Single-Use Continuous Manufacturing: The New Paradigm In Biopharmaceutical Processing

By Jerry Martin

Two significant trends in biopharmaceutical production are coming together. For years, single-use systems have been gaining traction as a way to make processing of biotherapies more efficient. More recently, the industry has also been eyeing continuous manufacturing options to replace traditional “batch” processing methods — again, with the goal of obtaining greater efficiencies. Currently, we see a convergence of these two complementary trends as manufacturers seek to integrate single-use systems into a continuous production platform. This represents a paradigm shift in how biotherapeutics are manufactured, and it offers promising benefits for both manufacturers and consumers.

Single-Use Systems Booming

Single-use technologies have been gaining ground in bioprocessing for the past two decades. At first, these systems were mostly used for clinical batch and pilot-scale operations, but as these operations have moved to full-scale production, we are seeing a much wider use of single-use technologies throughout the industry, with commensurate increases in demand. In fact, earlier this year several key industry suppliers reported double-digit growth in sales of single-use equipment.¹

There’s good reason for the uptick in adoption. Overall, single-use technologies reduce manufacturing costs by eliminating cleaning and cleaning validation steps. Besides saving time and labor and eliminating contamination risks, they also reduce capital costs and energy requirements. There’s a lot of hardware involved in cleaning permanent systems. By freeing up production line footprints, companies can cut costs and increase efficiencies.

While it is true that single-use systems create waste from discarding and incinerating plastic materials, their use still results in a smaller carbon footprint compared to permanent steel systems. The carbon dioxide that is produced from generating steam for water for injection (WFI) used in cleaning and for steam-in-place sterilization of piping, stainless steel vessels, and other hardware is far greater than the carbon dioxide produced from manufacture and disposal of plastic single-use systems. Steam, WFI, and cleaning agent usage are reduced significantly by incorporating single-use platforms. Furthermore, if waste-to-energy incineration is employed, the heat of combustion from the clean-burning plastic materials (generally derived from natural gas without chlorinated hydrocarbons) can further reduce demand for fossil fuels.

Complementary Technologies

While single-use systems have gained a strong foothold in the biopharmaceutical industry, it’s safe to say that adoption of continuous processing is still in its infancy. Interestingly, single-use systems and continuous manufacturing are quite parallel and complementary technologies because of the efficiencies they each offer. Continuous manufacturing moves the industry closer to the goal of continuous monitoring, which enhances process reliability compared to batch testing. When manufacturers operate and monitor continuously, they are able to detect problems or abnormalities in real time, and potentially improve overall quality of biotherapies.

The FDA has been pushing manufacturers to adopt continuous practices because of the qualitative improvements they offer over traditional batch processes. The agency sees continuous manufacturing as a means of improving safety margins and drug quality assurance by keeping production within compliance of set limits. It also reduces variability between individual batches and, by extension, the risk of adverse events with patients.

While continuous manufacturing is well-established in industries such as automotive, pulp and paper, and food production, the biopharmaceutical industry has been slow to adopt. This is in large part due to a lack of regulatory guidance and concerns about validation and approval. All good manufacturing practices (GMPs) have been written for traditional batch processes, and therefore shifting to new methods entails some complications and costs. For manufacturers of products like generics, with low-margin profits, the costs of shifting to continuous methods may not justify the long-term improvement in efficiencies.

Flexible Definitions Of “Continuous”

The FDA recognizes that there are significant financial barriers to adoption, and that the designation of a batch process is somewhat subjective. The distinctions between continuous versus batch manufacturing can be arbitrary, and the FDA has demonstrated some flexibility in how companies define their process. Two manufacturers can make the same drug but at two different scales and batch sizes. If one of them elects to adopt a continuous process, it may be possible to define this process as a “batch.” This flexibility in FDA interpretation may provide an opening for manufacturers to adopt continuous technologies. (Editor’s note: For further discussion on the meaning of continuous manufacturing in the pharmaceutical industry, read What Is Continuous Manufacturing, Anyway? Agreeing On A (Proper) Definition.)

Until recently, companies have been hesitant to adopt continuous manufacturing for fear that FDA may not approve the changes to their processes. These fears have dissipated somewhat following several key recent FDA drug approvals. In July 2015, FDA approved Orkambi (lumacaftor/ivacaftor), the cystic fibrosis drug from Vertex Pharmaceuticals, which has been produced using continuous manufacturing methods. Even more significant was FDA’s approval last April of Janssen’s HIV-1 medication Prezista (darunavir). This represents the first time the FDA has approved an actual change from batch to continuous manufacturing.¹ The precedent has been set for future adoptions.

Single-Use Technologies For Continuous Applications

A new generation of single-use systems is being developed to fit within a continuous processing paradigm. The area most likely to see widespread adoption of single-use continuous manufacturing is small molecule processing. Filling operations can be fairly easily configured to single-use in a continuous method. For single-use filling, drugs can be formulated in a single-use mixer, filtered with a single-use capsule filter, and filled with a pre-sterilized feeding tube and needle. Eliminating the downtime necessary for cleaning and steam sterilization by incorporating single-use for filling operations can save manufacturers a whole day of production.

For biopharmaceuticals produced in cell culture, there is a trend toward extending the traditional 7- to 14-day batch fermentation process time to 30 to 100 days, and perhaps longer. Typical fermentation processes for mammalian cell cultures last 10 to 14 days in duration. There are some new technologies that enable continual batch feeding, extending the duration of the process. Some of these technologies include new methods of separating and recycling cells. Other technologies are being developed to enable continuous bioreactor operations, which maintain sterility while eliminating the downtime of starting over new batches. Some new single-use mixing methods enable manufacturers to produce cell culture media and aseptically transfer it to a bioreactor. Sterile tubing welders and sterile connectors are now being used for single-use process-scale applications for culture media.

For chromatography operations, new simulated moving beds have been introduced as replacements for large columns traditionally used for batch processing. Instead, a series of smaller columns are used in which antibodies are loaded onto down-sized columns for continuous separation processing. New single-use/single-pass ultrafiltration systems have also been introduced for downstream buffer exchange and diafiltration processes.

Vaccine manufacturing represents a final frontier of sorts for continuous manufacturing methods. Influenza vaccines are changing constantly; however, some companies are exploring the development of a more universal flu vaccine. Once developed, it may make sense to adopt continuous manufacturing methods.

Looking Forward

Greater control of drug quality and lower costs are the benefits that single-use continuous manufacturing potentially offers. Thanks to some demonstrated FDA flexibility and encouragement, look for more technologies to be developed and the trend towards continuous single-use manufacturing to accelerate.

References:

1. Stanton, D. "Single-use driving double digit growth for Pall and Sartorius." BioPharma-Reporter.com. Jul. 26, 2016.
2. Source: Yu, L., "Continuous Manufacturing Has a Strong Impact on Drug Quality," FDA Voice (blog). April 12, 2016.

Image credit: Bosch PreVas Single-use Filling System, courtesy of Bosch

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