Batch processing is the historical and dominant form of manufacturing in the pharmaceutical industry, but continuous manufacturing is beginning to take root. Where does it stand with respect to bioprocessing?

Continuous biomanufacturing offers the promise of improved productivity and the ability to operate in a smaller manufacturing footprint. But what are the challenges and where does the industry stand in overcoming these challenges in continuous biomanufacturing. DCAT Value Chain Insights takes an inside look.

Some latest developments
One recent advance in continuous bioprocessing comes from The Center for Process Innovation (CPI), the UK’s technology innovation provider for process manufacturing, which announced in late August 2017 of its participation in a consortium to develop an automated continuous biologics purification unit for the more efficient manufacture of a wide range of biologic drugs. The project brings together biopharmaceutical companies with UK operations, process technology suppliers, and CPI’s National Biologics Manufacturing Center, part of the High Value Manufacturing Catapult, to develop an automated continuous biologics purification unit. The consortium’s participating organizations are: Pall Europe, CPI, Allergan, Fujifilm, Diosynth Biotechnologies, AstraZeneca’s Medimmune, and GlaxoSmithKline. The consortium is funded by £4.5 million ($5.87 million) from Innovate UK, an innovation agency of the UK goverment. The High Value Manufacturing Catapult is part of a group of manufacturing research centers funded by the UK government to advance manufacturing and to bridge the gap between technology concept and commercialization. There are seven such innovation and technology centers, including a dedicated center for biologics. 

The project will involve a new unit that will consist of integrated, multiple operations running concurrently. All the lab work will be completed at the facilities of CPI using equipment provided by Pall and using feedstock from the manufacturers in the consortium. “This project will integrate all downstream processing operations into one unit so that a range of biologics are purified and formulated in hours, compared to many days. The value brought to process development and preclinical studies will also be transcribed to clinical manufacturing scenarios,” said Rob Noel, business development manager EU and Asia, Pall, in commenting on the project.

Continuous processes offer potential advantages, including better scalability, higher productivity with reduced running times and materials usage, smaller manufacturing footprints, and less capital- intensive facilities. In addition, automated continuous bioprocesses can minimize human intervention and thus the potential for errors, according to information from CPI. “As the biologics industry moves to drive the cost of complex therapies down and increase productivity, continuous processing while effectively utilized in other manufacturing sectors, is relatively new to ours. With the expertise assembled within this consortium, we believe a significant contribution will be made to the way the industry manufactures biologics”, said Mark Bustard, business development director biologics, CPI.

Continuous bioprocessing: the challenges in adoption
A 2016 study by the National Institute for Bioprocessing Research and Training (NIBRT) identified continuous manufacturing in biologics as one of the five areas of leading impact in biomanufacturing over the next five years, second only to single-use technologies. NIBRT is a global center of excellence, based in Dublin, Ireland, for training and research in bioprocessing. NIBRT is based on a collaboration between University College Dublin, Trinity College Dublin, Dublin City University and the Institute of Technology, Sligo and is primarily funded by the government of Ireland. Other high-impact areas identified in the NIBRT study were data analytics, process analytical technologies, automation and robotics, and cell-free protein synthesis. The study also identified the leading technical challenges to continuous biomanufacturing, which included challenges in process development, regulatory uncertainties, challenges in technology transfer, a lack of real-time monitoring technologies, and the unproven nature of the technology.

A recent study, the 14th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production,  by BioPlan Associates, a Rockville, Maryland consulting firm, further identified challenges with continuous biomanufacturing. As a test for how the industry views continuous versus 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 (1). Other difficulties cited by the study in adopting continuous bioprocessing included al ack of practical know-how, precedents, and cost-effective equipment (1).

The BioPlan study points out that continuous bioprocessing is still lead by smaller-scale perfusion-based systems that increasingly single-use bioreactors. In BioPlan’s annual study, respondents were asked about their plans to evaluate or consider continuous bioprocessing technologies in the coming year. 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 about one quarter (26.5% in 2016 and 24.3% in 2017) stated they were evaluating downstream technologies (1).

A recent article in Bioengineering and Translational Medicine, a journal of the American Institute of Chemical Engineers, points to the evolution of continuous biomanufacturing (2). It noted that perfusion cell-culture processes in which fresh medium is added on a continuous basis to the culture and spent medium containing product is continuously withdrawn have historically been used for unstable or low-titer products for products that could not be expressed to high levels in fed-batch cultures. It noted that perfusion cell-culture processes are becoming more prevalent due to improved productivity (2). The article also points out that there is growing interest in applying continuous biomanufacturing as a means to integrate upstream and downstream bioprocessing and to move from traditional batch-based chromatography used in downstream bioprocessing to continuous or semi-continuous purification. The article cites recent economic analyses of continuous production processes that indicate that continuous production techniques can achieve the same cost of goods sold (COGS) from a significantly smaller bioreactor as compared to conventional batch production processes (2, 3). The article points to continuous production operations at a 500-liter bioreactor scale that can achieve COGS as low as $17/gram.

With respect to continuous chromatography used in bioprocessing, the article points to several applications. They include period counter current chromatography (GE Healthcare), multicolumn countercurrent solvent gradient purification with systems from several companies (ChromaCon, Pall, and Semba Bio) (2).

References
1. K. Estees and E. Langer, “Update on Continuous Bioprocessing: From the Industry’s Perception to Reality,” Pharmaceutical Technology,  Volume 41, Issue 6, pg 70–72.

2. A. Shukla et al., “Evolving Trends in mAb Production Processes,” Bioengineering and Translational Medicine, DOI 10.1002/btm2.10061 (2017).

3. W. Godawat et al., “The Business Impact of an Integrated Continuous Biomanufacturing Platform for Recombinant Protein Production,” Journal of Biotechnology, doi.org/10.1016/j.jbiotec.2015.05.010 (2015).