Continuous Manufacturing for the Modernization of Pharmaceutical Production Proceedings of a Workshop (2019) / Chapter Skim
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Proceedings of a Workshop
Proceedings of a Workshop
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. This workshop1 discussed the business and regulatory concerns associated with adopting continuous manufacturing techniques to produce biologics such as enzymes, monoclonal antibodies, and vaccines (see Box 1, Statement of Task)
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. Going forward, while many regulatory agencies have expressed strong support for continuous manufacturing, adopting continuous processes for purifying an already marketed biologic product would mean going first, which is not the preference of most pharmaceutical companies.
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and (2) integrated upstream small molecule synthesis and purification (including control strategies such as process analytical technology and real-time release testing strategies)
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Other than NIIMBL, there has been no coordinated effort to ensure that biomanufacturing keeps pace with an increasingly diversified product pipeline, to support the biomanufacturing supply chain in the United States, and to develop the knowledge base needed to mitigate the risk of adopting new processing technology in a highly regulated industry. The Future of Access to Medical Countermeasures Rick Bright from BARDA explained that his agency is interested in continuous manufacturing as a means of rapidly producing medical countermeasures to evolving and increasing natural and human-made health security threats.
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FDA is focused on developing the regulatory science to address operational and technical challenges, while BARDA focuses on evaluating continuous manufacturing processes, improving process efficiency, and ensuring the sustainability of medical countermeasure manufacturing. Ensuring drug access for all, said Bright, requires a continued strong partnership with FDA to address regulatory challenges as new technologies emerge.
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FDA is now overseeing the development of continuous processes in the small molecule space, as well as modelbased control strategies that would lead to real-time release of products, and it expects a handful of regulatory submissions over the coming year. The agency is also overseeing work being done on the continuous synthesis of biopolymers such as therapeutic DNA and RNA molecules.
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One challenge according to Woodcock is to develop advanced control strategies and incorporate real-time data strategies for CQAs. Others are to integrate downstream unit operations in an effective manner that satisfies purity requirements and for the community to agree on real-time release methods.
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Hewig said that productivity improvements in fed-batch manufacturing processes have plateaued after three decades of commercial production of therapeutic proteins. As a result, companies have been turning to new technologies such as perfusion processes and high cell density processes to start shrinking the footprint from a productivity standpoint.
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The hurdle to implementing continuous processes is easier with known unit operations transformed from batch to continuous, rather than starting from scratch. From his perspective as a chemical engineer, Futran said the biggest benefit of continuous manufacturing is that all operations can be run simultaneously in a single room, enabling continuous monitoring of all production steps, something that is lost in batch production.
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Regarding operational considerations, Jimenez said that continuous processes require improved process controls, including the need for on-line, in-line, and at-line measurements, to maintain a steady state in the bioreactor. This is needed to lower the complexity of the process and reduce shop floor instruc 10
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Reklaitis from Purdue University, the session speakers discussed that the challenges for moving existing approved products to continuous processes and establishing comparability between the processes is not trivial. The three speakers agreed that there are fewer drivers to implement fully continuous immobilized cell bioreactor compared to implementing a continuous perfusion bioreactor only, and that it is best to implement continuous processes in stages, not all at once.
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What Boehringer Ingelheim envisions is building a new facility using the integrated SKID with a 100-liter bioreactor to produce enough material for toxicology testing and a 1,000-liter bioreactor for commercial-scale production that would be capable of producing 1,200 kilograms of material per year. In summary, Ogawa said that a non-steady state perfusion system using concentrated media feeds could fit into a commercial 12-kiloliter facility with little capital investment.
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The aim is to increase volumetric productivity, leverage in-house medium formulations, and reduce cell-specific perfusion rate to minimize media flow through the system, while maintaining desirable product quality attributes, process robustness over extended run times, and consistent cell densities in a system that can be scaled to support intensified processes. The technology development focus, he added, is on monoclonal antibodies and monoclonal antibody-like products that are in the company's early pipeline with the intent of minimizing or eliminating the need for process optimization in the early stage of development.
