Transitioning from Fed-Batch to Continuous Biomanufacturing Processes

From left to right, Jon Gunther (Just–Evotec) and Sundar Ramanan (Enzene), with Millie Nelson (BioProcess Insider)

As effective automation systems and supportive technologies emerge, biopharmaceutical companies are beginning to explore the feasibility of continuous biomanufacturing (CB). On the second day of the BPI Theater at the 2024 Biotechnology Innovation Organization (BIO) International Conference in San Diego, CA, BioProcess Insider editor Millie Nelson moderated a panel discussion about CB implementation with Jon Gunther (vice president of business development at Just–Evotec Biologics) and Sundar Ramanan (chief quality officer at Enzene Biosciences). Both panelists’ companies are contract development and manufacturing organizations (CDMOs) that have established platforms for continuous biologics production. The trio discussed factors that might convince other drug manufacturers to transition from traditional fed-batch (FB) processes to operations based on CB.

Accelerating Development To Expand Patient Access

Nelson pointed out that patient access remains limited for many biologics. Global demand for such drugs still exceeds supply, and biomanufacturing capabilities are unavailable in many regions. High prices and inadequate reimbursement models also diminish access. In principle, CB capabilities could abate such problems by optimizing biologics production and decreasing costs. She wondered whether continuous manufacturing might increase patient access in other, less considered ways.

Gunther explained that CB platforms require less capital expenditure (CapEx) and facility infrastructure than do operations based on FB processes. Such advantages could simplify facility builds. He expressed hope about highly intensified facilities “being constructed in geographies that are not the typical places you see bioprocessing and biomanufacturing capabilities today.” Global dispersion of CB capabilities ultimately would be a boon for healthcare: “Bringing that manufacturing capability closer to patients, wherever they may be, also will better enable access.”

Ramanan added that emerging CB platforms could help to address concerns with drug-development timelines and chemistry, manufacturing, and controls (CMC). Demand for therapies based on monoclonal antibodies (mAbs) is expected to grow in the coming years. Many candidate mAbs will undergo a typical drug-development cycle that spans a decade or more and that includes three clinical phases before regulatory approval. Increasingly, though, candidates are being fast-tracked to address indications with significant unmet medical need, receiving conditional approval based on phase 2 clinical data. In such cases, Ramanan said, “CMC becomes the bottleneck.” Developers have less time than usual to transfer a FB process to manufacturing, scale up that process, resolve ensuing concerns, and validate the results. Developers could work more quickly, he suggested, by establishing CB for early clinical studies, scaling up a process for late-stage trials, and then cloning that process or extending its duration. By preserving the same scale between clinical and commercial phases, CB effectively eliminates the need to demonstrate product comparability across scales. That could expedite patient access to innovative treatments.

Increasing Industry Uptake

When asked about how CB technologies would benefit manufacturers as well as patients, Ramanan noted that continuous capabilities provide assurance of quality. Clinical trials require multimillion-dollar investments at high risk. Using CB platforms, “all CMC-related risks can be derisked completely by design,” providing “peace of mind.”

Gunther agreed, highlighting that CB could provide quality advantages during manufacturing of new modalities. Bispecific antibodies (bsAbs) and fusion proteins involve greater manufacturing complexity than conventional mAbs do. But published studies from Amgen suggest that continuous harvesting of a bsAb product from a bioreactor helps to preserve critical quality attributes (CQAs). “If a product is sitting in a bioreactor for two weeks,” Gunther explained, “two weeks is a lot of opportunity to be degraded.” Continuous harvest would reduce the amount of time that bsAbs are subjected to degradative influences, thus improving quality.

Despite such advantages, the biopharmaceutical industry seems reluctant to transition from FB to CB processes. Gunther acknowledged that CB remains limited for commercial operations, but many companies are “developing their own continuous-manufacturing platforms.” CB simply could be on the cusp of widespread use. Emerging biologics might encourage adoption, too. “Some of these novel modalities . . . don’t fit well within the FB paradigm,” so perfusion-mode bioreactors and related platforms must become broadly available to accommodate complex products.

