The rush to control the COVID-19 pandemic has demonstrated that the global scientific community can tackle emergencies on a tight timeframe. In a matter of months, drugmakers have brought a host of vaccine and drug candidates into clinical testing, including at least six antibody drugs that could neutralize the virus.
But compressing timetables is also pushing the limits of drug manufacturing capabilities. This is particularly true for biologic agents such as neutralizing antibodies, which must be produced via a complex and labour-intensive process that begins with big bioreactor tanks of protein-producing cells. Michael Vandiver, SVP Biologics Operations at Seattle, Washington-based Just – Evotec Biologics, believes that the industry remains too focused on this ‘big fit-for-purpose’ model. “That’s simply old thinking,” he says.
Vandiver is championing a more flexible and adaptable biologics platform known as J.DESIGN™, which could greatly reduce the time and cost of producing such therapeutic molecules. By coupling computer-assisted molecular design and process optimization with a production workflow based on modular pods carrying disposable components, J.DESIGN™ gives drug developers the ability to rapidly configure and reconfigure their pipeline to meet specific needs.
Biologics, antibody drugs in particular, are big business. In 2017, the biologics market was estimated at US$236 billion worldwide, with more than 2,000 antibody or antibody-like drugs either approved or in clinical development. But building out manufacturing capacity for new drugs is expensive. Vandiver estimates that a traditional facility can cost at least $500 million up-front; yet, once the manufacturing and testing facilities are constructed, it becomes exceedingly difficult to modify the workflow. This inflexibility introduces serious inefficiencies. “A lot of these big facilities are under-utilized,” he says.
Many biologic drug manufacturing programmes are further constrained by siloed organizational structures. Teams developing the manufacturing process may lack important data produced by the drug discovery team; conversely, lessons learned while developing a production workflow may not be passed back to those responsible for advancing drug leads.
J.DESIGN™ was conceived as a solution to these problems, integrating lead development, manufacturing-process design, and scalable production. “You’re optimizing the molecule for manufacturing while maintaining biological activity,” says Vandiver, “and developing processes that leverage your manufacturing capabilities effectively.” Above all, the goal is to render the final production pipeline as compact and streamlined as possible, producing appropriate amounts of drug while minimizing factory footprint and staffing requirements.
Early in a project, J.DESIGN™ uses a suite of computational tools to assess the structural and biochemical properties of drug candidates. One of these tools, a proprietary program called Abacus™, uses experimental datasets from large numbers of other antibodies to predict better ways to make drug candidates or to improve their clinical performance. This could include humanizing antibodies, improving behaviour of a solution, or generating molecules that are better able to tolerate particular temperature or pH conditions. Randal Ketchem, VP Molecular Design at Just – Evotec Biologics, explains that Abacus™ builds molecular profiles of panels of antibody therapeutic candidates, which can guide the selection of an optimal lead candidate. “This information may then be used in conjunction with structure models to design a new antibody variant, optimized for manufacturing,” says Ketchem.
Abacus™ incorporates machine-learning algorithms that can be trained with new data to further strengthen its predictive power for areas such as immunogenicity, sequence optimization and purification behaviour. These computational analyses, along with experimentally derived biophysical properties, can help guide the design of the manufacturing process.
The power of pods
Once the intensified manufacturing process has been designed, it is executed by assembling a network of autonomous cleanrooms that use J.POD® technology. J.POD® is a small, relatively inexpensive biologics manufacturing plant that uses disposable equipment to execute any step in the manufacturing process. Instead of filling a factory space with massive stainless-steel tanks and other bulky piping and instrumentation, biopharma companies can have a flexible set-up with these small modular units. “This eliminates the need for centralized utilities such as clean-in-place and steam-in-place,” says Vandiver. “You focus on putting only the critical equipment inside the pods.” Furthermore, the manufacturing pipeline feeds information back to the computational side, so that data collected during production can guide further process learning and understanding.
Shrinking steps to J.POD® scale can yield considerable savings. “Clean room space is expensive — more than $1,000 a square foot [~$10,000 per square metre],” says Vandiver. He adds that traditional production facilities are often as large as 80,000 m2, and even some of the more contemporary ‘flexible’ manufacturing models still require around 20,000 m2. In contrast, a J.POD-based production facility would cost half as much, take up only 10,000–13,000 m2, and require roughly half the number of full-time employees to produce an equivalent amount of antibody drug substance.
The modular design means that manufacturing capacity can be added quickly and easily, as a biologic candidate moves from early clinical testing to pivotal trials or commercial deployment, for example. Pods can also be repurposed to meet new processing requirements or deployed elsewhere as needs change — a feature that would be valuable today, as biopharma companies look to bring promising COVID-19 biotherapeutics into trials as quickly as possible.
Just – Evotec Biologics began construction of its first dedicated J.POD® facility in Redmond, Washington in May 2020, scheduled for completion by November 2021. Just – Evotec Biologics, along with select industry partners, has made significant advancements in ‘end-to-end continuous’ biologics manufacturing at 500-litre scale. Here, the output from each manufacturing step directly becomes the input for the following step, as opposed to standard batch processes where each stage yields discrete lots of intermediate products that are walked sequentially through subsequent steps. A few other companies have also turned to Just – Evotec Biologics for contract manufacturing services. For example, Advanced BioScience Laboratories is using J.DESIGN™ to scale up production of an antibody drug candidate against HIV.
Vandiver is most excited about how J.DESIGN™ could move the industry away from centralized biologics manufacturing altogether. Regional manufacturing facilities could help reduce risk in the supply pipeline. “I worry about things such as contamination or a natural disaster like an earthquake or hurricane. One incident in your large-scale centralized facility could completely disrupt your ability to meet production demands,” says Vandiver. “But if you have a network of smaller and more productive plants and one goes offline, you still have others that you can strategically use.”
Another benefit is improved distribution: it will be easier for resource-limited countries to bring domestic biologics manufacturing capacity online — for example, to make biosimilars of newly off-patent blockbuster drugs. “We can potentially take a pod from Seattle and ship it to South Africa,” says Vandiver. “Simply put, this is about producing large amounts of biologics drug substance in small, relatively inexpensive, and flexible plants.”