The Facility Challenges of Developing Continuous Process based Biopharmaceutical Products
While there has been much discussion around the regulatory issues of Continuous Processes (CP), the most significant challenges are associated with managing the product development activities of building Continuous Manufacturing (CM) processes in the context of a product pipeline. Keeping manufacturing capacity off the critical path of developing and launching new products is a crucial goal of any biopharmaceutical manufacturing organization. Efficient and rapid product development has a significant impact on the timely supply of critical products to patients and for developing a company’s product pipeline to increase revenues. Products that use or require CM processes are especially difficult to develop and launch because of the high uncertainty in the process’s format and operating scale from integrating new, rapidly evolving technologies.
Developing CM based products introduces a number of troublesome product and process development problems. The industry cannot risk the success of any important product on novel process technology. Significant new products will likely have to be developed using a combination of batch and CP unit operations that required very different facilities to test, scale-up, and operate for preclinical thru commercial manufacturing. Which combination of batch and CP unit operations will provide the optimal product development timeline, product quality, and operating economics will be difficult to determine until a great deal of process and product development has been completed.
The final commercial process, particularly for the first generation of CM produced products, may be developed in a variety of configurations or may even be launched as a combination of some or all batch processes that are later converted to CM processes as product economics and appropriate CP technologies evolve and are perfected. The CM processes may take on many different configurations and scales during development and scale-up from early to late-stage clinical manufacturing. As a result, products developed in CM processes will have a very high uncertainty regarding the manufacturing facility assets and resources required for development and commercialization. Before describing a facility that has the flexibility to deal with the high resource requirement uncertainty, the development path for new products will be described.
To better understand the problem of developing and launching new products, the interconnections between Research and Development (R&D) and GMP manufacturing resources are summarized in Figure 1. Two very different facility assets are required to develop biopharmaceutical processes. A GLP laboratory is required for R&D to create process and early product information. Using the process R&D information, a GMP manufacturing capability is required to accomplish the following manufacturing tasks:
- Build Master (MCB) and Working (WCB) cell banks,
- Building large volume working cell banks (10mL), if and when needed,
- Make development material at larger scale for further R&D
- Manufacture material for pre-clinical testing
- Make early and late stage product for clinical testing
- Manufacture late Phase III material at commercial scale
- Build prelaunch inventories
- Provide commercial manufacturing until long-term capacity is available.
The common practice today is to divide these activities between a variety of facilities and organizations requiring a significant amount of tech transfer along with its associated delays and risks. Such activities can be much more efficiently performed within a single manufacturing enterprise that is capable of efficiently executing all the tasks in a seamless manufacturing environment. The facility can belong to either the sponsoring company or a Contract Development and Manufacturing Organization (CDMO). If a single manufacturing asset is used, continuity and consistency of operating personnel, procedural controls, and equipment resources can be maintained. As shown in Figure 1, if a single GMP facility is used, it must be capable of quickly and efficiently operating anything between laboratory scale for cell bank development to commercial scale capacities for launching the product.
Figure 1 – Possible interactions between a GLP R&D laboratory and a highly flexible cGMP capable manufacturing facility for efficiently developing and launching biopharmaceutical products. The GMP capability is required to make material or run larger scale operations. The intimate connection between the two facilities allows for a single development group to coordinate all activities virtually eliminating tech transfer between R&D and manufacturing.
CM is generally regarded as the manufacturing technology of the future, particularly over the long haul, for making biopharmaceutical products. 1 , 2 , 3 However, developing commercial CM biopharmaceutical processes will have some significant technical challenges. One of the most difficult challenges will be defining the type of facilities necessary to develop and then launch products produced using CM processes. Early CPs will have high uncertainty with respect to the process’s Unit Operation (UO) sequence, operating scale, yield, and especially equipment requirements. Access to highly qualified and experienced manufacturing personnel will be essential for success. Efficiently managing such uncertainty will require a facility with the flexibility to rapidly adapt to a wide variety of process scales and configurations to support the GMP manufacturing requirements described above.
One recently proposed facility concept is the Multi-Purpose Facility (MPF) shown in Figure 2. 4 ,5 The MPF is capable of handling virtually any manufacturing process, including CPs, implemented in movable equipment from the lab scale necessary to test small scale CM processes to multiple 2,000 liter fed-batch or perfusion Single Use Bioreactors (SUBs). 5 The MPF is designed around an operating core of multi-functional rooms that can be configured and reconfigure to support a wide variety of both manufacturing processes for multiproduct operation along with being able to expand or contract media and buffer operations.
