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Development and adoption of new technologies create challenges that may take years to resolve.
Modern bioprocessing and antibody manufacturing are mature fields; however, challenges remain, and the advances themselves often bring new challenges. This is the nature of progress. The current challenges are exemplified by the ongoing advances and industry adoption of technologies such as continuous processing, the importance of modeling bioprocesses, increasingly seamless downscaling of processes, and other factors that are expected-and even required-by regulatory agencies.
Over the past 15 years, the industry has evolved into a mature, productivity-oriented segment. Of the dozens of trends evaluated in the annual BioPlan Associates survey (1), productivity continues to show the highest focus as an industry objective (See Figure 1). This suggests that other operational aspects must address industry challenges around improving productivity and efficiency.
Figure 1: Single most important biomanufacturing trend or operational area, 2014-2017. Source: Summary Data, 14th Annual Report and Survey of Biopharmaceutical Manufacturing, BioPlan Associates, Inc., April 2017. (Figure courtesy of author)
But to achieve successes, operational challenges must be worked out. As an example, continuous bioprocessing is one of, if not the most, challenging area for process development. Continuous processing-including both upstream perfusion and downstream continuous purification processing--remains rare and elusive despite the fact these technologies have been established for some time. These challenges particularly stand out when continuous and conventional batch processing options are compared.
Figure 2 shows survey results when bioprocessing professionals were asked to indicate issues with adoption of upstream perfusion that are much or somewhat bigger.
Figure 2: Selected concerns, perfusion vs. batch-fed processes. Red is much bigger concern with perfusion. Blue is somewhat more concern. White is at least somewhat of a concern, 2017 Source: Summary Data, 14th Annual Report and Survey of Biopharmaceutical Manufacturing, BioPlan Associates, Inc., April 2017. (Figure courtesy of author)
Bioprocessing professionals clearly see a number operational problems remaining with upstream perfusion versus conventional batch processing. In 2017, a number of concerns were cited by more than 50% of respondents to BioPlan’s survey:
This daunting collection of concerns about perfusion persists despite it being in use and marketed for multiple decades-including for commercial biopharmaceutical manufacture-notably for Factor VIII. In many respects, perfusion may be viewed as a technology adoption model in bioprocessing that demonstrates the slow nature of adoption of rational, effective technologies. BioPlan market research studies (1) have shown that approximately 5% of bioreactors use perfusion, with many of these being feeder and not production bioreactors. Further, while perfusion is seen by users as highly productive, often better and cheaper versus batch processing, most using it in early manufacturing continue to avoid its use in commercial manufacturing, viewing the challenges as high and the risks significant, in terms of regulatory approvals. One challenge for perfusion process adoption is that single-use perfusion units only recently became available. This lack of familiarity could be a factor in the reporting of high levels of concerns with--and even fears of--perfusion versus batch bioreactors likely among those not using the technology. Many challenges remain before the industry gains experience and confidence in this option for continuous upstream processing.
Downstream continuous operations, particularly chromatography, has more challenges; suitable hardware with built-in data systems are just starting to become available from suppliers. Downstream continuous bioprocessing was cited as the second single-most important bioprocessing trend or operational area on which the industry must focus its efforts. In BioPlan’s study, perceived need for improvements carries over to facility budgets with interviewees reporting an average increase of 8.8% in their 2017 downstream technology budgets vs. 7.7% for upstream; 33.8% cited continuous chromatography as a “top area where suppliers should place their efforts on.”
Adoption of continuous chromatography, generally involving use of multiple interfaced columns with integrated controls, is growing more rapidly than perfusion adoption; however, adoption has only recently started from a near zero baseline and is low. Combined with other downstream advances (e.g., increasing use of membranes in place of resin-filled columns, automated in-line buffer dilution and column packing, better resins, and more single-use and recyclable columns), downstream processing is in many respects changing and evolving more rapidly than upstream, but the adoption and integration into actual bioprocessing remain slow. When asked to cite the top downstream areas where suppliers should focus their development efforts, disposable purification systems were cited by 35.9% of respondents, followed closely by continuous purification cited by 33.9%. Geographically, European respondents are much more interested in continuous purification compared with those in the United States (44.4% vs. 25.3%).
But basic problems remain with broader adoption of both upstream and downstream continuous bioprocessing, including the inability to integrate related manufacturing systems. Currently, implementation of end-to-end continuous bioprocessing, or even upstream or downstream segments, remains rare or nonexistent, with at best one or a few unit processes implemented as continuous.
Bioprocessing modeling and understanding of implications of changes in scale remains another challenging area. The industry has naturally concentrated on scale-up, as drug product volumetric requirements increase as products advance in development. More is known about scaling up versus scaling down. But the importance of scaling down is rapidly increasing, including the ability to model and predict what happens in research and development by using smaller scales, rather than having to run experimental studies at various scales, including full scale. Having scale-down capabilities and understanding is increasingly expected, if not required, in FDA and other major market regulatory filings, particularly for product approvals. Being able to scale down and have related models and knowledge are now key parts of process analytical technology, quality by design, and other regulatory/quality initiatives. In addition, validated process down-scaling methods often are required for cost-effective design and refinement of bioprocessing. This is exemplified in the use of down-scaled bioprocesses to validate process biosafety, including reduction in virus titers from virus filtration and chromatography steps. The costs of validating virus removal and inactivation would be too expensive and time-consuming if run for full-scale processes.
Bioprocess system designers also want the ability to conduct computer-based modeling to scale up and scale down a process using bioprocessing equipment from the same product line.
This particularly applies to purchases of bioreactors, mixers, chromatography, and other major bioprocessing systems, but also extends to filters and other equipment. Scalability, particularly including scale-down ability, is a top equipment/technology selection factor cited in bioprocessing supplies-related market research studies. Many facilities will not purchase equipment unless reasonable scalability is known and documented among products throughout a product line, particularly for bioreactors and chromatography and filtration systems. Bioprocessing professionals regularly cite an expectation that bioprocessing systems will seamlessly scale up and down. In addition, the users want to model or predict the operation of the systems at scales higher than anticipated use to provide better assurance of actual scalability throughout the range of scales they actually will use, such as from mini/desktop to 2000-L or larger production bioreactors.
To move forward, industry and its investors need to recognize this segment has historically been one of the slowest, but also the most persistent, in terms of adopting the advances that the industry requires. To achieve success, operational challenges must be worked out, but in this regulated, high-stakes environment, the timelines for development and adoption of new technologies create challenges that, sometimes, require years to resolve.
1. E.S. Langer, et al., Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, 13th Annual (BioPlan Associates, 2016).
Vol. 31, No. 3
When referring to this article, please cite it as R.A. Rader, "Current Challenges in Bioprocesses Development," BioPharm International 31 (3) 2018.