Accelerating Continuous API Synthesis

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PTSM: Pharmaceutical Technology Sourcing and Management

PTSM: Pharmaceutical Technology Sourcing and Management-08-05-2015, Volume 11, Issue 8

Early adopters look to speed up the use of continuous API manufacturing, but lack of expertise hinders adoption of continuous API synthesis.


Despite a few significant investments in continuous manufacturing facilities by pharmaceutical companies, including Vertex Pharmaceuticals, Johnson & Johnson, GlaxoSmithKline, and Novartis (1), the adoption of flow chemistry for commercial production of APIs generally remains in the early stages. FDA has encouraged the adoption of continuous manufacturing since 2004, but specific guidelines are lacking from the agency and other regulators around the globe. Both former FDA Commissioner Margaret Hamburg (1) and Center for Drug Evaluation and Research Director Janet Woodcock (2) have been more vocal about the issue, particularly in relation to the proposed 21st Century Cures Act. This legislation requires FDA to support the development and implementation of continuous manufacturing for drugs and biologicals as one of several approaches to speeding up drug development and commercialization (3). In addition to a lack of comprehensive regulatory guidance, however, a dearth of industry personnel with expertise in flow chemistry is a hindrance to rapid adoption of continuous technologies.

Early adopters and fast followers drive change
“While the industry as a whole is in the early stages of adopting flow chemistry for small-molecule API manufacturing, the early adopters and fast followers not only recognize that flow chemistry is the future of manufacturing, but also believe that they can implement it effectively,” asserts Tim Jamison, professor of chemistry and incoming department head at the Massachusetts Institute of Technology (MIT) and CEO of Snapdragon Chemistry, a new company dedicated to catalyzing the adoption of continuous flow synthesis. “Ultimately, when these companies realize the many benefits of flow chemistry, including reduced operating costs, footprint, and capital expenditures combined with improved process efficiencies, control, and product quality, investors likely will modify their expectations and demand this increased value from the industry as a whole. The rest of the industry will then have to scramble to catch up, and the early adopters and fast followers should reap the rewards of their forward-thinking actions. At that point, the entire industry--out of necessity to remain competitive--likely would shift its view on flow technology,” he explains.

Most large pharmaceutical companies, according to Peter Poechlauer, innovation manager with Patheon, have at least installed advocate groups with a mission to showcase successful applications of flow processes. Dominique Roberge, head of chemical technologies with Lonza Pharma & Biotech agrees that flow chemistry has become an accepted technology for small-molecule manufacturing, largely for the development of new chemical reactions that have not been feasible in batch operations, to reduce the cost of goods, and to decrease capital expenditures (CAPEX) via process intensification. “These projects are significantly more focused and give a better understanding of what is achievable via flow chemistry. As a result, we have moved past focusing on feasibility studies only and are now evaluating projects that are more mature for tech transfer and scale-up,” he notes.

“The decision to develop a certain step as a flow process is, however, opportunistic and may be motivated by the speed provided in early development, the need for smooth scale-up of hazardous reactions, and/or the savings in investment for a new drug whose future is still uncertain,” Poechlauer observes. In addition, he notes that these criteria apply to single steps of multi-step pharmaceutical syntheses, and therefore hybrid approaches that combine continuous and batch operations are most common; few companies have developed end-to-end continuous syntheses of pharmaceuticals that combine drug-substance manufacturing and drug-product formulation.

“Continuous flow manufacturing occupies a similar position to where a technology like spray drying was 10-15 years ago. It shows great promise but the ‘mainstream’ commercial viability within the pharmaceutical industry has yet to mature,” says Patrick Kaiser, a principal scientist in the process development business of SAFC. He believes that, like spray drying, a clear commercial pathway and, more importantly, a clear regulatory pathway will drive more entrants as developers embrace the technology’s promise. Even so, Kaiser expects there will be limitations to its full embrace, because certain systems lend themselves to be more relevant to continuous processing, while others make less sense to perform via continuous means, and this dissonance complicates the pathway forward. “The reality is that CMOs must embrace such disruptive technologies moving forward to ensure long-term competitiveness in the marketplace,” he concludes.

