The American Chemical Society (ACS) Green Chemistry Institute (GCI) Pharmaceutical Roundtable consists of 15 members, including mostly pharmaceutical companies, but also some suppliers. The Roundtable has defined continuous processing and process intensification as key green-engineering research areas for sustainable manufacturing. In 2012, the group conducted a survey of its members to evaluate the extent to which the industry is interested in and pursuing continuous processing. Peter Poechlauer, principle scientist with DSM Chemtech Center, which is a Roundtable member, spoke with Cynthia Challener, editor of the Pharmaceutical Sciences, Manufacturing & Marketplace Report about the results of the survey as they relate to chemical manufacturing of pharmaceutical ingredients and APIs.
Why continuous means green
Pharmaceutical Sciences, Manufacturing and Marketplace Report: Why did the ACS GCI Pharmaceutical Roundtable define continuous processing and process intensification for API manufacturing as key green engineering research areas?
Poechlauer (DSM): The mission of the Roundtable is to promote the implementation of green chemistry and engineering practices. The group studied a number of different technologies for their potential benefits, and determined that “process intensification” is very important because it provides for better use of starting materials with reduced byproduct formation and waste generation, a smaller footprint, reduced consumption of water and energy, and lower overall cost.
Pharmaceutical Sciences, Manufacturing and Marketplace Report: What are CMOs/CDMOs doing with respect to continuous processing and the use of microreactor technology?
Poechlauer (DSM): DSM and others have engaged in continuous processing efforts and have very quickly implemented scaled-up processes and done so in a cost-efficient way. We are very interested in microreactor technology and continuous processing because in some case it makes it easy to scale up reactions that can’t easily be done otherwise due to the nature of the raw materials or the kinetics of the reaction. However, there are uncertainties about scale-up, and managing intellectual property issues must be done carefully, given that in many cases new process chemistry is involved.
Pharmaceutical Sciences, Manufacturing and Marketplace Report: Where is continuous processing most likely to be used in API and intermediate manufacturing and why?
Poechlauer (DSM): Today, given that most microreactors are laboratory scale, continuous processing is often used early in the development process and can speed up development times and lower costs. It will eventually be used at scale, as well, as the equipment issues are addressed, particularly for reactions that require high temperature and pressure because they can be both hazardous and quite expensive. Ultimately, continuous processing will be beneficial for numerous stages of both GMP and non-GMP primary and secondary manufacturing steps.
Pharmaceutical Sciences, Manufacturing and Marketplace Report: Manufacturers of microreactors and flow-chemistry equipment were identified as important drivers of the adoption of continuous processing, but there are still issues with the technology. What are the main concerns?
Poechlauer (DSM): One of the biggest issues is scaling up to commercial production levels. Most early equipment for flow chemistry was designed for the laboratory. Chemical manufacturers and pharmaceutical companies, including DSM, have been working with microreactor manufacturers to address this issue, though, and pilot- and small commercial-scale equipment is becoming available, often by “numbering up” and running several microreactors in parallel. One advantage is that modular designs that can be fitted to the specific needs of different reactions are possible. This advantage was taken into consideration when DSM installed its commercial-scale microreactor suite.
Another issue indirectly related to microreactors is the lack of development of appropriate laboratory-scale models of downstream processing equipment, such as small-scale extractors, distillation units, and crystallizers.
Integrating with existing processes
Pharmaceutical Sciences, Manufacturing and Marketplace Report: In addition to actual reactions, what other upstream/downstream processes can be carried out in a continuous manner? What types of equipment are needed?
Poechlauer (DSM): Most downstream processes can be easily adapted to run continuously. Extractions, phase separations, and distillations are actually more effective when done continuously. Solids-handling processes, such as filtration and crystallization, present some difficulties, but there are solutions being introduced to the market, such as belt filters and spray-drying, and others will follow.
Pharmaceutical Sciences, Manufacturing and Marketplace Report: How do continuous processes fit in an overall production process that still involves several batch operations? How are the benefits realized?
Poechlauer (DSM): Most pharmaceutical companies own large-scale batch production plants and won’t be doing away with them. Continuous equipment like microreactors will be added when needed, and the existing vessels will be modified to serve other purposes, such as hold-up tanks used to define the batch for regulatory purposes.
Typically, API syntheses are multistep processes. In most cases, some steps will benefit from continuous operation while others will not, and thus most pharmaceutical syntheses will continue to be a mix of continuous and batch-manufacturing operations. Mixing continuous and batch processes also enables manufacturers to build in some inventory buffer zones, so that if there is a problem with one part of the process, there will remain some time to fix it without halting the entire production process.
Hurdles to overcome
Pharmaceutical Sciences, Manufacturing and Marketplace Report: How can the pharmaceutical industry overcome the hurdles to adoption of continuous processing for API manufacture, such as the reluctance to invest in technology, the uncertainty with respect to the benefits for any given specific process, and the sometimes questionable fit with the pharmaceutical process development process overall?
Poechlauer (DSM): Our partners in the pharmaceutical industry are in a transition stage and are moving toward integrated solutions. Laboratory chemists consider the environmental consequences of raw materials and processes when developing synthetic routes. Drug manufacturers are also forming closer collaborations with suppliers to explore new technologies and concepts, such as continuous processing and the use of microreactors. Such relationships will help demonstrate the benefits of this approach and ultimately lead to adoption of process intensification when it is the most effective solution.
Pharmaceutical Sciences, Manufacturing and Marketplace Report: What is the role of the regulatory agencies in driving the adoption of continuous processing and the use of microreactor technology?
Poechlauer (DSM): The regulatory agencies are generally supportive of continuous processing because it provides better process control and thus improved product quality. Process intensification involves a scientific approach to the development of manufacturing processes, including identification of key parameters to monitor and how to react to process changes. Such features are highly appreciated by the regulatory agencies.