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Modeling the cost of goods for a generic monoclonal antibody produced using intensified perfusion integrated with continuous capture showed that a 2,000-liter perfusion system had the potential to produce a dramatic reduction in cost of goods. He noted that with increasing plant capacity, a 2.5-fold increase in titer could decrease cost of goods by approximately 50 percent.
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It also wants to enable smaller, more reconfigurable facilities that can be built at lower cost and on a much faster timeline. To meet that goal, Just Biotherapeutics is designing a semi-continuous process with continuous capture chromatography and batch downstream processing for final purification and virus removal, similar to the approach Barrett discussed.
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Low utilization, said Arnold, does not push innovation. The strategy, then, is to take a modular, one-unit-at-a-time approach and introduce continuous processing in places where batch processing comes up short in terms of productivity and efficiency, thereby gaining experience and building a knowledge base for when the company needs to expand its production capabilities and build a new facility.
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What Can Be Learned from the Chemical Industry Andrew Zydney from The Pennsylvania State University reiterated Lee's statement in the day's first presentation that many industries have converted from batch to continuous processing. The chemical industry, for example, made this transition nearly one century ago, which provided significant increases in productivity, reductions in pollution, improved product quality, and enhanced process safety.
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FIGURE 3 Conceptual diagram of a continuous countercurrent tangential chromatography product. NOTE: CCF refers to cell culture fluid, mAb refers to monoclonal antibodies.
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The system includes process analytical tools that enable operators to intervene if the system deviates from the desired parameters. These tools also generate data that power multivariate modeling for process control and improvement.
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Ohtake noted that rotary vacuum drying is a batch process, so it would be necessary to couple droplet formation to multiple drying units to create a semi-continuous process. A third company is developing a continuous spray freeze-drying technology that replaces the rotary vacuum dryer with a vibrating, agitated drying chamber.
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In short, digital biomanufacturing has the potential to support enterprise-level manufacturing intelligence in the form of reporting analytics for quality assurance and quality control support; monitoring analytics for process control, development, and optimization; and predictive analytics for scheduling, supply chain optimization, and optimal harvesting of product. Digital biomanufacturing also fits well with next generation quality-bydesign initiatives.
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For example, being able to measure glycoform production in near-real time offers new approaches to using changes in product attributes for process control functions rather than using a representative value, such as pH or glucose levels. In addition, being able to monitor many divergent process parameters in both upstream and downstream processes offers the possibility of using this mass of data to control processes more efficiently.
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This enabled the team to use a 50-liter perfusion reactor and couple it directly to the downstream processes, thereby reducing the labor component and the need for repetitive quality control testing, creating a highly intensified process through fill and finish. Overall, process yields are high enough to enable the entire process to fit inside a refrigerator-sized unit complete with automated process control.
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24 FIGURE 5 Diagrams displaying how engineering of the antigen can improve product quality. SOURCE: Mukhopadhyay, slide 6.
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To him, mapping out the integration process before attempting to do it is imperative. The project his group has been working on is part of DARPA's Biologically Derived Medicines on Demand project, which envisions a different supply chain in which raw materials are transported around the world and the final product is made in a multi-product facility near the site of intended use.
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Strategy for Implementing Real-Time Release Testing Richard Braatz from MIT recalled that an MIT-Novartis project several years ago had designed a plant-wide control system from first principles, built the fully integrated, end-to-end system, and showed that it reduced production costs by approximately 50 percent and met all purity specifications (Lakerveld et al., 2015; Mascia et al., 2013)
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. Real-time release testing, said Braatz, requires being able to evaluate and ensure the quality of in-process and/or final drug product based on process data, which typically include a valid combination of measured material attributes and process controls (see Figure 6)
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SOURCE: Braatz, slide 11. Advancements Toward Real-Time Release Doug Richardson from Merck spoke about how he and his colleagues are addressing adaptive process control and process analytical technology to learn more about these processes in the near term and with the eventual goal of realizing real-time product release.
