Despite the benefits of continuous processing adoption has been slow, except for a few process areas.
The biopharmaceutical industry, with annual sales for recombinant biotherapeutics of more than $200 billion, is maturing its manufacturing. While biopharmaceuticals may be one of the most complex and profitable high-technology products, the fundamental aspects of manufacturing have not changed in decades. This contrasts with other manufacturing industries, such as steel or chemical, which have adopted continuous manufacturing. Continuous manufacturing can be more efficient and cost effective than current methods of manufacturing. But until recently, the technologies to accomplish commercial-scale continuous manufacturing have been works in progress. In fact, in a BioPlan Associates’ survey (1), 222 industry respondents indicated that the penultimate critical operational area where the industry must focus its efforts was in the development of continuous bioprocessing technologies for downstream production.
Traditionally, biopharmaceuticals are manufactured using batch processing, in which unit operations are performed and completed before the process stream moves to the next step. In continuous processing, the processed products are moved to the next step as each unit process is completed. This process can provide considerable benefit to the manufacturers by being more cost-effective, requiring less infrastructure, less space, less investment, less staff, all while manufacturing products in the same or perhaps less time than traditional batch methods. Although widespread adoption of continuous bioprocessing has been slow, some processes in the industry, such as perfusion, have been an exception.
Despite the benefits of continuous processing, which include reduced cost, increased productivity, improved quality, and increased flexibility, adoption has been slow. Batch processing works well and is familiar, while continuous processing is seen as more complex and susceptible to problems. As a litmus test for how the industry views continuous vs. batch processing, BioPlan Associates asked biopharmaceutical manufacturing professionals about their concerns with regards to perfusion (a continuous process) as compared to batch processing. Of the 19 areas specified, their top concerns were contamination risks, process development control challenges, and process operational complexity. Although these results are similar to previous years’ data, perfusion and other continuous bioprocessing are becoming significantly less complex, less prone to contamination, more regulatory-friendly, and more easily scalable than fed-batch methods. Therefore, some of the concerns today are the result of the perceptions of continuous bioprocessing as being overly complex and contamination-prone. These perceptions are increasingly not matching the advances taking place in the industry (see Figure 1).
While there are many benefits to continuous processing, there are some substantial reasons why its adoption has been slow. Basic changes in biomanufacturing paradigms take decades, partially because the industry is so highly regulated. The regulatory agencies must be convinced that the changes do not compromise drug quality or patient safety. FDA and other regulatory agencies, however, are generally quite open to continuous bioprocessing because they see it provides improved process control, product quality, and allows simpler application of process analytical technology. Even though the regulatory agencies are welcoming of continuous bioprocessing, few manufacturers want to act as the test case when they can use the old standby of batch-fed technology. Other difficulties in adopting continuous bioprocessing include lack of practical know-how, precedents, and cost-effective equipment.
Adoption of continuous bioprocessing at any substantial scale has been restricted to a few unit processes at a minority of facilities. For the most part, continuous bioprocessing is dominated by smaller-scale perfusion, increasingly single-use, bioreactors.
In BioPlan’s annual report, respondents were asked about their plans to evaluate or consider continuous bioprocessing technologies in the coming year. Comparing 2016 to 2017 results, the responses were consistent; nearly one third (31.9% in 2016 and 30.4% in 2017) responded that they were actively evaluating or testing at least one continuous bioprocessing upstream technology, and slightly less (26.5% in 2016 and 24.3% in 2017) stated they were evaluating downstream technologies (see Figure 2).
In upstream processing, perfusion equipment is becoming more accepted, likely explaining the higher percentage of respondents saying they are actively investigating upstream continuous processing. Downstream operations such as purification, however, have not been moving toward continuous processing nearly to the same degree.
