward.

The Road to Advanced Manufacturing

The conference opened 28 September with a keynote address by Peter Marks, MD, PhD, Director, Center for Biologics Evaluation and Research (CBER) at the US Food and Drug Administration (FDA). He presented “Advancing the Manufacturing of Complex Biologic Products” and discussed the potential of advanced manufacturing, case studies in COVID-19 and individual gene therapy, and resources from the FDA for product developers.

Marks described some of the successes and challenges of the vaccine production in response to COVID-19. Process development and scale up of manufacturing have been the greatest challenges to COVID-19 vaccine development and deployment, Marks noted. He observed how the development of COVID-19 vaccines was able to compress the traditional de-risked approach to vaccine development to meet the needs of the pandemic. “Condensing phases of development and concomitant manufacturing development can be done, and Operation Warp Speed essentially did this” through Phase 1, 2, and 3 trials, and when data supported good immune response, scale-up occurred. He emphasized that millions of vaccines were produced, found effec-tive and safe, and were rapidly rolled out. “The ability to do so probably saved lives.”

The process was not without challenges, Marks noted. Bottlenecks occurred and insufficient raw materials, such as lipids early on for mRNAs, took some time to resolve. A dearth of disposable supplies and plasticware was another challenge, as were bioreactor capacity and the need for well-trained individuals to make the vaccines. Marks said sterile techniques are a little different for the vaccines than in other areas of manufacturing. “One thing I never thought a lot about until the pandemic was fill-finish capacity, which turned out to be quite limiting early on. Also having enough glass vials to put the vaccines in! That is one reason why there were multiple-dose presentations, since there were not enough glass vials for single doses.” He remarked that having a sufficient skilled workforce to complete all that was necessary was a tremendous challenge.

These challenges can help in the industry transition to advanced manufacturing, such as improved agility, flexibility, reliability, and reduced costs of the manufacturing process for biological products by continuous or semicontinuous production, he said. There is potential for vaccines, cell- and gene-based therapies, and other complex biologics.

Vaccine supply could more easily be ramped up on short notice and more rapidly modified for emerging infectious diseases, he suggested, saying that many such diseases come in waves, so a baseline production at 25% to 50% capacity could be in place that could ramp up when an infectious dis-ease surge occurs.

Marks spoke about the promise of advanced biologics manufacturing, giving an example of a bioreactor harvest and feed directly into a purification system, ultimately to be able to formulate into drug product and fill-finish it. Such a concept could help address some of the challenges experienced during the COVID-19 vaccine development, and help essentially decrease the footprint of production. Advanced manufacturing that could work with a prefabricated clean room could allow more distributed manufacturing closer to where the product is going, and could distribute manufacturing more evenly across a country or multiple countries.

The opportunity to produce on a small scale could help with therapies for rare diseases and disorders, Marks said, foreseeing a possible paradigm ahead to move into genome editing to try to correct more common diseases.

Individualized therapies that create the right drug to reach each patient are another challenge in manufacturing because commercial manufacturing has setup costs, such as capital investment to build a site and buy the equipment required to produce the drug. These costs cannot be recouped if production is less than a few hundred doses per year. The technology is there to create small numbers of drugs, but the need is to make these at a cost that is viable to try to treat patients and with capacity to do so on a lot of small-scale dosing regimens. He said leveraging validated processes can potentially facilitate the development of new products.

Devices may be a way to move ahead for upstream production of vectors and for downstream purification. Such devices are being worked on by academics and companies, Marks said. Standard methods for bespoke gene therapy could be a way to make it easier.

Advanced manufacturing offers potential for improved agility, flexibility, reliability, and cost reduction

At the FDA, Marks said the agency is thinking about ways to streamline some regulatory aspects. In appropriate situations, nonclinical data and manufacturing from one product may be able to be leveraged to another (possibly where an original product was already approved). The FDA is working with the National Institutes of Health on a bespoke gene therapy consortium that is a public/private partnership. Other support includes CBER Advanced Technologies Team (CATT) meetings that can benefit those interested in looking at advanced technologies for product manufacturing technologies or platforms. Early and ongoing interaction with CBER before filing a regulatory submission allows for informal interaction that is nonbinding. The FDA’s Initial Targeted Engagement for Regulatory Advice on CBER Products (INTERACT) program allows early dialogue to set people up for success.

Advanced manufacturing offers potential for improved agility, flexibility, reliability, and cost reduction for manufacturing biological products, Marks said in summary, and he looks forward to working with science and manufacturing communities in this area.

Narendra B. Bam, PhD, Senior Vice President, MedicineDevelopment and Supply at GlaxoSmithKline, was the next speaker in the opening session, with a presentation on “Biopharmaceutical Manufacturing on the Horizon.” He reviewed some work underway at GSK, including innovation in continuous small molecule manufacturing with continuous integrated drug substance and continuous drug product manufacturing; small molecule continuously manufactured product recently launched; and applying the learnings to biopharmaceuticals. GSK is developing an integrated drug substance manufacturing platform with, what Bam said was, a significantly lower capital/footprint and increased flexibility. (He said the bioreactor size could be reduced to under 900 kg per year production rate, which is becoming a “sweet spot.”) The company is also working on increased process control with steady-state, highly automated, PAT-enabled production to reduce residence time and help eliminate intermediate holds; supply chain velocity with a scaled-out model for replication; simplified tech transfer; and mitigation of scale-up risk. Bam said, “We hope to make supply chains completely agile!”

