Moving Beyond The Batch

By Eric Langer, President and Managing Partner, BioPlan Associates, Inc.

Best practices, opportunities, and challenges in continuous bioprocessing

The traditional approach to upstream and downstream biopharmaceutical processing remains batch processing, but despite ever-increasing yields, technological advances are now making continuous bioprocessing an appealing alternative. What the industry is experiencing is not necessarily a case of old versus new (fiberbased perfusion bioreactors were widely used in the 1980s), but a resurgence in the attractiveness of continuous bioprocessing. New developments, such as the resolution of regulatory barriers (e.g., of how to define lots) and a shift toward QbD (quality by design) and PAT (process analytical technology) with which continuous bioprocessing fits well, are putting the benefits of continuous processing in focus.

In fact, there are several benefits, and a number of emerging technologies complement those of single-use and modular systems (two other current industry trends). The most commonly associated benefits to bioprocessing are:

• Reduced Costs: Continuous processing allows for the use of smaller-scale equipment, reducing up-front capital investments, and generally enabling manufacturers to use smaller facilities and equipment. This doesn’t come at the expense of productivity: A smaller volume bioreactor using continuous processing can, over time, match the output of a much larger one operating in fed-batch mode.
• Increased Productivity and Flexibility: By eliminating the need for large transfer/ storage vessels, as well as long transfer times and halts between processes, continuous processing runs more smoothly relative to traditional batch-fed processing. This allows manufacturers to attain considerably higher bioreactor cell densities, leading to higher product yield and concentration.
• Better Quality: Biological molecules are produced continuously and naturally. And when comparing continuous culture to batch culture, the former tends to be more controllable and less intense and stressful; it experiences less shear while media nutrient levels keep constant. Product variability (e.g., later culture stage-related loss of cell viability or altered glycosylation) is reduced, with continuous bioprocessing inherently more consistent and robust. And if any problems do occur, only part of the, not the entire, production run will likely need to be rejected.

Other potential benefits associated with continuous bioprocessing include:

• fewer manual interactions
• more automation
• increased use of single-use equipment
• reduced bioprocessing supplies inventory and storage needs
• easier implementation of PAT and up-front bioprocess design using lower staffing levels, presuming adequate automation
• similar equipment and setups being used for manufacture at different scales, up to commercial manufacturing; thus reducing costs and time spent scaling up.

DESPITE POTENTIAL BENEFITS, SIGNIFICANT CONCERNS REMAIN
While there are obvious benefits to continuous bioprocessing, biomanufacturers are faced with several concerns from its use. Not surprisingly, survey respondents to our 11th Annual Report and Survey of Biopharmaceutical Manufacturers associate far greater concerns with perfusion operations than with time-tested batch-fed operations.

In this year’s survey, we identified selected areas where there were differences in the perception of problems and concerns about perfusion vs. batch-fed. Some of the highlights included:

• Process operational complexity (76.8 percent indicating factor is a “much bigger” or “somewhat bigger” concern for perfusion, versus 3.6 percent, indicating it to be a bigger concern for batch-fed processes)
• Process development control challenges (75.9 percent and 3.6 percent, respectively)
• Contamination risks (68.8 percent and 6.3 percent, respectively)
• Ability to scale-up process (58.9 percent and 12.5 percent, respectively)

In many cases, perceptions worsened from last year’s survey, an interesting result that doesn’t track with trends in the marketplace, with perfusion being increasingly adopted for many new processes and even retrofitting of existing processes. This increase in concern may be the result of increased awareness of the technology as an alternative. Additionally, users and vendors claim that many problem areas have been addressed and that reactions may reflect dated knowledge or experience. In other words, the industry may be behind where it could or should be in terms of adopting perfusion technologies.

WHAT’S TO COME?
Perceptions and attitudes regarding perfusion will likely change for the better in coming years, as more bioprocessing professionals develop hands-on experience or otherwise become more familiar with perfusion operations and its advantages.

There are signs that adoption of perfusion operations is already on course, despite its perceived challenges. In order to assess potential demand for new technologies at both clinical and commercial manufacturing scales, we presented respondents to our annual study with five bioreactor types and asked, “If you were responsible for specifying a bioreactor type for a new clinical or commercial scale biologics facility two years from now, how likely might you be to implement each of the following?”

While single-use batch-fed bioreactors emerged as the most commonly preferred platform for clinical manufacture and batch-fed stainless steel bioreactors for commercial manufacture, it’s instructive (and striking) that slightly more than one-quarter would use a single-use perfusion system for commercial manufacture and close to one-third would use this type for clinical supply manufacture.

Already, leading adopters such as Genzyme and Bayer are known to have manufactured a dozen or more marketed recombinant protein products (but still under 10 percent) by using perfusion or other continuous bioprocessing technologies. BioPlan Associates and others expect increased adoption of continuous bioprocessing at all scales, including commercial manufacture, as the allure of cost savings, flexibility, and increased product entices otherwise skeptical industry segments to explore and adopt continuous bioprocessing.

Survey Methodology: The 2014 Eleventh Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production yields a composite view and trend analysis from 238 responsible individuals at biopharmaceutical manufacturers and contract manufacturing organizations (CMOs) in 31 countries. The methodology also included over 173 direct suppliers of materials, services and equipment to this industry. This year’s study covers such issues as: new product needs, facility budget changes, current capacity, future capacity constraints, expansions, use of disposables, trends and budgets in disposables, trends in downstream purifi cation, quality management and control, hiring issues, and employment. The quantitative trend analysis provides details and comparisons of production by biotherapeutic developers and CMOs. It also evaluates trends over time and assesses differences in the world’s major markets in the U.S. and Europe.