Expanding toolbox
A positive indication for the future of flow chemistry is its increasing use for different types of reactions and downstream separation/purification operations. With respect to chemical reactions, using flow processes allows better control of yield and selectivity, which have a direct influence on purification and separation steps, according to Roberge. “The best approach is to develop new processes that can and will lead to a significant improvement in the synthetic route, but will typically not work in a traditional batch process,” he comments. His examples include various oxidation reactions (with molecular oxygen or hydrogen peroxide), azide chemistry, and high-temperature/pressure reactions developed via microwave chemistry.

Jamison adds that the use of flow chemistry for photochemical and electrochemical reactions is also exciting, because these reaction classes are typically difficult to carry out and control and also challenging to translate from laboratory scale to pilot or manufacturing scale, but afford significant opportunities to access completely novel chemical scaffolds and greatly streamline current synthetic routes. “By using flow chemistry to gain better control, predictability, and scalability for these reaction classes, chemists can increase their utilization, which will ultimately result in significant advances and broader adoption in the pharma industry,” Jamison states.

Integration of chemical synthesis reactions in flow with an increasing diversity of work-up operations in flow, such as continuous extraction, membrane processes, and the crystallization and separation of solids, is also an important development, according to Poechlauer. He further notes that the application of parallel, analytical instruments with sufficiently short response times have been developed, allowing efficient control of these processes.

The development of a complete toolbox of flow reactors that can be used for all types of reaction rates and phases (e.g., liquid-liquid, solid-liquid, etc.) is also necessary for the broad application of flow chemistry to be achieved, according to Roberge. To address some of this need, Lonza has developed the pulsating coil reactor for liquid-liquid phase reactions and an efficient de-plugging system based on ultrasound technology. “Ultimately, true innovation in this field will come from a few key players in the market who have the variety of experience and infrastructure to optimize multiple reaction platforms,” asserts Roberge.





Shortage of expertise
In fact, the inadequate supply of scientific talent and expertise necessary to implement continuous flow technology at scale is perhaps the largest factor hindering more rapid adoption of flow chemistry for small-molecule API synthesis, according to Jamison. “It’s not as simple as asking current chemists to start working with continuous flow technology. That is like asking a saxophonist to play oboe. While both instruments are woodwinds, a saxophone uses one reed, while the oboe uses two. Thus, saxophonists can certainly become oboists, but it is not automatic; there will be a learning curve in most, if not all cases. Currently, flow chemistry is generally not in most university chemistry curricula. Thus, there will continue to be a lack of expertise in this area until this situation is changed,” he explains. “In the long run, industry demand will accelerate such changes; as the industry requires more expertise in this area, education/training standards will shift to meet this demand. This shift will not occur immediately, however, and there will likely be a short- to mid-term lack of human resource supply,” Jamison says.

Rhony Aufdenblatten, manager of small-molecule business development with Lonza Pharma & Biotech, agrees that flow chemistry remains a specialized technology, because it requires specific technical know-how that can only be developed over years of manufacturing different chemical products. “The key challenge for any small-molecule development program is management of scale-up of the lab process for industrialization. Moving this type of scale-up into a new platform like flow chemistry can only be handled by the few players who have experience working with a variety of chemistries and processes,” he observes.

Poechlauer is not convinced that continuous processing is “experts only” territory any longer, but he also believes that this perception certainly affects decisions regarding adoption of the technology. As a result, he does believe that CMOs with a proven track record in continuous processing may be favored as demand for this capability increases.

Regulatory and infrastructure issues
Two other factors that are influencing the rate of adoption of flow chemistry for API synthesis include a lack of clear regulatory guidelines and the existing batch-based manufacturing infrastructure. Although FDA representatives recently made a number of public comments in support of continuous manufacturing in the pharmaceutical industry, from a regulatory standpoint, there remains a need to develop clear, harmonized guidelines accepted across the various regulatory authorities that will facilitate the development of continuous manufacturing routes in a manner that guarantees a consistent way to monitor/regulate their output, according to Jamison. In addition, while there are a growing number of flow processes being filed with auditors despite this lack of clarity, Poechlauer notes that there is little experience with respect to the auditing of continuous process steps.

The International Conference on Harmonization (ICH) may be an effective body for achieving international guidelines. The organization may in fact be making continuous flow manufacturing a focus issue over the next year to 18 months.

The impact of existing batch plants is less straightforward. For companies with unused batch capacity, Aufdenblatten notes that additional motivation for further investment into large-scale flow chemistry will be needed to overcome the additional CAPEX for flow infrastructure. “Typically, a gain in yield of 2-3% will not be sufficient; reduced cost of goods, safer processes, and breakthroughs in process platforms must also be considered,” he explains.