Suppliers are developing technologies for continuous bioprocessing such as Pall Corporation, which launched the Cadence BioSMB Process system. The platform is a disposable flow path, continuous multi-column chromatography solution, scalable from the process development laboratory to GMP manufacturing. These, and other similar offerings will allow manufacturers to transition into process-scale continuous purification, thus addressing some of the downstream bioprocessing needs identified in BioPlan’s annual report.
In another new development-an industry-meets-academia venture-Novartis has teamed up with the Massachusetts Institute of Technology (MIT) to create the Novartis-MIT Center for Continuous Manufacturing. The center is “a 10-year research collaboration aimed at transforming pharmaceutical production” (2). The center develops new technologies for continuous manufacturing processes. The center’s website states advantages of continuous manufacturing as:
Novartis has committed $65 million, as well as its manufacturing and R&D resources to the center for 10 years.
Looking at the regulatory concerns, FDA recently approved, for the first time, a manufacturer’s change in their production method from batch to continuous manufacturing (3). This approval was for Janssen Products, LP’s, treatment of HIV-1 called Prezista (darunavir). FDA encourages continued efforts by other manufacturers to move in the direction of continuous bioprocessing.
Capacity constraints are perceived as an issue within the biopharmaceutical industry. Analysis in BioPlan’s report shows that 29.9% (vs. 27.2% in 2016) of respondents are experiencing “severe” or “significant” constraints at the commercial manufacturing level, up again from 2015 (26.8%). When evaluating future concerns of capacity constraints, the largest percentage of concern for commercial-scale production were “significant” (34.5% in 2017, vs 29.0% in 2016) in severity, while early-stage clinical systems report 20.3% with “significant” or “severe” expected constraints (vs 15% in 2016).
This trend toward increasing severity of capacity constraints suggests any competent platform capable of addressing capacity issues will be of interest and relevance to the industry. The number-one factor identified as likely creating biopharmaceutical production capacity constraints over the next five years was overall facility constraints. This factor was followed by analytical testing and drug product release, and the inability to hire experienced technical staff. However, the factors identified as key areas to address to avoid future capacity constraints included developing better continuous bioprocessing downstream technologies, which was listed as the third highest factor.
Ongoing technology developments and the new products becoming available have not been enough to spur adoption of continuous bioprocessing in purification and other downstream processing operations. Despite the view within the industry that continuous bioprocessing downstream is a necessity for maintaining and increasing capacity going forward, few have begun the transition. And this is taking into account some of the new available technologies, such as simulated moving bed and cell retention and periodic countercurrent chromatography that are projected to provide a 20-30% cost savings compared to current methods. Even these substantial savings and benefits have not been enough to motivate the majority of the industry to adopt these systems, with the one obvious exception discussed previously from Pall.
While it is clear the industry has been slow to adopt continuous manufacturing, unlike many other mature manufacturing industries, changes are happening. Gradual adoption of continuous bioprocessing will occur as products are initially developed using these methods, such as Vertex’s cystic fibrosis drug Orkambi, which has been using continuous manufacturing processes since its approval in 2015. The drivers of cost-savings, flexibility, and product quality will push the industry to explore and adopt continuous processing. Once some of this adoption has occurred, as it must to a certain extent already in the case of perfusion, the industry’s knowledge base and experience will grow and ease the adoption of major changes in manufacturing platforms.
The adoption of continuous bioprocessing will likely follow a trajectory similar to that of single-use systems. While continuous bioprocessing will eventually become the dominant approach over time, the widespread adoption of single-use systems may have reduced the critical needs for cost-savings, flexibility, and other benefits derived from continuous bioprocessing. It is clear, however, that those within the industry recognize the need for continuous bioprocessing, particularly in downstream processes, and so the lumbering biomanufacturing industry will adapt.
1. BioPlan Associates, 14th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production (BioPlan Associates, Inc., April 2017).
3. L. Yu, “Continuous Manufacturing Has a Strong Impact on Drug Quality,” FDA Voice blog post, FDA.gov, April 12, 2016.