The Future of Bioprocessing

Imagine a research and development lab where 90% of the work is done off the bench, using mechanistic modeling to inform a set of experiments that are executed by a fully connected, continuous bench-scale process requiring very little human intervention. Smart processes continuously learn from real-time data to not only predict optimal states but also to ensure the system stays within those states automatically. Experiments are completed quickly, and change-over to the next set of experiments is done just as quickly. The entire process development workflow, from concept to final validation, can be completed in as little as two months.

This is the picture of the Biopharma 4.0-equipped laboratory—the result of the convergence between processing, automation, and software technologies that will propel biopharma R&D to be more efficient, connected, and, of course, profitable. Biopharma 4.0 has taken earlier concept initiatives such as quality by design (QbD) and process analytical technology (PAT) and expanded upon them, focusing not just on a narrow, well-defined set of activities but on the entire production chain.

Although the hypothetical lab we toured at the outset of this article might seem a bit out of reach, it’s built upon the ideas and knowledge of experts in the field who are actually making the Biopharma 4.0 lab a reality. We talked to some of these experts to learn about the challenges facing the industry, how they’re addressing those challenges, and the momentum building across the industry as a whole. We bring you their insight in this article.

The challenge of 4.0

One of the major drivers behind a collective movement toward Biopharma 4.0 is the need for a step change in efficiency. Merrilee Whitney, head of the BioContinuum™ Platform at MilliporeSigma, says that with current market dynamics, the minor changes and improvements that enabled biopharma companies to squeeze out just a bit more efficiency are no longer acceptable.

Of course, the benefits to implementing 4.0 capabilities aren’t a new realization—the need to develop flexible and robust processes that lead to safer, better, and more affordable biologics has been the goal for quite some time. But addressing the entire chain of custody—from drug discovery to commercial manufacturing—is not without its challenges.

The industry has met these challenges head-on, however, in part leading to and in part from the birth of organizations such as the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL), which have provided a much-needed consolidated voice that Whitney likens to a North Star for the industry. Progress has been significant.

The cost of 4.0

Many of the historical issues that had previously challenged the adoption of Biopharma 4.0 have already been effectively addressed, says David Rubin, Director, Business Development at Cytiva.

“Cybersecurity was a huge concern, but today, the industry has started to feel more comfortable in its ability to provide secure systems—both on-premises and, to some extent, in the cloud,” he says. The cost of such a foundational transition has also been a significant concern historically and even still today, but costs are dropping quickly, maybe even more quickly than many companies realize.

“Many manufacturers are not aware that the ROI on expenses associated with Biopharma 4.0 can be quite attractive despite upfront capital costs,” explains Rubin. “We’ve met with companies that don’t even consider the necessary technology, thinking they are out of reach. The further productization of software and creating an environment where all data can be stored with contextualization will help even further.”

Whitney agrees that cost is becoming less of a problem, particularly as companies realize that 4.0 can be adopted piecemeal rather than as an all-or-nothing proposition.

“There is going to be evolution over time, from level one, paper based and individual process steps to level five, lights-out manufacturing,” she says. “The key is solving the challenges that biopharma companies have today and figuring out what is more expensive—implementing a technology or not doing anything about it?”

The reality of 4.0

Whitney and Rubin agree that this is really where technology providers can make a difference, by offering modular, plug-and-play solutions that seamlessly integrate with a constantly evolving and fully automated workflow. “Equipment manufactures need to imagine their products as part of the drug development process with data and connectivity built into the instruments, and not as islands of data,” emphasizes Rubin. “We cannot have solutions in silo,” adds Whitney, emphasizing that adaptability as key technologies evolve will be critical.

This need for a holistic solution is what has driven MilliporeSigma’s efforts to help their customers get from level one to level five in the next eight years, says Whitney. They’re chipping away at this goal by breaking it down into the three critical areas of the process development chain: processing technology, automation, and process analytics. The ability to address each aspect of process development piecemeal enables MilliporeSigma to help their customers at whatever stage of progression toward 4.0 they are currently at. But the biggest impact is being made by M Lab™ Collaboration Centers, which enable researchers to experience what a 4.0-equipped lab feels like.

“Until you experience it, you can’t understand it,” says Whitney. “Bringing together digital and process into one experiential lab has made all the difference for our scientists. Living in each others’ worlds and figuring out, even at bench scale, what are the challenges to bringing all of this together will really pay off in future years.”

Rubin’s company Cytiva has also developed several solutions to help lab personnel experience the benefits of Biopharma 4.0 and introduce solutions into their laboratories. From VR solutions for training operators to mechanistic modeling for creating simulations, Cytiva is maximizing speed and efficiency, two key characteristics of the 4.0-equipped laboratory. But, their efforts are also centered around automation and data democratization, says Rubin’s colleague Chris Sandusky, Director of Automation Solutions Product & Lifecycle Management at Cytiva.

“We have productized Distributed Control Systems (DCS) platforms, we have adopted automated workflows through the productization of MES, and we are democratizing data from our instruments using industry standards like OPC-UA,” he explains.

There are some outstanding challenges to fully implementing the 4.0-equipped laboratory, such as proven, standard, pre-developed, and verified manufacturing execution software systems, says Rubin. Sandusky adds that process analytic instrumentation isn’t currently recognized by regulatory agencies as a reliable means to test critical process parameters, so further development of this tech is needed to get agencies such as the U.S. Food and Drug Administration on board. Whitney sees organizations like NIIMBL playing a key role in facilitating the collaboration between biotech and regulatory agencies and anticipates that even this challenge will be addressed in the near future.

The future is today

The question of whether to adopt biopharma 4.0 technologies is no longer a question—it’s a reality. Many therapeutics—mostly based on monoclonal antibodies—have already come to market using 4.0 technologies. And, as Whitney, Rubin, and Sandusky have been witness to, there has been a lot of research into other modalities that are coming to market. It’s only a matter of time before biopharma 4.0 is the reality across biopharma. It’s only a matter of time until fully connected, smart process enabled, continuous processing is the only way to bring safer, better, and more affordable biologics to market.