Service providers obviously do not want to turn away partners that request traditional processes, Gunther continued.Going forward, CDMOs are likely to provide both FB and CB formats. To make that happen, however, the industry will need to address “an expertise gap.” CB capabilities cannot be established easily without experienced staff.

Ramanan said that by offering CB platforms, some CDMOs simply are anticipating where the biopharmaceutical industry is already heading. That said, many drug companies find it difficult to make a business case for transitioning immediately from FB to CB processes. He posited, “When you have a multibillion-dollar product that is working in patients [and in which] you have invested

US$2 billion in fixed CapEx, would you risk switching from that [setup] to a new technology for that program?”

Underscoring CB’s advantages for environmental sustainability could boost industry uptake, Nelson observed. She asked the panelists about how Enzene and Just–Evotec might augment the sustainability of their offerings and how broader CB adoption might increase sustainability in biomanufacturing.

Ramanan noted that his company’s current CB setups already reduce manufacturing footprints by 50–75% compared with requirements for FB processes. One possibility for increasing sustainability is “to democratize the technology that we have already,” making it accessible and enabling its use for other biopharmaceutical modalities. A second option is to refine technologies in ways that reduce their manufacturing footprints further still. Regardless, system sustainability will continue to improve, he said. At Enzene, “we are not just shooting for carbon-neutrality. We’re looking to be carbon-negative.”

Gunther highlighted his company’s site in Toulouse, France, as an example of how CB can reduce manufacturing and carbon footprints: “Being substantially smaller than traditional facilities just enables us to achieve our ESG [environmental, social, and governance] goals substantially.” He added that “even beyond what is achievable with a manufacturing process . . . modern design principles can be incorporated into new facilities that help all of us achieve our sustainability goals.” The Toulouse facility runs on electricity from sustainable sources, and solar panels around the campus provide additional energy. The site also leverages France’s strong infrastructure for nuclear power.

Persisting on the Path to Continuous Manufacturing

Gunther highlighted that CB adoption has particular exigency for cases in which cost is a critical factor, as is true with biosimilars. Just–Evotec is collaborating with biosimilar developer Sandoz to manufacture several products. Gunther added that the partnership will help to demonstrate the quality and cost-effectiveness of continuous processing.

Further encouragement could come from robust and reproducible scale-down models, he continued, because drug developers need ways to understand how CB operations would work for commercial production. Tools for economic modeling also would be welcome so that users can explore how to operate their facilities — e.g., over a year with a given level of demand. Such tools are helpful for both drug developers and contract development and manufacturing organizations (CDMOs). Gunther said, “We operate [CB] with a CDMO business model, so we are initiating multiple partner campaigns in a given year.” Simulations explore ways to optimize operations with multiple programs.

Perseverance will be essential for both CB suppliers and users. Ramanan said that adoption requires time and investment. Setbacks are likely to occur, too. He recalled that Enzene’s early work with continuous processing was rocky: “We did fail quite a bit early on, and we learned from those mistakes.” Now, the company’s success rate for continuous processes in commercial facilities (in terms of meeting lot-release criteria) exceeds 95%, and the CDMO has supported conversion from FB to CB processes for about a dozen programs. Manufacturers that have yet to develop CB capabilities will need to catch up quickly to remain competitive, especially considering the steep learning curve associated with implementation.

When asked whether current regulations support transitions to CB, Ramanan explained that the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) both have adopted the ICH Q13 guideline, which provides a framework for defining batches and control criteria in CB processes. Because the guidance is new, “we will have to take the time to generate a risk-based approach to identifying all the risks, creating data and evidence to mitigate those risks.” Users ultimately will need to communicate with regulators early and often. “At the end of the day, it is [about] comparability for the regulators.”

Gunther added that regulators have been highly supportive of CB implementation. They “see this as an important opportunity to expand access to patients” and have become committed partners in the endeavor.

Brian Gazaille, PhD, is managing editor of BioProcess International; [email protected]; 1-212-600-3594.

Watch Online

See all panel discussions online from BPI Theater at BIO 2024.