For CDMOs, Industry 4.0 isn’t a vague notion. It’s a stark reality. Industry 4.0—the utilization of “smart” and autonomous systems to enhance the computer control of manufacturing—is how CDMOs hope to satisfy increasingly stringent customer demands. These include more exacting product specifications, tighter timelines, and more parsimonious payers. If any CDMO fails to step up its game, other CDMOs will happily step in.

Given that CDMOs are manufacturing specialists, it’s little wonder CDMOs have embraced Industry 4.0 principles and digital manufacturing technologies to a greater extent than have many companies in the wider pharmaceutical industry, including many biopharmaceutical companies. Digital manufacturing technologies offer contractors the transparency, efficiency, and flexibility they need to keep pace with evolving customer demand and emerging market opportunities.

Process intensification

Many CDMOs are committed to process intensification. The ability to make more product using fewer resources is key for contractors looking to compete on price in what is a highly fragmented outsourcing market. (According to a November 2019 report issued by PricewaterhouseCoopers, more than 75% of the participants in the CDMO market had revenues below $50 million, and the five leading CDMOs held only 15% of the total market share.)

Catalent indicates that perfusion processing during the N-1 stage of seed train intensification allows production bioreactors to be inoculated at very high cell densities. The N-1 perfusion system shown in this image is used by Catalent at the company’s facility in Bloomington, IN. The system employs alternating tangential flow for cell retention.

Investing in technologies that support intensified production is a strategic imperative for CMDOs such as Lonza. “We are continuing to invest in state-of-the-art technologies focused on process intensification,” says Atul Mohindra, PhD, the company’s senior director of research and development. “We have initially focused on perfusing the inoculum expansion steps within the upstream cell culture area prior to the production stage. Intensification of these unit operations allows us to shorten the production stage.

“We have also focused on intensifying Lonza’s purification process by evaluating next-generation resins and continuous chromatography technologies. Combined, these technologies have resulted in increasing facility throughput, as well as a significant improvement to the overall titers and yields of our processes.”

Process intensification is also a major focus for Catalent Pharma Solutions. “For process intensification, we have been working on different components of continuous bioprocessing in both upstream and downstream,” notes Claudia Berdugo, PhD, the company’s director of process development. “In upstream, we have demonstrated that N-1 perfusion using alternating tangential flow (ATF) provides the potential to improve facility utilization by achieving the same titer in fewer days. Alternatively, we have demonstrated that intensified fed-batch process implemented in the seed train can increase titer when the standard seed train duration is maintained.

“The other technologies that we will be implementing for process intensification include production perfusion and continuous chromatography. The expected benefits are improved productivity as well as quality, along with economic benefits for the reduction of raw materials in the process.”

Such investments are also a reflection of growing competition, suggests Michael Larner, a principal analyst at consulting group ABI Research. “Competition is the key investment driver,” he explains. “[CDMOs are] investing in their facilities to attract more business. They may work with their key customers and align investment plans with their requirements, but the more ambitious ones will invest in order to win net new customers.

“For CDMOs, it’s all about yield—additional yield goes straight to the bottom line. In terms of technology investments, data analytics is a priority investment area to understand the effects of changes in the environment on the condition of the batch.”

Strategic technologies

Most technologies promise to let us do less and get more. Certainly, that’s the case with the process intensification technologies that are being considered by companies that outsource work to CDMOs. But what, exactly, might a particular company want to do less of, or get more of? Clarifying these points is often up to the company’s CDMO. That is, the CDMO may need to inquire into its client’s goals before it can define an effective process intensification strategy.

“When looking at the intensification of the purification, the downstream process, it is important to have the objective in mind,” declares Andreas Castan, PhD, strategic technology partnerships leader, Cytiva. “Is it to run the process with greater speed, with a smaller footprint, or with improved process economy? How does the upstream process impact the downstream strategy? What is the production scenario? What does the existing infrastructure look like?”

“The technologies we are using in the upstream part of the process—that is, the cell culture—are almost all connected to increase cell densities and volumetric productivities,” he continues. “[They also serve to debottleneck] the operation in the manufacturing process.”

Castan cites the CDMO sector’s use of high-density, high-volume cell banks and perfusion strategies, which he says can help to bypass stages used in traditional seed trains and shorten bioreactor processing times by producing more cells.

“In the production bioreactor, process intensification is about optimizing the conditions for the cells for optimal production by selecting high-performance media and feeds,” he continues. “However, it is also about pushing up cell densities and getting more product from more cells in the same span of time.”

Castan observes that in downstream operations, intensification is increasing the use of high-capacity resins, fiber absorbents, and multicolumn chromatography systems. He adds that choosing the right downstream technologies involves answering questions rather like the ones just considered for upstream operations, that is, questions about process time, footprint size, and process economy.

Analytics and automation

Analytics has also been a major investment focus for CDMOs in recent years. One reason CDMOs (and their clients) have been interested in collecting more detailed manufacturing data, Mohindra suggests, has been to accommodate regulators that have been seeking more information about the processes used to make medicines.

