If biopharma firms want to get the most out of continuous manufacturing, they must rethink their viral safety strategies. Existing strategies work well for batch-mode production, as hard-won experience attests. These strategies, however, are still being adapted to continuous-mode production, where protocols and equipment preferences are in flux.
Biopharma firms have been battling viral contamination for as long as they’ve been growing medicine-making cells in bioreactors, and the underlying rational for viral safety remains the same. The raw materials, culture media, and even the cell lines used to make biopharmaceuticals may harbour viruses. If these viruses find their way into finished drugs, they could infect patients.
As a result, biopharma production, whether it is in batch mode or continuous mode, includes virus inactivation and removal steps. Tried-and-true steps are available for batch-mode production, suggests Paul Barone, PhD, associate director, Biomanufacturing Research Program at the MIT Center for Biomedical Innovation.
“Viral clearance for protein therapeutics has a long history and works well using established technologies,” says Barone. “If viral clearance is considered during process development, and if feasibility clearance studies are performed for new steps, there is usually not a problem achieving viral reduction targets. Many downstream processes can achieve greater than 1015 reduction in potential load.”
Encountering new challenges
Ensuring the production of virus-free biopharmaceuticals is more difficult in continuous processing than it is in traditional processing, suggests research conducted by the U.S. Food and Drug Administration (FDA). In traditional processing, biopharmaceuticals are made in batches. Production begins, runs for a finite period, and then stops. Continuous processing, as the name suggests, uses processes that run all the time or at least for extended periods.
Continuous production is attractive because it promises to boost output, lower costs, and reduce waste. It could also improve quality, maintains the FDA, which has encouraged industry to adopt the approach for more than a decade.1
Despite the encouragement, biopharma has been slow to embrace continuous manufacturing. Many firms prefer to squeeze more value from existing, well-understood processes rather than replace or modify them. Taking these concerns into account, the FDA issued a report in 2016 that assessed to degree to which current viral clearance methods were suited to continuous manufacturing. According to one review,2 the FDA suggested that in continuous processing, viral safety was underdeveloped.
“In many of these proposed continuous processing model systems, viral safety has not been comprehensively addressed,” the review noted. “Viral safety and detection is a highly important and often expensive regulatory requirement for any new biological product.
“To ensure success in the adaption of continuous processing to large-scale production, there is a need to consider the development of approaches that allow for seamless incorporation of viral testing and clearance/inactivation methods.”
Looking for cooperation
For firms using continuous manufacturing, one major difficulty is the need to prove that clearance and inactivation steps are effective. “The biggest challenge currently facing the industry regarding viral clearance is how to validate viral clearance unit operations for continuous manufacturing operations,” Barone points out. “Moving to continuous operations raises a number of questions and challenges that are not typically experienced in fed-batch operation.”
A similar view is expressed by Per Kaersgaard, a research scientist at Novo Nordisk. “Continuous processes create new viral clearance challenges,” he says. “We follow the international guidelines closely when we are dealing with the virus safety of our products.” Kaersgaard’s comment about guidelines suggests that Novo Nordisk recognizes the importance of taking a proactive approach.
Regulators have clearly stated that they want the users of continuous manufacturing to help set new standards, indicates Andrew Bulpin, PhD, executive vice president, process solutions, MilliporeSigma. “Regulators know that continuous processing provides many advantages for manufacturers and
encourage the use of the new technologies that enable it,” he elaborates. “However, they expect that manufacturers work with regulators to determine the best way to evaluate the viral clearance capacity of process steps run in this new manner.”
Designing clearance studies
In batch biomanufacturing, experiments conducted during process development are what shape viral clearance strategies. Clearance studies are used to test how well each process step inactivates or removes viruses.
In a typical experiment, a sample spike is passed through the processing step. The concentration of virus that remains is measured and compared with the starting concentration. Conceptually, viral clearance studies are straightforward. Practically, they are difficult, costly, and time consuming. Carrying them out requires expertise, specialist techniques, and containment systems.
“Viral clearance studies to support an early-stage submission require less time than those needed for a late-stage submission,” Bulpin maintains. “A study to support an early-stage submission that uses one or two viruses is likely to take about three months, while a study to support a late-stage submission that uses more viruses and more extensive investigations into clearance might require an additional month or two.”