Condensing phases of development and concomitant manufacturing development can be done, and Operation Warp Speed essentially did this” through Phase 1, 2, and 3 trials, and when data supported good immune response, scale-up occurred.

Two Journeys to Vaccines and Beyond

A Foundation for the Future

In the opening session on 28 June, Oliver Hennig, PhD, Senior Vice President, Operations at BioNTech SE, presented on “Manufacturing of High Precision mRNA Medicines Against Cancer.” His talk traced achievements of BioNTech in development of the mRNA vaccine for COVID-19 alongside its partners, and looked at the road ahead in applying the science and technology to new areas, including oncology.

He gave an overview of the company’s development from its launch in 2008 through Project Lightspeed for the development of the mRNA COVID-19 vaccine. He noted the great importance of risk consideration, having a process to assess and understand it, and discussing it, which enabled and empowered decisions. Partners—including Fosun Pharma, Pfizer, and regulatory agencies—collaborated and participated in the development and rollout of the vaccine in just 11 months.

The new class of medicines possible through mRNA is creating huge opportunities for the entire industry, Hennig said, including vaccines, protein substitutes, and reprogramming for treatment of cancer, infectious and autoimmune diseases, and regenerative medicine. “mRNA is just getting started,” he said.

The mRNA manufacturing process allows for rapid expansion, which may be helpful in responding to the needs in cancer therapy for individualized approaches and fast production. BioNTech has two mRNA platforms for cancer: FixVac, an off-the-shelf indication-specific mRNA cancer vaccine platform targeting a fixed combination of shared antigens, and iNeST, an individualized mRNA cancer vaccine platform, targeting 20 neoantigens unique to each patient. These are the basis of the company’s work to expand offerings and make them available broadly around the world through its BioNTainers concept, a modular and scalable vaccine production approach for which models are being developed. Smaller-footprint standard manufacturing with ready-built modules that can be shipped to different locations is the goal, he explained, although it will not be suitable for all manufacturing needs.

Building a New Platform

Juan Andres, Chief Technical Operations and Quality Officer, Moderna, gave the closing keynote on 30 September, “Ideas to Performance: The Impossible Journey.” He traced the journey of Moderna through its achievement of producing a vaccine for COVID-19 (which turned out to not be an impossible goal!). He spoke about the first decade of Moderna and its work with mRNA, and the path to preparing the vaccine and then ramping up distribution, as well as current realities and the path forward.

The journey began with the idea that making mRNA work for one solution could provide opportunities to apply it to many other solutions. This was not without risk; as Andres noted, risk management is essential to the work of building a new class of medicine. Moderna approached its development with the idea of building a manufacturing site that could scale up quickly, choosing from the start to work with an MES system, in a paper-free environment, and by monitoring movement of people to determine placement of equipment. All of these early decisions helped the company tremendously in its approach to creating a fully integrated and digital facility to produce mRNA and applying it as a platform to address rare diseases.

In 2015, Moderna introduced its first development candidate in its prophylactic disease modality, an H10N8 flu vaccine candidate; the next year, it began to build its Norwood, Massachusetts, facility, which opened in 2018. The ongoing development required every decision to consider both funding and technology focuses, he said. By 2019, among other achievements, the company announced dosing of its first monoclonal antibody encoded in mRNA in a clinical trial.

By January 2020, discussions were underway about whether the company was going to become involved in developing a vaccine to combat the “new virus,” COVID-19. Although there were concerns that the company was not ready to produce product at the needed level, it decided to proceed. Within days, it had several mRNA candidates to consider. Its mRNA platform and technology helped the company be able to move swiftly to a first GMP batch on 7 February 2020, with clinical trials started in early March 2020. The science, previous work on mRNA, and prior collaboration with the government were all helpful, Andres noted, despite the lack of scale, infrastructure (including people), and funds.

The mRNA manufacturing process allows for rapid expansion, which may be helpful in responding to the needs in cancer therapy for individualized approaches and fast production.

Through March and April 2020, Moderna employees worked seven days a week for up to 14-hour days. The company had experience with preclinical and clinical batches, and CMC variability was top of mind. The kit concept was established—a standard drug substance production train linking mRNA and lipid nanoparticles (LNP) manufacturing—to allow for reproducible production to permit broader-scale production. After success at small-scale production, Moderna joined forces with partners, including Catalent and Lonza, as the vaccine progressed through Phase III and then emergency use authorization (EUA) status. Having experienced partners was necessary to success, he noted, and included Operation Warp Speed officials as well as suppliers. Shortages of materials (including plastic and glass), funds to purchase equipment, and the wait for equipment were also challenges.

The launch of the vaccine was a collaborative effort, he noted, with great commitment from Moderna employees and those working with its partners. The lessons learned during those months have potential to be applied elsewhere. Moderna has grown from 300 people to 3,000 and has over 40 programs underway in vaccines as well as immunology, oncology, and rare diseases. “This is just the beginning,” he said.