“Gathering and using process data is at the core of Lonza’s development and manufacturing services,” Mohindra asserts. “Helping to develop many different molecules using our clinical platforms allows us to gather huge bodies of data, which can be used to further improve process control and also ensures that our customers are successful at each critical milestone.

As cell culture processes intensify, cell densities and product concentrations rise, as do the concentrations of impurities. Consequently, cell separation and product harvesting become more challenging. To accomplish these tasks in a 6,000-L suite in its Portsmouth, NH, facility, Lonza relies on harvest depth filtration.

“In addition, the process data collected is also used as part of transferring processes within the Lonza network, for example, from Slough to Hayward, from Slough to Singapore, or from Lonza facilities to customer facilities. Process integration and automation do come with challenges, particularly as suppliers have a control system with a preferred process automation strategy that isn’t always compatible with all the other unit operations.”

A similar view is held by Chris Demers, PhD, a senior automation and data scientist at Catalent Pharma Solutions. He says that the bioprocessing technologies used by the CDMO must be able to gather and transmit processing information in real time.

“It is essential in this era of digital manufacturing that the equipment we purchase fits into our automation and data stack,” he elaborates. “It needs to not only adhere to regulatory standards—such as 21 CFR Part 11 and standards pertaining to electronic signatures and audit trails—but also, ideally, to global communications standards—such as the OPC Unified Architecture and global connectivity standards including Ethernet IP.”

Future needs

Industry 4.0 is a reality for CDMOs, but it is also an ongoing process. The strategic rationale that prompts a forward-thinking contractor to invest in digital manufacturing technology also demands that firms reinvest as technologies and market needs evolve.

Currently, the biggest evolutionary pressure is the COVID-19 pandemic, which is having a significant impact on CDMO technology investments. “The demands of the pandemic mean that the promise of disruptive technologies—such as real-time digital quality management, advanced logistics due to serialization, and virtual reality inspections—no longer seems so unrealistic,” says Fiona Barry, an analyst at GlobalData’s PharmSource. “The pandemic prompted regulators to temporarily adopt remote CDMO facility inspections or ‘desk assessments,’ which has only emphasized the importance of real-time digital quality control technology for transparent remote monitoring.”

Barry predicts industry’s current focus on vaccines will prompt a wave of CDMO sector investment in viral vector production: “There is a worldwide capacity crunch for viral vectors, which are a vital part of manufacturing many advanced therapy medicinal products and some pipeline COVID-19 vaccines. Improving virus manufacturing, especially upstream titers, would hugely help ease this problem.”

COVID-19 isn’t the only factor driving technology investments among CDMOs, notes Dirk Voelkel, PhD, chief innovation officer, Cytiva. Another factor, he insists, is growth in the precision medicine market.

“We have seen mRNA as a new platform, and Pfizer has already announced that it will develop other vaccines leveraging this new technology for many other indications,” Voelkel details. “This influx of investment as well as the emergence of new therapies will drive innovation in life sciences at a faster pace than ever before.

“We will continue to see precision medicine growing as the genomics revolution progresses, helping us dramatically improve our understanding of the biological roots of many diseases. The advances in single-cell analysis are driving new insights that are being explored by new drugs. These more precise therapies require a different processing approach, much smaller production batches, and scale out rather than scale up.”

Intensification and integration

The goal of process intensification may be reached in different ways. At one extreme, manufacturing systems may be overhauled. Alternatively, existing systems can be improved and optimized.

“Over the next few years, we would like to see advances in a number of areas including single-use technologies, inline sensor technologies, machine learning, and artificial intelligence,” says Mohindra. “In addition, we would also like to see advances in purification technologies with respect to both the integration of unit operations but also in the ability to measure process-related impurities. We would also like to see advances in expression technologies that would help boost titers and, therefore, reduce the cost of goods.”

Mohindra also predicts that as continuous processing becomes more common in the CDMO sector, single-use technologies and other technologies will continue to evolve: “We need to ensure that the disposable components are robust enough to allow for longer process durations. In addition, we have invested significant efforts into setting up collaborations with several universities and start-up companies across the globe.”

Similarly, Demers predicts that rather than fully revamping their manufacturing systems, CDMOs will opt for next-generation versions of systems that are easier to use. “There is so much great technology out there already that the barrier is less the technology itself, but more how it will fit within our existing systems,” he explains. “With that in mind, I would like to see an increased prioritization on open-source, plug-and-play technologies that would allow us to simply drop in new technologies without significant modification to our code or system architecture.

“We, like most biomanufacturing companies, leverage a variety of control systems and new platforms across our network. A process analytical technology that we could plug into our existing Rockwell Automation, Emerson, or Inductive Automation supervisory control and data acquisition system—and have it visible and controllable with little custom coding—would allow us to quickly roll out the technology across our network.”

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