Design An Adaptable, Efficient Platform Process For Complex Biologics

By Life Science Connect Editorial Staff

Since monoclonal antibodies (mAbs) first emerged on the scene as powerful therapeutic mechanisms, manufacturers have steadily developed plug and play platforms that accommodate fast pathways to the clinic. However, as the molecular structures used in biologic therapies grow increasingly complex, existing platforms must be recalibrated to better suit them. AltruBio’s chief technical officer, Gene Lee, Ph.D., and his team are working to create innovative immune therapies that can be delivered to patients quickly and safely. Another leader in the industry, Avril Vermunt, sr. director of manufacturing sciences and technology at EQRx, is working with her company to create greater accessibility for patients in need of innovative biologic medicines. To realize their goal of state-of-the-art, rapidly produced therapies and widespread patient access, Lee and Vermunt are working to identify and adopt high-quality, molecule-specific manufacturing techniques.

The Inefficiencies Of Existing Platforms

Many mAb manufacturing platforms offer highly uniform production strategies that aren’t necessarily suited to the diverse molecules being developed for clinical trials. Though many platforms still work with highly complex molecules, the molecules’ unique properties must be factored into operating parameters. Unfortunately, much of the existing manufacturing technology hasn’t caught up to the sophistication of molecular design. According to Vermunt, “Putting these more complex molecules through older technology is more like using blunt force instruments to get mediocre separation, rather than measuring and separating [based on the molecule’s complex nature].”

Significant understanding of a molecule’s behavior is gained by scientists during the research and discovery (R&D) phase yet, often, this molecular knowledge isn’t shared with the downstream manufacturing and process development teams, which might be limiting to the efficiency of their processes. In a similar vein, manufacturing teams sometimes fail to communicate with R&D scientists about the components of their platform and its constraints, which can help protein engineering teams gain insight into how their molecule might respond to certain technologies. This lack of communication between key parties perpetuates the limitations of mAbs platforms.

How To Design An Adaptable Platform Process

Technology improvements throughout the manufacturing process help build smarter, more streamlined platforms. In some cases, the high-end technology used throughout the drug discovery process might be retooled for application within the process development phase or at least to better inform the decisions made during process development. These technologies include artificial intelligence (AI), computational power, high-throughput analytics, and miniaturization.

To better attune platforms to complicated molecules, Vermunt emphasizes using critical thinking skills: “There is not only complexity in our molecules but complexity in our different manufacturing options. Do some critical thinking, not just on the individual technologies but on the interdependencies of those technologies. Once you layer on regulatory and other guiding aspects of our industry, it gets complex fast. You need a big picture view to get it right.”

As such, it is vital to employ staff who can think critically about how each component of a platform will serve the process, particularly which components are ill-suited for a specific molecule’s attributes. “We [must choose] the pieces of the platform that serve us, [rather than] blindly saying, everything is going to the platform. That's the tricky part: how do we make sure we use the right aspects of a platform to get the objective we want?” advises Vermunt.

Building clear paths of communication between R&D, process development, and manufacturing is one strategy to help ensure the right platform components are utilized. By considering the R&D team’s knowledge of a molecule’s properties, manufacturing can better avoid bottlenecks. To support this initiative, Lee recommends conducting a developability assessment up front, which is a series of tests to help you to determine whether a molecule can be made using a specific platform and to identify any manufacturing obstacles that may come up. Per Lee, “You’re doing work with that molecule in the discovery labs anyway. You might as well build in the small investment [of developability assessments] early to move your product more quickly into manufacturing and the clinic.”

Furthermore, manufacturing teams can provide R&D with a more elaborate understanding of their process to gain greater insight into how the molecule will work in a manufacturing setting. Both teams should have a mutual understanding of what the platform consists of and how it works most efficiently.

The Benefits Of Implementing Process Intensification

The pressure to produce an exceptional drug product while still beating others to market is mounting. “You can’t just be better, you have to be faster as well,” says Lee. Often, the idea of modifying a reliable platform is disconcerting for companies that are trying to ensure fast timelines and minimal budget deviations. Luckily, neither Lee nor Vermunt recommends rebuilding platforms from scratch but, rather, modifying them with process intensification, which has enabled companies to bring products to clinic quickly and affordably. A 2022 article published in Chemical Engineering and Processing: Process Intensification by Müller et al, defines process intensification as such:

“Process intensification strives for more efficient conversion of raw materials into products while minimizing resource usage. In the biopharma industry, typical intensification gains include increased plant capacities, reduced raw material costs, smaller facilities, and improved sustainability.”¹

Process intensification largely works to adapt existing infrastructure and processes for highly complex molecules. Both Lee and Vermunt have experience with process intensification in their respective organizations. When considering process intensification, Vermunt recommends leveraging a process model, which can help a team conducting an intensification predict any failures. For Lee, the AltruBio team recently utilized process intensification with a low expression molecule that needed to get into the clinic rapidly: “It was clear that the existing platform wouldn’t be able to accommodate our strategic goals. We were able to use process intensification strategies with our CDMO to enable us to get into the clinic on time with sufficient material to meet our short-term needs.”

Choosing The Right CDMO

In the drug manufacturing world, CDMO selection is key. Lee breaks CDMOs down into two categories: “Specialized versus one-stop shops. One-stop shops are leveraging a platform process for mAbs manufacturing. More complex molecules don’t necessarily fit that one-stop shop mentality, [which is more] focused on what the majority of customers might need, rather than the niche activities and adjustments that a company like AltruBio might need.” The CDMO route you choose is entirely dependent on the needs of your company and your molecule, and either way, there will be trade-offs.

Opting to go with a specialty CRO may allow you to be more inventive with your approach but will likely require a tech transfer to a manufacturer down the road. Alternately, opting to work with a CDMO that works with standard mAbs will provide a more straightforward manufacturing plan and path to approval. The right CDMO might also help to conduct continuous manufacturing protocols. Despite the time and investment associated with enacting continuous manufacturing, Vermunt and Lee both see it as a viable possibility for those who can pull it off. From Vermunt’s perspective, “There are many case studies showing what companies have successfully achieved [with continuous manufacturing]. It eliminates a lot of non-value-added steps.”

Lee emphasizes the benefits as well: “The beauty is that it doesn’t require a wholesale change in how the process works. It is taking the unit operations and making them continuous. The logic of how the process operates is largely intact.” Determine what makes sense for your team by assessing your budget and the milestones you aim to reach.

Looking Ahead: Collaborate To Innovate

Though the cost to upgrade and retool systems might be daunting, in the long run it builds a more robust platform. Implementing automation, real-time monitoring, and data sharing as well as strategic collaboration between sponsor, supplier, and CDMO will yield more efficient processes that help save money in the long term. Since many of these decisions are specific to the needs of your organization, Vermunt has a recommendation for finding your way: “One part is understanding the floor in terms of cost for all the different things you need to do, including development, manufacturing, and raw materials. When making decisions, ask yourself, does this serve our mission?”

Lee elaborates on this, “The challenge is to keep pace with the advances and innovation occurring in the drug development and discovery space. We need to thoroughly explore the landscape of service providers to make sure that their technologies allow us to be competitive and make good on our mission to provide our product direct to patients.”

References

1. Müller, D., et. al. (2022). Process intensification in the biopharma industry: Improving efficiency of protein manufacturing processes from development to production scale using synergistic approaches. Chemical Engineering and Processing - Process Intensification, 171. https://doi.org/10.1016/j.cep.2021.108727

The content of this article originally appeared in a Bioprocess Online Live event hosted by Chief Editor of Bioprocess Online, Matt Pillar. To watch the whole conversation, visit our website.