By Ben Littler, Vertex Pharmaceuticals
This is the second part of a two-part article intended to highlight the growing need for innovator biopharmaceutical companies to build partnerships with contract development and manufacturing organizations (CDMOs) in establishing facilities for continuous manufacture of active pharmaceutical ingredients (APIs). Part 1 provided the underlying reasons for an emerging demand by innovator biopharmaceutical companies for small-volume continuous production, along with some of the challenges that may be impeding the implementation of these technologies. Part 2 explains why it is of increasing importance and value to both innovator biopharmaceutical companies and CDMOs to meet the demand for this nascent manufacturing approach.
An Introduction To Small-Volume Continuous Manufacturing
Small-volume continuous (SVC) manufacturing techniques have emerged in recent years to bridge the gap between the two classical continuous manufacturing (CM) approaches.1 The SVC approach is characterized by equipment and facilities that are typical of kilo lab facilities that have historically been used to provide API supplies to support pre-clinical and first-in-human studies. These facilities can readily produce approximately 1 to 15 kg of product each day, which aligns nicely with the annual demand of many emerging medicines. Another feature of the SVC approach is that a variety of continuous and automated repeating batch processing elements are combined to create a flow of material under a state of control. By utilizing simple automation, many conventional semi-batch techniques and items of equipment can be run repetitively at frequent intervals and fed into buffer tanks to create a flow of material. This hybrid approach widens the chemical space and processing options available to fit the needs of the substrate and reagents, as compared to dogmatically using only elements, such as pipe-flow reactors, that are classically considered as “continuous.”
Aside from matching the annual demand required of many emerging APIs, the SVC approach has several additional advantages that align with current and emerging trends that are attractive to innovator biopharmaceutical companies.
- Flexibility: The facility is flexible and can be rapidly reconfigured to accommodate many projects over the course of a year. The reactor modules are small enough to be constructed on carts that can be readily moved in and out of the walk-in fume hoods. It is also possible to perform multiple operations in the same fume hood, provided suitable storage points in the sequence can be identified.
- Smaller Footprint: The facility is compact. This means that the facilities can be placed in more geographically favored locations. Ideally, the SVC facilities would be located close to the R&D teams of the innovator biopharmaceutical companies. Although operating with CDMO partners across many time zones is possible, this becomes more difficult as the complexity of a project increases and the timelines for development decrease. The operation of an SVC (or any CM) facility is initially more complex than for a semi-batch facility, requiring process engineers and systems control experts in addition to chemists, analysts, and chemical engineers.
- Simplified Scale-Up: Scale-up from the R&D lab to the final manufacturing facility is greatly simplified because pilot runs can be performed at full scale. If scale-up is required, it is typically quite predictable, and if any unexpected events do occur, the whole batch of material is rarely at risk because the process can be stopped or the material diverted during the excursion until the desired state of control is regained. This greatly increases the robustness of the supply of API throughout the development cycle and into commercial manufacturing.
- Robust Analytics: CM processes in general acquire a lot more data when operating, compared to semi-batch processes. The additional data allows potential problems to be identified earlier and can also facilitate continual improvement of the process over the life cycle of the product, which is especially important if the time available before commercial launch is being reduced.
- Application Specific: The cost of the individual reactor components is very low, and the equipment has a small footprint, so they can be dedicated to a specific application, which eliminates the possibility of cross-contamination and greatly reduces the cleaning burden between runs. Other elements of the equipment that contact the process stream, such as transfer tubing, are of minimal cost and are therefore disposable.
- Safety: Performing the chemistry in a fume hood has multiple advantages. First, the risk of operator exposure is greatly reduced in normal operation, which is important because many of the products being manufactured by SVC techniques will have low threshold limits for operator exposure. Second, operating in a fume hood provides secondary containment for CM equipment that can operate outside of a range typically accessible using semi-batch manufacturing techniques. Specifically, high temperatures and pressures are accessible using CM techniques that would require significant additional engineering and safety measures if they were to be operated in a conventional open manufacturing facility. The added level of containment in an SVC facility and the low inventory of material in-process greatly reduce the severity of any unexpected leak of material.
Clearing The Hurdles To SVC Adoption At CDMOs
Many of the features listed above should also align with the business models of CDMOs; however, there are a few challenges that need to be overcome.