- 1Lee, L “Modernizing the Way Drugs Are Made: A Transition to Continuous Manufacturing,” FDA – Spotlight on CDER Science, https://www.fda.gov/Drugs/NewsEvents/ucm557448.htm
- 2M.M. Nasr et al. Regulatory Perspectives on Continuous Pharmaceutical Manufacturing: Moving from Theory to Practice: September 26-27, 2016, International Symposium on the Continuous Manufacturing of Pharmaceuticals; Journal of Pharmaceutical Sciences. http://dx.doi.org/10.1016/j.xphs.2017.06.015 (2017) 1-8
- 3Madurawe, R., “Enabling Continuous Manufacturing: An FDA Perspective,” 3rd PQRI/FDA Conference on Advancing Product Quality, March 22-24, 2017
- 4Witcher, M. and H. Silver, "Multi-Purpose Biopharmaceutical Manufacturing Facilities Part 1: Product Pipeline Manufacturing," Pharmaceutical Technology 42 (9) 2018 http://www.pharmtech.com/multi-purpose- biopharmaceutical-manufacturing-facilities-part-1-product-pipeline- manufacturing?pageID=1
- 5 a b Witcher, M. and H. Silver, "Multi-Purpose Biopharmaceutical Manufacturing Facilities Part 2: Large-Scale Manufacturing," Pharmaceutical Technology 42 (11) 2018 http://www.pharmtech.com/multi-purpose-biopharmaceutical-manufacturing-facilities-part-ii-large-scale-production
Figure 2 – Multi-Purpose Layout – Facility layout shown is a matrix of individual nondedicated multi-purpose rooms in three arms (A-C) each having six rooms (1–6) that can be independently configured to house a variety of process and support operations necessary to achieve the require manufacturing capabilities. All equipment, primarily single use, is movable for placement or relocation within the matrix as required to operate a wide variety of process implementations. 4 , 5
While perhaps not as efficient as purpose built or ballroom concepts designed to handle well defined process, the MPF’s flexibility provides a significant strategic advantage for launching new products. 4 The basic concept behind the MPF is a facility of multipurpose operating areas that can be rapidly adapted to the process’s scale and equipment requirements. The process is divided into Logical Operating Units (LOUs) of sequences of Unit Operations (UOs) that should or can be operated together. As an example, a seed SUB sequence can be operated with the main production SUB to realized personnel and operating efficiencies. Segregation requirements, such as pre and post viral separation, can be easily achieved by dividing the LOUs between different areas depending on room availability and adjacency opportunities. Depending on the manufacturing scale, equipment requirements, and the number of LOUs, the process may require only a few or as many operating rooms as necessary. If desired, only parts of the process’s LOUs can be placed into the MPF to satisfy whatever intermediate manufacturing tasks are required to support product development and then removed upon completion of the manufacturing campaign. Different products are separated to prevent operating interference and cross contamination risks. 4 , 5
The flexibility of the operating areas also allows for the addition of support functions such as media and buffer preparation in nearby or adjacent rooms. One of the frustrating problems with intensified or CM processes is that some implementations will have very large media and buffer requirements. Increasing or decreasing the support requirements can be readily accommodated by using an additional operating area for support LOUs. If the support services are not needed, then the operating space can be redeployed for another process LOU or product.
Because of the layout design, the corridor configuration allows for the rapid insertion and removal of process equipment allowing the MPF to independently run many different campaigns to satisfy a wide variety of development and manufacturing challenges. For a large pipeline, the MPF can have a high utilization rate providing a highly capable development resource that can be scheduled based on product and process priorities. When appropriately sized, an MPF provides immediate access to manufacturing capacity at all scales and capacities needed to move new products through the complete development cycle quickly and efficiently. 4
The Multi-Purpose Facility (MPF) provides an ideal product development resource because it can adapt to a wide variety of batch, continuous, or highly intensified batch processes leading to potentially very efficient, high quality manufacturing. The uncertain facility resource requirements of developing and commercializing products using Continuous Manufacturing (CM) requires extreme flexibility in adapting internal facility resources to accommodate a wide variety of process formats and scales. In addition, the facility must be able to work on the product’s process development activities for some combination of both batch and CM processes in order to assure the timely launch of expedited products to the patients. Given the challenges of commercially developing continuous processes, the MPF is a critical strategic resource for pushing through the development challenges to realizing the wide spread use of continuous manufacturing into the biopharmaceutical industry.