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There are several technical challenges to address before process analytical technologies can enable real-time release, including the development of robust, single-use sensors, advanced data analytics and process modeling, and robust aseptic sampling and clarification. In a panel discussion with all the session speakers, Charles Cooney, the discussion moderator, summarized some themes from the session: (1)
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In continuous manufacturing, special considerations include the state of control, raw materials and intermediates, equipment, product collection or rejection, traceability, process monitoring and sampling, and specifications. Regarding the state of control, Nasr explained that maintaining a state of control provides assurance of consistent and desired product quality, which means that the control strategy should have the ability to detect process upsets and institute corrective actions to bring the process back into conformance.
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Other considerations include detailing startup and shutdown procedures, how production collection and in-process sampling will occur as a means of assuring continued process performance and product quality, process validation and continued process verification procedures, material traceability, personnel and training procedures, and how cleaning will be validated. To bridge an existing batch manufacturing process to a continuous process, the continuous process can be introduced as a new process for a new molecular entity or as a post-approval manufacturing change.
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This approach does not work for continuous manufacturing, as it will not determine how well an individual step removes a virus and it is likely to underestimate viral clearance, said ConnellCrowley. What she and her colleagues do with a homogeneous load is to quantify viral clearance for each discrete step in the continuous process.
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33 FIGURE 7 Challenges with virus removal in different spiking scenarios. SOURCE: Connell-Crowley, slide 14.
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Using qPCR, she and her colleagues found that there are high levels of RVLPs in the bioreactor and three to four logs lower levels in the permeate, which feeds into downstream processes, with three different perfusion membranes. In conclusion, Connell-Crowley said that the challenges of continuous downstream processes require rethinking how viral clearance assessments are done given that current virus spiking strategies will not necessarily work in all situations.
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For example, since the 1990s, when the field of continuous pharmaceutical manufacturing was first implemented, to today, manufacturing of monoclonal antibodies has evolved from state-of-the-art large fed-batch and batch processes to intensified, semi-continuous processes. Given where the community is, she predicted that it will eventually develop a fully continuous process for producing monoclonal antibodies and other biologics and reap the associated benefits that other industries have realized from continuous manufacturing.
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She explained that process analytical technologies provide real-time process monitoring, real-time process control, and automation with redundancies. Liquid flow rates through all unit operations are controlled continuously so that they are synchronous as a means of mitigating deviations.
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Breakout Group 2: Upstream Processing Question 1: What are the major challenges to moving continuous manufacturing forward within upstream processing? Ken Lee of MedImmune discussed some of the points made in the upstream processing breakout session.
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Breakout Group 3: Downstream Processing Question 1: What are some major challenges to moving continuous manufacturing forward within downstream processing? Eva Gefroh of Just Biotherapeutics reported back from the downstream processing breakout session.
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According to Gefroh, the group determined that three key areas of research focus for downstream processing include developing better process analytical technologies, predictive and self-learning models, and novel continuous processes; for example, finding a game-changing equivalent to Protein A for continuous processing, identifying new affinity ligands, developing alternate hosts that may allow novel processes to work, and designing new sorbents or membrane surfaces that are more selective for product rather than impurities. Question 3: Are there other mechanisms that could address a specific challenge, such as a change in regulation, a shift in organizational policies, or even a targeted short-term research contest such as a challenge or a code-a-thon?
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Breakout Group 5: Integration Question 1: What are the major challenges to moving continuous manufacturing forward within integration? Charles Cooney of MIT moderated the breakout session on integration.
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The European Medicines Agency has a process analytical technology team that has expanded its interests to include quality by design and continuous manufacturing. Japan has an innovative manufacturing technology working group and a forum for academia, industry, and regulators to hold ongoing discussions about continuous manufacturing.
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Currently, companies determine how to ensure quality and how much information to include in a submission. Other concerns Roper said the group discussed include the need for adequate and representative process analytical technology control sensor probes to ensure adequate sampling frequency.
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For batch processes, the components are used for several cycles and then virus spiking is done to validate that the membrane is clean and the process worked as designed. With continuous manufacturing, there is a question about how frequently validation would be required.
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2018. Multi-angle light scattering as a process analytical technology measuring real-time molecular weight for downstream process control.
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