By Mark F. Witcher, Ph.D., biopharma operations subject matter expert
As was the case in the chemical and petroleum industries (CPI) in the 20th century, continuous manufacturing (CM) will be critical to the long-term success of the pharmaceutical and biopharmaceutical industries (PBI) efficiently delivering important therapeutic products to patients in the 21st century. While the business drivers are similar, CPI and PBI have very different risk environments.
CPI is dominated by product capacity and cost-of-goods (COGs) business drivers and has straightforward product risks. On the other hand, PBI has a much more complicated product risk profile that changes significantly as the product moves through a highly regulated clinical testing and manufacturing pathway. In addition, PBI has a critical product quality imperative that greatly complicates successfully negotiating the product development life cycle.
This article describes how CM can be used to satisfy important business drivers as part of the product’s development strategy. Understanding how CM interacts within the PBI’s dynamic risk profile as it interacts with business drivers is critical to CM’s success. CM’s long-term success is also threatened by several misconceptions that could delay or hinder its implementation.
Understanding and managing regulatory risks associated with CM processes for getting a new product through the various regulatory approval steps are important. From a process standpoint, the regulatory issues for CM processes are largely defined by ICH Q13.1, 2 The regulatory agencies have been proactive and are very supportive of efforts to use CM for manufacturing BPI products. Their contention that CM processes operating under control at steady states results in better product quality is supported by past experience with CM processes. In general, if the developing enterprise understands the CM regulatory guideline requirements and utilizes good science and engineering (GSE) practices to develop the processes and manufacturing facilities, regulatory goals should be achievable and the regulatory risks manageable and acceptable.
One threat to CM’s success is implementing it to satisfy the perception of CM as either a regulatory requirement or an approach that would receive preferential treatment. CM’s advantage is primarily reducing capital investments required to satisfy critical capacity and COG business drivers. Delaying the delivery of an important new therapeutic to patients by developing a CM process without defining significant business driver advantages over batch processes is not in the best interests of either the patients or the developing enterprise.
The product development life cycle is summarized in the figure below.
Manufacturing Life Cycle: The critical product and business risk drivers are shown on the left and the relative capacity scales for the batch and CM process options on the right. Other drivers include rapid execution of the development life cycle while minimizing the capital investment required to reach each product development milestone.
The primary business driver is to deliver the product to patients as soon as possible at the lowest COGs after a minimal capital investment using an efficient process in facilities with high utilization rates. The primary product risk is that the product could fail to meet important therapeutic goals of efficacy or safety at any point from preclinical testing through commercial launch. If the product fails critical clinical milestones or is withdrawn because of safety concerns, then all process development and manufacturing facility investments are lost. As shown in the figure, the primary product and business drivers shown on the left have to be satisfied by selecting the best route through the manufacturing process options shown on the right.
The decision is based on managing the product’s risk profile to achieve the business objectives quickly and efficiently. Manufacturing processes also can be a mixture of batch and continuous processes depending on the nature of the various unit operations necessary to make the product for each manufacturing campaign.
Virtually every product will start as a batch process in research and development and then progress down the manufacturing options to complete the product’s manufacturing requirements. Although the decision to begin development of a CM process can be made at any time, the decision to initiate CM development can be summarized using four points in the development life cycle as shown on the right side of the figure.
1. R&D/Early Process Development
The primary driver initially is establishing therapeutic viability necessary to know the product is likely to have efficacy, along with information that the product might be safe. In some cases, CM processes have some advantages for making products with high yields that have the necessary critical quality attributes (CQAs) for both efficacy and safety. CM processes typically have lower residence times than batch processes and if the process degrades the product, CM may be significantly more likely to efficiently produce the desired product CQA profile than batch processes. As CM technology advances, additional product quality advantages over batch processes may be identified.
After initial development, the product undergoes preclinical testing in in vitro and animal models to develop information that strongly suggests a reasonable likelihood of efficacy and safety in humans. At the present time, most products will exit this phase as batch processes. If the product’s CQAs require CM processes, then product development would continue as a small-scale CM process.
