By: Howard Levine (hlevinebptccom) and Frank Riske (friskebptcom)
As in years past, the Recovery of Biological Products XVI Meeting in Rostock, Germany (July 27‑31) provided a forum for lively debate on new technologies for downstream processing, new applications of old technology, and glimpses of what the future of our industry might hold. High among the topics of interest at the conference was continuous processing as a replacement for traditional batch processing of monoclonal antibodies and other recombinant proteins. Jon Coffman (Boehringer Ingelheim) began the conference pointing out that the cost of manufacturing per se is not limiting our ability to deliver products at a cost effective level but rather the high failure rate of products in clinical trials and the time required for overall product development were more critical in driving the cost of medicines today. Jon then showed how continuous processing might help accelerate production of material for clinical trials, allowing companies to shorten overall timelines to commercialization. This was followed by a presentation from Charlie Cooney (MIT) in which he reviewed the evolution of continuous processing for traditional pharmaceuticals and argued that the biopharmaceutical industry can also benefit from the efficiencies and flexibility continuous processing can provide.
Later in the program, Veena Warikoo (Genzyme), Oliver Kaltenbrunner (Amgen), and Alex Xenopoulos (Merck Millipore) presented their views on the development and implementation of integrated, fully continuous processes for recombinant proteins and monoclonal antibodies. While there was discussion and some disagreement over implementation of “end to end” continuous processes, these presentations and several posters at the meeting, did make the case for the use of continuous perfusion cell culture and continuous chromatography for initial product capture for recombinant proteins that are relatively unstable (e.g. Factor VIII) and helped define the objectives for implementing continuous processing for more stable products such as monoclonal antibodies. In these cases, continuous processing, whether for a single unit operation such as Protein A capture or a more fully integrated end-to-end process, there may be economic and/or productivity gains to be had through continuous (or semi-continuous) processing. Furthermore, advances in process analytical technology (PAT) may also favor using aspects of continuous downstream processing. With FDA and most industry experts embracing the concept of continuous processing, it is likely that some level of continuous processing will become commonplace in biopharmaceutical industry in the near future. Looking toward this future, Karol Lacki (GE Healthcare) gave an excellent presentation on a unified approach to process development that supports batch, semi-, and fully continuous processing without a need to repeat costly process development and process characterization studies should a switch be made from one operational mode to another later on.
The case for sticking with batch processing was made in comments by Brian Kelley (Genentech). According to Brian, conventional batch processes can be economical and suitable for production of biopharmaceuticals, even if very large columns or multiple cycles per column are required to process increasing levels of product in the harvest from large volume bioreactors. For a company like Genentech, with a large base of installed capacity and manufacturing assets, perhaps this is true. However, as companies look toward designing and building “factories of the future,” smaller facilities incorporating some aspects of continuous (perfusion) cell culture and continuous chromatography may be more cost effective and productive than larger facilities built around traditional batch processing. In conclusion, a company decision to use aspects of continuous processing may well depend on the stability of the protein, and an economic and risk analysis of placing such technology into an existing facility, or planned new construction.
Drs. Susan Dana Jones and Sheila Magil will be leading a 1.5-day training course titled, “Introduction to Bioprocessing” from August 18-19, 2014 at the Renaissance Waterfront Hotel in Boston, MA, to be held in conjunction with CHI’s Bioprocessing Summit (running August 18-22). This training seminar offers a comprehensive survey of the steps needed to produce today’s complex biopharmaceuticals from early development through commercial. The seminar begins with a brief introduction to biologic drugs and the aspects of protein science that drive the intricate progression of analytical and process steps that follows. We then step through the stages of bioprocessing, beginning with the development of cell lines and ending at the packaging of a finished drug product. The seminar also will explore emerging process technologies, facility design considerations and the regulatory and quality standards that govern our industry throughout development. The important roles played by the analytical and formulation in developing and gaining approval for a biopharmaceutical are also examined. This 1.5-day class is directed to attendees working in any aspect of industry, including scientific, technical, business, marketing or support functions, who would benefit from receiving a detailed overview of this field. For more information and to register for this seminar, please click here. Interested in learning more about BPTC’s CMC consulting expertise? Please email Julie Adam (jadambptccom) to pre-arrange a meeting at the conference.