First, new SVC facilities will need to be constructed at CDMOs. Initial work forays into SVC manufacturing can be performed in traditional kilo laboratories, but this will limit the number of steps that can be readily linked together. Construction of a dedicated SVC facility is not a minor undertaking for an individual CDMO; the SVC facility constructed by Lilly at Kinsale in Ireland cost approximately $40 million.2 A justifiable concern for any CDMO is that the demand for SVC capacity has not yet been demonstrated by the innovator biopharmaceutical companies, so this leads to a chicken-and-egg situation where each side is waiting for the other to invest. The primary purpose of this article is to highlight that a number of innovator biopharmaceutical companies are actively pursuing API CM, including SVC, and would be interested in working with CDMO partners who are open to employing these novel manufacturing techniques.
In addition, SVC facilities will require new equipment and, at present, there are few off-the-shelf pieces of SVC equipment that can be purchased. Any reasonable CDMO would be concerned about investing in an equipment platform that proves to be the equivalent of Betamax rather than VHS. This situation is improving as equipment manufacturers recognize the demand, but again there is something of a chicken-and-egg situation. Fortunately, as more biopharmaceutical companies work in CM and SVC, the equipment requirements are becoming clearer. Much of the general equipment investment required by a CDMO would be well-established pumps and control systems that are adapted from other elements of the chemical and petrochemical industries. The equipment investment for individual projects is typically much lower when compared to a semi-batch reactor required to obtain the same throughput.
Many CDMOs also do not have the skilled workforce required to more widely implement SVC. This is due to the entrenched dominance of the semi-batch manufacturing paradigm and is consequently a systemic challenge for the whole biopharmaceutical industry, rather than being specific to CDMOs. The main capability gaps are in developing control strategies and equipment engineering. Indeed, a forward-looking CDMO that is able to assemble a team skilled at implementing SVC could potentially gain a significant advantage by providing expertise that many of the innovator biopharmaceutical companies do not have in-house.
Finally, any new biopharmaceutical manufacturing technology introduces concerns as to whether the new technology aligns with the existing regulatory guidance documents, inspection practices, and review mechanisms. To address some of these concerns, the FDA issued a draft guidance in early 2019 titled Quality Considerations for Continuous Manufacturing. This guidance document focuses on scientific and regulatory considerations that are specific or unique to continuous manufacturing, but most relevant for this article is that the guidance clearly reaffirms the long-term commitment of the FDA to CM with statements such as, “FDA supports the adoption of modern manufacturing technology as a foundation for improving the overall quality of products and availability to patients. FDA recognizes that continuous manufacturing is an emerging technology that can enable pharmaceutical modernization and deliver potential benefits to both industry and patients.” As more continuous manufacturing examples are implemented by biopharmaceutical companies and approved by the regulatory agencies, these regulatory concerns are diminishing. Building a robust CDMO network is another logical step in further reducing the concern around regulatory risk.
Overall, API CM and SVC should offer significant benefits for both innovator biopharmaceutical companies and CDMOs. Although there are challenges to implementing API CM and SVC, many of the challenges are common to any new technology that emerges in an area where entrenched business practices already exist. With the confluence of many factors, including reduced annual API requirements and expedited development timelines, there is an unmet demand for facilities at CDMOs in the U.S. and the EU that can support this new manufacturing approach.
- Cole, K. P., Groh, J. M., Johnson, M. D., Burcham, C. L., Campbell, B. M., Diseroad, W. D., . . . Mitchell, D. (2017). Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions. Science, 356(6343), 1144-1150. doi:10.1126/science.aan0745
- Palmer, E. (2016, April 5). Lilly commits to continuous manufacturing with Ireland plant. Retrieved September 22, 2019, from FiercePharma: https://www.fiercepharma.com/manufacturing/lilly-commits-to-continuous-manufacturing-ireland-plant
About The Author:
Ben Littler received his B.A. in chemistry and his Ph.D. in organic chemistry in the United Kingdom and then completed postdoctoral studies at North Carolina State University before joining the Chemical Development team at AMRI. In 2004, Littler joined Vertex Pharmaceuticals, and he has led the Vertex Process Chemistry team in San Diego since 2005. He has worked on projects from preclinical development to Phase 3 manufacture in disease areas including cystic fibrosis, hepatitis C, oncology, and pain. Littler is currently a senior director in Process Chemistry and the chair of Vertex’s cross-functional team to implement advanced manufacturing techniques for small molecule APIs.