2. Clinical Trials
After the appropriate regulatory filing and approval, the manufacturing of clinical material would begin. Most products would enter this phase as batch processes at small scale. Batch processes require minimal capital investment and are easy to operate and scale up to satisfy clinical manufacturing requirements. The speed and investment drivers heavily favor batch processes to quickly gather the critical efficacy and safety data to establish viability and minimize the economic impact of clinical failure risks.
As the product’s safety and efficacy risks begin to become better defined, the future drivers of capacity and COG can be considered. As the clinical trials progress, dose, indication, and market penetration potential may be better understood.
Initiation of CM development would have to occur in parallel with the existing batch process given the uncertainty of successfully developing a CM process. CM would only be initiated if there was considerable information to believe that it might be an appropriate investment to achieve long-term COG and capacity business drivers. If a parallel CM program is initiated, a product comparability analytical plan must also be initiated with a successful CM process used for clinical crossover studies to establish bio‑similarity between the batch and CM products prior to product launch.3
3. Product Launch
At the point a product is launched, the capacity requirements and baseline COGs can usually be better defined. In some cases, the product’s potential can be fully understood, and it may be appropriate to begin investment in a more efficient CM process to reduce additional long-term capital investment requirements and for reducing COGs required to support the expanding market. For large-scale, high-value products, development of an efficient CM process may be an effective strategy to either prevent or combat market penetration by competitive companies developing lower-cost biosimilar processes.
However, the later the decision to develop a CM biosimilar is made, the more difficult the regulatory hurdle of demonstrating comparability will become. Conversion of the manufacturing process from an initial batch to an internal biosimilar CM process would require a clinical program followed by Phase 4 side-by-side crossover studies to demonstrate comparability for regulatory approval. If the product launch goes well, consideration of CM development should start as soon as possible, especially if the product looks promising for additional indications.
4. Long-term Commercial Supply
For products that mature and expand into large markets having long commercial life cycles, it may be appropriate to convert largescale batch processes to CM processes using an internal biosimilar mechanism.4 Originator companies have a significant product CQA and process comparability information advantage for efficiently developing and launching internal biosimilars. Converting to a CM process could provide significant capacity and COGs advantages for protecting high-value markets from competitive biosimilar business threats.
If you decide to attempt conversion to CM processes, you should consider the all-in costs of conducting the required comparability programs, building and starting new manufacturing capacity, and inventory and logistical management costs in your return on investment calculations.
The capital cost, capacity, and cost-of-goods advantages of CM will eventually make it the primary method of manufacturing large-scale, high-value biopharmaceutical products. However, appropriately managing the optimal transition from batch to CM processes requires managing the complex and dynamic risks of developing and licensing biopharmaceutical and pharmaceutical products against significant business drivers.
- FDA Guidance Document – Q13 Continuous Manufacturing of Drug Substance and Drug Products, March 2023. Q13 Continuous Manufacturing of Drug Substances and Drug Products | FDA
- Mitchell, M. An Analysis of ICH Draft Guidance Q13: Continuous Manufacturing of Drug Substance and Drug Products, BioProcess Online, Aug. 23, 2021. https://www.bioprocessonline.com/doc/an-analysis-of-ich-draft-guidance-q-continuous-manufacturing-of-drug-substance-and-drug-products-0001
- Witcher, M.F. “The Facility Challenges of Developing Continuous Process based Biopharmaceutical Products,” March 2019. The Facility Challenges of Developing Continuous Process based Biopharmaceutical Products | Pharmaceutical Engineering (ispe.org)
- Witcher, M.F., Can Biosimilars Be the Bridge to More Widespread Continuous Processes? BioProcess Online, May 19, 2020. https://www.bioprocessonline.com/doc/can-biosimilars-be-the-bridge-to-more-widespread-continuous-bioprocessing-0001
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 firstname.lastname@example.org or on LinkedIn (linkedin.com/in/mark-witcher).