“The cost of the study,” he emphasizes, “will depend on the starting materials and, hence, the number of viruses that will be used in the spiking study. Early-stage studies can cost from $100,000 to more than $200,000.”
Late-stage studies, he continues, may evaluate additional viruses: “They will look at the robustness of the manufacturing process, the efficacy of chromatography column sanitization procedures, and whether chromatography resins that have been used provide the same viral clearance as do new resins. These studies are likely to cost from $200,000 to $400,000 or more.”
Searching for consensus
In a continuous manufacturing setting, the cost and time taken to perform and validate a viral clearance study is hard to estimate. As stated earlier, continuous manufacturing is a new idea for biopharma. As a result, the industry has yet to settle on preferred approaches or technologies for clearance studies, suggests David Cetlin, founder and CEO of MockV Solutions.
“I’ve had several recent conversations surrounding viral clearance and continuous processing,” he recalls. “There are several challenges. One is how do you go about performing a validation spiking study.”
In traditional bioprocessing, nearly all clearance studies use the AKTA chromatography platform from GE Healthcare. “The near ubiquity of the system makes process transfer to a CRO relatively straightforward,” says Cetlin. “A small-scale process step developed at a biopharmaceutical company can be executed identically at a CRO since the hardware is the same. This is taken for granted and simplifies the thought process involved in performing a spiking down validation.”
In continuous manufacturing, no preferred system has emerged. This makes finding a contractor that can carry out validation studies much harder. “If a biopharma firm were to develop a continuous process on a particular system,” says Cetlin, “it would be beneficial to find a CRO that can provide access to that same system.”
Another problem is that regulators and industry have yet to agree on how to model real-world continuous manufacturing in clearance studies. In a commercial continuous manufacturing operation, viruses would feed into the system all the time. But a study protocol that would recreate these conditions would be impractical or too costly.
“Regulatory agencies and companies have sought other means to show viral clearance of continuous steps,” Cetlin tells GEN. “For example, the FDA in a 2017 manuscript3 proposed that validation of continuous steps could be accomplished through in-line spikes of virus. In contrast, an industry vendor proposed several strategies during a presentation at a recent industry conference which included the concept of a single batch spike at process onset, with replenishment spikes after each step.”
“Pros and cons for each approach exist depending on the engineering of each system, the mode of separation, and the economics” Cetlin continues. “One thing is clear: the industry has not settled on a single viral challenge strategy for continuous processing.”
Anticipating future needs
Better viral clearance methods would benefit all biomanufacturers, irrespective of whether they are using continuous manufacturing or batch-based production. Viral clearance could be improved if a way of accelerating infectivity assays could be found.
“Viral clearance studies are dependent on virus infectivity endpoint assays, most of which require a week or more of incubation time,” states Bulpin. “Anything that would decrease the time required to detect infectious virus would certainly reduce the timeline for clearance studies.”
Likewise, technological innovation could help biopharma develop clearance study protocols that would be flexible enough for all modes of manufacturing. Flexibility is a point emphasized by Cetlin: “MockV Solutions is commercializing an economic and biosafety level 1–compatible Minute Virus of Mice surrogate, which could be used to help companies sort out these complex issues and determine the best modes of operating their systems to demonstrate viral clearance. Basically, through the use of our surrogate, a company could kick the tires of their system and try different strategies of operation, spiking, etc.”
Biopharma would also be helped, Bulpin argues, if regulations were updated to take new manufacturing techniques into consideration. “Most of the viral safety regulatory documents were written a decade or more ago and need updating,” he details. “In fact, revision of ICH Q5A will soon begin. However, the basic principles of using a risk-based approach are sound.”
How soon decades-old regulations can be revised is hard to predict. “Regulatory expectations are typically in place before regulations and regulatory documents can be written,” Bulpin tells GEN. Preparation of these documents is a lengthy process, and regulatory documents often lag behind the implementation of new technologies.
3. Johnson SA et al. Adopting viral safety assurance strategies to continuous processing of biological products. Biotechnol. Bioeng. 2017; 114(1): 21–32.