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Jennifer Markarian is manufacturing editor of BioPharm International.
Collaboration between equipment suppliers and users is leading to innovation and optimization in biopharmaceutical manufacturing.
Process development is moving at unprecedented speed as manufacturers race to produce COVID-19 vaccines and treatments and the products needed to make them, such as viral vectors, as well as keep up with the burgeoning cell and gene therapy sector. Optimizing single-use bioprocessing equipment, including both upstream and downstream equipment as well as consumables and starting materials, is a crucial piece of process development. Knowledge of the equipment, the process, and the product are paramount, and successful projects rely on experts embedded throughout the supply chain. Close cooperation between equipment suppliers and the users of the equipment is a key to success, as the industry seeks to address the expanding need for process development, manufacturing capacity, and training.
At EMD Millipore, the Life Science business of Merck KGaA (operating as MilliporeSigma in the US and Canada), process development is provided through the company’s contract development and manufacturing organization (CDMO). The CMDO works closely with the other parts of the company’s business, including the consumable products businesses, such as filters and media, and the company’s bioprocessing equipment business, says Sébastien Ribault, vice-president and head of end-to-end CDMO Services, Process Solutions at Merck Life Science. As users of the equipment, the CDMO gives feedback to the equipment business.
“When we have an idea at the bench or in the manufacturing area, where we see we could manufacture faster, cheaper, with higher quality, or with fewer mistakes by users, we reach out to our equipment and product suppliers so that they can translate these ideas into new products,” says Ribault. He points to a 2000-L bioreactor that MilliporeSigma’s equipment business introduced in 2015 as an example. “The team members on this product included our head of process development who brought experience in scale-up and scale-down. Now we can scale up directly from 3-L bench-scale to 2000-L commercial scale. We can save two months by not having to do an engineering run at intermediate scale (100–500 L), and we optimize our use of good manufacturing practice (GMP) suites.”
Since 2020, EMD Millipore has been hard at work supporting developers of treatments for COVID-19. In one example, the CDMO worked with an innovator of an antibody that needed to speed the development process. “We reinvented the process development template and went from DNA to final drug substance in nine months, when a more typical timeframe is 15 months. We could do this because of the close connection between our process developers and the EMD Millipore equipment business,” says Ribault. The product is now moving through tech transfer to GMP production. “This new way of process development took into account expectations from regulators and also adapted to quality requirements. The use of pre-packed purification columns instead of manually assembled is one good example to speed up processes through the use of products that did not exist years ago. It is faster to implement, easier to use, and eliminates a sometimes-difficult packing step,” he says.
In the fast-growing cell and gene therapy area, projects are also moving quickly. “Clients want to get to first-in-human stages quickly,” says Ribault. “The process needs to be developed to allow rapid advancement to clinical stages that match with the regulatory framework that will be needed to move to GMP manufacturing.”
While cell and gene therapy has been more research-oriented, it now needs to move to a focus on robust, reproducible processes, says Ribault. “Here is where a connection between the equipment developers and the process developers is key to make a templated approach and create the equipment,” he notes. Automation is becoming a more visible part of cell and gene therapy processes. “For some, the importance of automation is that it eliminates the risk of error. For others, automation is key for gaining throughput and allowing the process to run continuously,” explains Ribault.
Cytiva has long offered its Fast Trak process development services to customers developing processes using the company’s bioprocessing equipment. The company’s seven Fast Trak centers—in Korea; Japan; Cambridge, UK; Uppsala, Sweden; Shanghai; Toronto; and Marlborough, MA—house processing equipment that can be used for training, development, and manufacturing. In December, Cytiva announced that it had expanded its services at several of the sites, so that all now offer process development, media and assay development, and contract development services. The expansion supports the cell and gene therapy industry and small to mid-sized biotech companies in particular.
“Start-up biotech companies that can’t yet afford space, labor, and time until they have clinical data are benefiting greatly from this initiative,” says Shannon Eaker, Cell and Gene Therapy’s FastTrak leader at Cytiva. He adds that large pharma companies with large product pipelines can also benefit from the company’s process development services. “Companies are looking to expand their pipelines. Starting with Cytiva’s platform processes, which have supported the cell therapy field for many years, Fast Trak saves customers time and money in doing the R&D work. Starting with Cytiva’s platform processes, which have supported the cell therapy field for many years, saves the customer time and money in doing the R&D work,” says Eaker. A key area of development is developing scalable processes that are flexible for multiple cell types and processes, such as both autologous and allogeneic therapies, notes Eaker.
