By Mark F. Witcher, Ph.D.
Some of the connections between continuous manufacturing (CM) and biosimilars are fairly obvious. CM has the potential to significantly lower the cost of goods (COGs) of manufacturing biopharmaceuticals, and the success of biosimilars relies heavily on significantly reducing COGs. However, CM technology is still in its infancy. The path to developing continuous process technology to the point where it can be widely used to rapidly and efficiently launch new and innovative biopharmaceutical products will be challenging. Perhaps the biggest hurdle to wide-scale use is that the development expertise and facility resources required to build CM processes are not widely available.1
However, as companies and healthcare systems continue to invest in biosimilars around the globe, there’s another important question that must be asked: Can CM benefit from biosimilars?
The answer is yes, and, most importantly, the ultimate success of CM may rest heavily on its use for making biosimilars. This article will examine the relationship between improved CM and biosimilar development, paying particular attention to the reasons why biosimilars are especially promising candidates for CM development and innovation.
The Challenges Of CM Use In Novel Biopharmaceutical Development
Though CM technology is not widespread, regulatory agencies — and particularly the FDA — have been championing the use of CM as a method of improving product quality. In order to facilitate the adoption of CM, regulatory agencies are currently developing ICH Q13 to establish the regulatory foundation for its introduction.2 However, to be clear, CM is no panacea for product quality problems. A manufacturing enterprise with an inadequate quality management system (QMS) that has been poorly integrated into the manufacturing process unit operations (UOs) and the surrounding facility processes will result in product quality problems, regardless of the process technology.3
While improved product quality is attractive to the pharmaceutical industry, the greatest incentive to the industry is a significant reduction in COGs. CM processes have intrinsically lower per-unit operating costs because they more efficiently use expensive operating and capital manufacturing assets at optimal conditions using automated control systems. CM is used almost exclusively in the petrochemical industry for these reasons. The petrochemical industry has clearly demonstrated much lower COGs and better product quality by using advanced process control strategies available from long-term steady state operation afforded by CM processes. Without highly optimized continuous processes, the cost of gasoline and other basic chemicals would be many times their current prices.
However, the development path for biopharmaceuticals and petrochemicals is very different. Basic petrochemicals have relatively straightforward market demand risks, whereas pharmaceuticals require a longer development, regulatory approval, and commercialization path. Developing and launching new biopharmaceuticals is a very risky endeavor for every new product or therapy.1,4 During initial product development, the primary driver is to get a proof of concept of a safe and effective product from preclinical and clinical testing as fast as possible. After likely safety and efficacy are established in early clinical trials, then the goal becomes to launch the product to make it available to patients and to begin recovering the product development costs and generating revenue. To ensure product approval, the initial commercial manufacturing process must be well controlled and nearly identical to the process used in the late-stage clinical trials so that no alterations to the molecule’s safety and efficacy profile arise. Should there be a clinically meaningful drift in the product, the company would be faced with additional clinical testing, delayed timelines, and a negative regulatory review. For new biopharmaceuticals, these two sequential milestones are the primary drivers; COGs is a subordinate — though still visible — third goal.
In the near term, batch processes will continue to be the more familiar bioprocess development technology for quickly generating small volumes of material for preclinical and early clinical testing. Batch processes can be run piecemeal as needed to provide intermediate material for building the process’ UO sequence using simple experimental methods. However, in contrast to batch processes, CM processes must be integrated fairly quickly to understand the inter-UO interactions needed to achieve steady state operation at optimal conditions for establishing consistent product quality.
Once regulatory momentum is generated from the product’s approval, changing from batch to CM becomes difficult. Until CM technology becomes widely used and considerable expertise is amassed within the biotech process development community, it will be difficult to develop CM processes for new products to support the early phases of a biopharmaceutical product. Companies originating new products will not be able to accept the additional cost and schedule delay risks on top of the product uncertainties and risks until CM-UO’s performance risks are minimized by significant advancement in CM technology.
The Synergies Between CM And Biosimilars
Biosimilars, on the other hand, have a fundamentally different risk profile than new products. Most of the safety and efficacy risks and market demand risk for the product have been significantly reduced or are better understood. The biosimilar developer is thus focused primarily on reducing the COGs, which makes the advantages of CM more important. Developing CM processes, especially for large-scale operation, has a fundamentally different economic risk profile. The investment can be more easily justified for creating a CM process for the reference product or the biosimilars already in the marketplace. In addition to well-known safety and efficacy profiles, products facing biosimilar competition also boast relatively well-defined critical quality attributes. In turn, the investment for translating a batch process into large-scale CM unit operations can be justified. Thus, the transition of existing products from batch processes to CM, by either the originator or biosimilar companies, can result in a significant advancement of CM technologies.
After a number of biosimilars have been switched, the overall CM technology will become developed to the point where the original innovating product developers can immediately take advantages of CM’s ability to cheaply manufacture high-quality new products for preclinical, clinical, and launch requirements without incurring significant process development risks over and above the inherent product’s safety, efficacy, and market requirement risks.
Biosimilars and continuous manufacturing can both benefit patients by reducing the cost of important biopharmaceuticals. The lower risk profile of biosimilars makes the risks associated with developing and launching new biosimilar products using CM technologies more manageable and acceptable. After CM technology advances and becomes more widely available, especially in the bioprocess development community, it can be used to develop and launch new products that benefit from the quality and significant cost advantages CM provides.
- Witcher,M.F.“TheFacilityChallengesofDevelopingContinuousProcess based Biopharmaceutical Products,” March 2019. https://ispe.org/pharmaceutical-engineering/ispeak/facility-challenges- developing-continuous-process-based-biopharma-products
- ICHQ13FinalConceptPaperICHQ13:ContinuousManufacturingofDrug Substances and Drug Products dated 14 November 2018 https://database.ich.org/sites/default/files/Q13_EWG_Concept_Paper.pdf
- Witcher,M.F.,AStraightforward,Risk-BasedApproachtoBetterQuality Management System Design, Pharmaceuticalonline.com, March 18, 2020 https://www.pharmaceuticalonline.com/doc/a-straightforward-risk-based- approach-to-better-quality-management-system-design-0001
- Witcher,M.F.“HowFDA’s21stCenturyGoalscanberealizedbyusinga Multi-purpose Manufacturing Facility,” Pharmaceutical Technology, 2018. http://www.pharmtech.com/how-fda-s-21st-century-goals-can-be-realized- using-multi-purpose-manufacturing-facility-0?pageID=2
About The Author:
Mark F. Witcher, Ph.D., has over 35 years of experience in biopharmaceuticals. He currently consults with a few select companies. Previously, he worked for several engineering companies on feasibility and conceptual design studies for advanced biopharmaceutical manufacturing facilities. Witcher was an independent consultant in the biopharmaceutical industry for 15 years on operational issues related to: product and process development, strategic business development, clinical and commercial manufacturing, tech transfer, and facility design. He also taught courses on process validation for ISPE. He was previously the SVP of manufacturing operations for Covance Biotechnology Services, where he was responsible for the design, construction, start-up, and operation of their $50-million contract manufacturing facility. Prior to joining Covance, Witcher was VP of manufacturing at Amgen. You can reach him at email@example.com or on LinkedIn.