BPTC is pleased to be exhibiting at the 2014 Biotechnology Industry Organization’s International Convention to be held in sunny San Diego, CA from June 23-26. We hope you’ll take some time to visit us at Booth 1214 in the Bioprocessing Zone to learn more about our extensive biopharmaceutical product development and manufacturing expertise and to enter our daily raffle to win two hours of free consulting. To pre-arrange a meeting to discuss your specific needs, please email Julie Adam (jadambptccom) . We look forward to seeing you in CA.
Dr. Keith Wells (kwellsbptccom) has been invited by Dr. Milana Boukhman Trounce, Clinical Associate Professor of Surgery, Divsion of Emergency Medicine, Stanford University School of Medicine, to serve as a special guest lecturer for her class entitled, “Biosecurity and Bioterrorism Response“. Dr. Wells will be speaking on Monday, 19 May at the Alway Building on the Stanford University School of Medicine Campus, and will be providing his perspectives on the technical potential for non-state actors to create strategic biological weapons and the development of a biodefense posture to counter that potential based on his 17+ years in the biodefense arena.
By Patti Seymour (pseymourbptccom)
Although the United States still has yet to work out the regulatory details to obtain approval for biosimilars, Europe and other countries, particularly growth markets, offer market potential for biosimilars. DCAT’s 2014 BioPharmaceutical Forum: Biosimilars—Development, Regulatory, and Marketing Experiences, held March 13, 2014, examined both the opportunities and challenges in biosimilar development and commercialization.
Assessing the opportunity
Biosimilars are a small, but growing segment of the global biopharmaceutical market accounting for 0.4% of the $137-billion biologics market in the so-called “mature eight” markets of the United States, EU5 (France, Germany, Italy, Spain, and United Kingdom), Canada, and Japan in 2012, according to IMS (1). In growth markets, biosimilars accounted for 10.7% of a $15-billion biologics market in 2012. By 2017, biosimilars are expected to represent 3–5% of an estimated $205-235 billon global biologics market(1).
For biosimilars in general and particularly with the opportunity of more complex molecules, such as monoclonal antibodies to become biosimilars, developers face the challenge of developing a manufacturing process that can achieve comparability to the reference product. Development activities center on replicating the process conditions of the reference product to drive the process toward producing a “highly similar product”. Because innovators do not typically publically disclose their manufacturing processes, biosimilar developers have to ascertain the process conditions that will allow them to achieve comparability, or “biosimilarity”. An added complication facing biosimilar developers is whether to take advantage of advances in cell line development and bioprocessing innovations to develop a more efficient manufacturing process to produce a biosimilar. The industry has seen titers increase from less than 1 g/L in 2000 to titers of 10 g/L or more in 2014. A fundamental issue for a biosimilar developer in evaluating the cost and time for biosimilar development is deciding whether to take advantage of innovative manufacturing processes that may result in better yields and more efficient manufacturing processes, but may generate a product sufficiently different from the reference standard that it would not be considered a “biosimilar.”
Biosimilar developers also face quandaries in cell-line development. In terms of conventional host cells systems, mammalian cell culture systems (primarily Chinese hamster ovary (CHO) cells) account for the majority of host cells or 56% of the systems used and E. coli comprise 29% of the host cells used in biopharmaceutical production. (2). An important issue in biosimilar development is determining whether a host cell system that is different from what was used by the innovator can be used for biosimilar development and commercialization.
Applying highly sophisticated analytical techniques to characterize these molecules and the potential to take advantage of a more advanced host cell and expression technology in the development of biosimilars is likely possible. However, regulatory authorities may be cautious and maintain a high bar regarding meeting the “biosimilar” criteria when a technology different from the innovatory process is used. In the U.S., we won’t know how the FDA will view the use of different technologies until they issue their long awaited guidance documents on development of biosimilars.
1. G. Lewis, “Pharma Transformation in Turbulent Times,” presented at DCAT Week 2014 (New York, 2014).
2. T. Fritz, C. Lightcap, and K. Shah, “Manufacturing Strategies for Biosimilars,” Pharma Manufacturing, June 12, 2012.