Jamison points out, though, that existing infrastructure is in various stages of maturity, and new capacity (whether batch or continuous) could be established naturally, with continuous plants being built in place of new batch plants, as appropriate. “In addition,” he says, “continuous manufacturing plants could have a 10- to 100-fold smaller footprint than a batch plant of comparable output. Therefore, the CAPEX investment is smaller, which might sway the economic analysis to favor the business case of mothballing a significant number of existing batch-mode plants.”

The mentality of the process development function must also be considered, according to Kaiser. The use of flow chemistry earlier in development requires both the innovator and CMO to be open to using continuous systems as an option in their process development efforts. Doing so potentially requires developing an initial batch process backed up by a second-generation flow process, perhaps simultaneously if the drug is on an accelerated approval pathway, which is not a small shift in today’s “fast-fail” drug development business. “Development companies are generally averse to investing too much in the manufacturing process until there is good clinical data to show manufacturing on a larger scale is necessary. Unfortunately, waiting too long to develop a continuous process also complicates a company’s regulatory strategy and potentially a challenge with different impurity profiles from different manufacturing processes,” he comments. The best strategy to combat this challenge, according to Kaiser, is to have experienced flow chemistry experts recognize where continuous systems provide the greatest opportunity for results early on in the process development effort.




End-to-end implementation of flow chemistry
Snapdragon Chemistry-a new company launched in early May 2015 by CEO Tim Jamison, a professor of chemistry and incoming department head at the Massachusetts Institute of Technology (MIT), with Boston University assistant professor of chemistry Aaron Beeler-intends to provide drug companies with assistance in developing flow chemistry strategies and systems. 

“Snapdragon Chemistry has the capability to help a drug-maker from end-to-end in implementing continuous flow manufacturing,” Jamison says. Backed by a scientific advisory board that includes Steve Buchwald and Klavs Jensen, well-respected MIT chemistry and chemical engineering professors, respectively, the company is offering solutions services that include evaluation of entire portfolios of molecules in development to identify the greatest opportunities for implementation of continuous flow chemistry. The company also offers the translation of desired organic syntheses end-to-end into a continuous-flow format, including the selection and/or design and development of laboratory- to commercial-scale continuous reactors.

“Our goal is to help adapt flow technology solutions to the context of a specific company. We have the deep technical expertise across chemical synthesis and engineering to help companies make the appropriate decisions on where to invest in flow chemistry and increase their probability of success in implementing the technology,” he adds. Snapdragon Chemistry has already formed partnerships with companies, such as drug-discovery service provider Paraza Pharma and equipment manufacturer Zaiput Flow Technologies, to bring the most innovative and effective continuous flow solutions to clients, according to Jamison.

CMOs continue to build expertise
SAFC has the capability to manufacture products using continuous systems on a 1-50 kg/day basis and currently is producing monomers, reagents, and building blocks for pharmaceutical and high-technology applications. The company is also investigating the addition of cGMP capacity that will include continuous manufacturing technologies.

Lonza has produced many intermediates on kilogram and hundreds of kilogram scales for APIs in clinical trials. In 2013, for instance, the company completed a technology transfer to a large-scale manufacturing process under high-temperature and pressure conditions that were not possible in a batch process, according to Rhony Aufdenblatten, manager of small-molecule business development with Lonza Pharma & Biotech. Lonza has also used flow chemistry for the multi-ton production of a niacin product under GMP conditions.

1. J.D. Rockoff, “Drug Making Breaks Away From Its Old Ways,” The Wall Street Journal, February 8, 2015,, accessed June 2, 2015.
2. J. Wechsler, “Congress Encourages Modern Drug ManufacturingPharmaceutical Technology website, May 1, 2015, , accessed June 2, 2015.
3. Energy & Commerce Committee, United States House of Representatives, “Full Committee Vote on the 21st Century Cures Act,” May 19, 2015, , accessed June 2, 2015.


Article DetailsPharmaceutical Technology
Vol. 39, No. 7
Pages: 30–33

When referring to this article, please cite it as C. Challener. “Lack of Expertise Hinders Adoption of Continuous API Synthesis,” Pharmaceutical Technology 39 (7) 2015.