Pall Biotech supplies single-use biopharmaceutical manufacturing equipment and also has a process development services team that designs processes and performs tech transfer to GMP manufacturing; the group has developed more than 30 viral vector-based processes in the past three years. In April 2020, Pall joined a consortium started by Oxford University and funded by the government of the United Kingdom (UK) to develop Oxford’s COVID-19 vaccine candidate based on its adenoviral vector vaccine platform. The consortium included the University of Oxford Jenner Institute, University of Oxford Clinical Biomanufacturing Facility, UK non-profit Vaccines Manufacturing and Innovation Centre, Pall Corporation, Oxford Biomedica, Cobra Biologics, and Halix. The group was joined in late April by AstraZeneca, when the company partnered with Oxford University’s vaccine developers and licensed the vaccine technology. As of early January 2021, the vaccine being marketed as COVID-19 Vaccine AstraZeneca (formerly AZD1222) was authorized for use in the UK, India, and others and was in the midst of a large Phase III clinical trials in the US.
The consortium members worked closely together to develop and enable manufacturing of the vaccine in record time, says Clive Glover, director of strategy at Pall Corporation and the lead on the vaccine project. He noted that Pall designed the commercial manufacturing process and installed the equipment at a contract manufacturing partner within two months, breaking Pall’s previous record of nine months.
One of the keys to this success was starting with a standard manufacturing process. Glover suggests that for viral vector-based therapeutics, such as this vaccine, 80% of the manufacturing process is standard—the same no matter what the product—and the remaining 20% needs to be tailored. “The process can vary in several ways,” explains Glover. “For example, on the upstream, each process will rely on different cell lines, each of which may have slightly different growth rates, which will drive different feeding strategies. On the downstream side, viral vector products will vary in their physical properties and so require optimization of each downstream step to affect stability and ability to be concentrated. Finally, different products will need to be put into different concentrations for administration to patients, [which] has to be customized to each process.”
With Pall’s standard manufacturing process and the University of Oxford’s research as starting points, the consortium collaborated to optimize the process. “Decisions around the process were data-driven, based on initial pilot scale runs done by the University of Oxford,” notes Glover. “This process was then recreated by the Pall team at our Process Development Services laboratory in Portsmouth, UK, and developed into a small-scale process. [The process] was designed as a scaled-down model of a commercial process, and it allowed us to determine the specific parameters that would work at larger scale. Following successful runs at the small scale, we then did commercial runs to ensure the process was fit for purpose, before transferring that process to the various contract manufacturing organizations (CMOs). It’s important to note that the whole time we were doing these scale-up runs, we were constantly collecting data that helped with filing of the CMC [chemistry, manufacturing, and controls] section for the regulatory authorities.”
Because rapid scale up to high volumes of commercial product were needed, AstraZeneca called on multiple CMOs for production. Glover notes that, through the consortium, the CMOs worked to each use as similar a process as possible, which simplified the supply chain for equipment and raw materials.
A challenge Pall faced was supplying equipment in the short time that was required to set up the manufacturing process. “We did this by working very closely with our manufacturing sites and manufacturing some units at risk in order to compress timelines,” says Glover.
Another challenge addressed by a team of 20 that Pall had dedicated to the project was tech transfer. “Ensuring that the process is well characterized is critical for a smooth tech transfer. Given that speed was critical in the case of COVID-19 vaccines, we sent Pall personnel who were involved in the process development onsite to the CMOs for their initial runs to make sure that everything went smoothly,” reports Glover.
In addition to the efforts of Pall personnel, keys to the record speed of process development included “a combination of ground-breaking innovation, secure funding streams, relentless effort from some of the greatest scientific minds on the planet and, crucially, a consortium-wide commitment to the principles of lean process development and production,” concludes Glover.
Although different ways of collaborating are being employed, the need for a growing body of experts with the knowledge and ability to move manufacturing processes into commercialization is crucial for all. The rapid growth of the cell and gene therapy industry, as well as biopharmaceutical manufacturing for COVID-19 vaccines and therapies, is creating a greater need for training and education as companies add staff who need to learn how to use the equipment.
For new therapeutics, equipment suppliers play a crucial role because of their detailed knowledge of process technologies. “Unlike more established therapeutics like monoclonal antibodies, with many of the novel therapeutics, such as viral vectors, there is not yet a critical mass of knowledge on how to design and run large-scale commercial processes,” notes Glover. “Over time, manufacturers will have much greater expertise on their specific therapeutic and manufacturing process, but even then, they [can benefit from] the depth of knowledge that we have as an equipment supplier. This [knowledge] is why we build long-term partnerships with customers in this space, because we can add real value to them throughout the whole process.”
Jennifer Markarian is manufacturing editor at Pharmaceutical Technology.