Continuous processing is usually portrayed as an ideal destination, one where costs are lower, footprints are smaller, system assembly is faster and easier, and operations are more secure and less prone to error. This destination, however, lacks a common approach. That is, different would-be implementers of continuous processing have different starting points. Some implementers plan to build all-new facilities. Others need to retrofit existing facilities. Some want to approach continuous processing piecemeal. Others want to adopt end-to-end solutions.
These differences may be explored at industry events. For example, there are conferences that cover various continuous processing configurations, including continuous throughout, continuous upstream/batch downstream, and intensified upstream/continuous harvest. Besides highlighting configuration issues, which are already becoming familiar, conferences may address relatively esoteric aspects of bioprocessing’s evolution.
Both basic and advanced topics will be addressed at the 11th Annual Bioprocessing Summit, which will take place in Boston and include a track on Continuous Processing in Biopharm Manufacturing. This track will run August 12–13, and it will emphasize process integration, intensification, and control. Previews of some of the track’s presentations appear in this article.
In 2017, the BioPhorum Operations Group, a cross-industry collaboration, released its technology roadmap with some “very aspirational goals” for biopharmaceutical manufacturing, says Shannon Ryan, PhD, associate director, downstream process integration, BioContinuum™ platform, MilliporeSigma. Among these goals are vast reductions in footprints, capital expenditures, construction times, and operating expenses. And while some wholesale changes lie ahead, industry can in the meantime effect more evolutionary changes to increase productivity.
There is a lot of interest around process analytics, software automation, and single-use components. Additionally, the perfusion bioreactor and continuous capture have already received lot of attention. “Where else can we now improve?” he asks. Supporting processes and additional unit operations will become increasingly important foci for manufacturers looking to cut costs, mitigate risk, and become more efficient.
On the upstream side, Ryan points to “reducing risk through the use of a high cell density cryopreservation in the seed train.” This, in turn, allows separating a process intermediate from the seed train, perhaps performing some operations off site, and enabling closed processing of the seed train once on site. Another area for potential improvement is using perfusion in the N-1 bioreactor, allowing a far higher seed density into the final (production) bioreactor and, therefore, the same productivity in a shorter production time.
One byproduct of more efficient, intensified processes is higher titers. Downstream buffer volume increases linearly with bioreactor titer, and that greater volume must be accommodated, often without any increase in available space. According to Ryan, MilliporeSigma’s automated skid-mounted BioContinuum platform uses buffer concentrates of 10×, 20×, and even 50× to “provide all the chemical composition in a much smaller footprint.”
Concentrates are “QC released” prior to use and diluted with the plant’s own water for injection into hold vessels. The 1× buffers can then be transferred around the facility. Process intensification via buffer delivery, says Ryan, is fast and flexible; avoids powder, dust, and debris; and is “incredibly accurate and precise.” And best of all, it reduces labor costs and increases operator safety.
For many companies looking to intensify their processes, “the final dream goal, the final step, is going fully continuous upstream: having a very high cell density process, which is run consistently, for a long period of time,” declares John Bonham Carter, product line leader, cell culture and clarification business, Repligen. He notes that when this goal is achieved, “there is no downtime between batches, and you’re at a high output from that facility.”
“That’s the most intense process,” Bonham Carter continues. “But [it] also requires the most amount of time to invest—the most amount of money to invest—and likely you’re going to build a new facility.”
According to Bonham Carter, process intensification isn’t a defined set of outcomes so much as “a range of options that people can choose from to suit their facility, or their situation, or their molecule, or their company.” Companies may shy away from continuous operation not just because of the time and expense, but also out of fear of complexity. The amount of effort involved in getting to that endpoint can be daunting as well.
Thankfully, there are stepping stones along the way that may can make the intensification journey more feasible or palatable. “The issue is, where is the cusp?” Bonham Carter asks. By implementing cell banking or N-1 perfusion, he points out, “you haven’t made a major change to the method of operation of the bioreactor, or the method of operation of the facility. It’s a relatively light retrofit, and it’s definitely easy to do in a new build, [but] you get a very quick gain of 30–40% output on your facility.”
Stepping stones to boost productivity can be found in the way fed-batch bioreactors are harvested as well. According to Bonham Carter, the key takeaway is that harvesting can be accomplished while preventing impurities, helping cells become more productive, and keeping cells alive. His presentation will show how Repligen’s XCell™ alternating tangential flow (ATF) filtration system can be used to extend the maximum productive peak cell density. The resulting high-productivity harvest—which can deliver as much as a twofold increase in protein or allow an earlier harvest—is pure enough to obviate the need for centrifugation and depth filtration, thus reducing the number of unit operations.
Continuous processing can help a biomanufacturer achieve many laudable goals, including greater efficiency, flexibility, and robustness (by reducing the number of steps and holds); smaller equipment and facility footprints; better product quality; and real-time product release. The key is an integrated approach. Critical quality attributes (CQAs) need to be identified, and the functional relationships that link the critical material attributes (CMAs) and critical process parameters (CPPs) to the product CQAs need to be understood, explains Robert Dream, PhD, managing director, HDR Company. Once the parameters are identified and understood, they can be controlled.
Knowing the product—including the CQAs of both the drug and its excipients—and how it’s made, and the potential impact of the CQAs on safety and efficacy, can allow more flexibility in the regulatory process. The biomanufacturer can demonstrate that it knows and can control what matters.
Dream thinks that it’s beneficial for a small company, or a large one bringing a new product to market, to start out with a smaller volume in a smaller facility. This can be done more flexibly, faster, and thus further along in the development process.
“Then you can manufacture what you need,” Dream says. “After that, you can repeat what you just designed, built, and licensed.” Basically, scale out rather than up. That puts regulators under pressure to approve it, since you “just repeated exactly the same thing without any changes,” he continues. “And if you build a shell that can house a few of those, you can basically extend your manufacturing with ease over time.”
Aside from that, he counsels, “you need to put together a complete automation so that humans are involved very little in it. Make sure that these unit operations can talk to each other back and forth. And if there is an adjustment needed, the automation and equipment adjust themselves accordingly to modify whatever needs to be modified” to keep the process within CPPs.
Integrated recovery and purification
The industry is bracing to produce huge amounts of biologics to treat Alzheimer’s disease, Parkinson’s disease, cancer, and other illnesses, and continuous operation will probably be the best approach to produce such large quantities, says keynote presenter Ping Y. Huang, PhD, director and head, bioprocess development, AbbVie at Redwood City. While it’s almost practical now to do continuous operation in cell culture, the same cannot yet be said for harvest and purification.
Most of the unit operations in downstream processing use disposable components. But if you want a continuous operation, Huang advises, “you don’t want to throw away the components in the unit operation.” The fundamental challenge, he notes, is that “disposable unit operations are not compatible with the traditional operation concept.”
Huang proposes instead an Integrated Recovery and Purification (IRP) concept. It takes all the same single-use unit operations, from harvest to purification, and integrates them into a single unit “the size of your desk.” This was made possible by converting columns into cassettes to achieve uniformity with membrane filtration operations. Huang likens this advance to the development of the integrated circuit in the electronics revolution.
He envisions continuous purification by alternating two to three IRP trains. Each train, from harvest to purified bulk, will be completed in approximately six hours, accomplishing what takes weeks in current batch operations. A proof-of-concept has been demonstrated at bench scale, and an IRP block is currently being constructed at pilot scale.
With the right connections, which Huang has been advocating for, robots will be able to replace the disposable components in an IRP block when a cycle is completed, reducing the chances of operator error and contamination, and allowing for 24/7 operation without operators on the manufacturing floor.