Contract Manufacturing and Continuous Flow Reactor Technology for Early-Stage Drug Development - Pharmaceutical Technology

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Contract Manufacturing and Continuous Flow Reactor Technology for Early-Stage Drug Development
Continuous flow reactor technology is gaining momentum in the pharmaceutical and fine-chemical industries. This article is part of a special issue on APIs.

Pharmaceutical Technology
pp. s18-s19

Small-molecule drug development processes are typically in the range of six to eight synthetic steps. Given the time constraints and level of technical challenge, the design of an initial six to eight step totally continuous-flow process for an early-stage drug development project is generally not practical and is typically reserved for established commercial processes. CFR technology, however, does offer the distinct advantage of broader scaling capabilities for chemistries not suitable to batch scale-up. This scalability feature of CFRs is appealing for circumventing nonscaling problematic chemistries in a timely fashion. It is not uncommon for there to be one or more steps in an initial discovery synthesis that is not amenable to batch processing. When this occurs, significant time, effort, and money have to be invested in process research and/or development to resolve the chemistry or retool the synthesis. CFR technology, on the other hand, offers the potential to scale the existing problematic chemistry to overcome the bottleneck. For example, Johnson and Johnson (New Brunswick, NJ) demonstrated the utility of CFR technology for rapidly scaling gram to kilogram quantities of early-stage clinical trial API where batch processing was a concern (4). Several classes of reactions that presented safety or hazardous concerns for batch manufacturing were shown to scale efficiently, safely, and with shorter process research times. The reaction classes reported by the Johnson and Johnson group included exothermic reactions, reactions at elevated temperatures, reactions with unstable intermediates, and reactions involving hazardous reagents (4). Implementing CFR technology in an otherwise batch process to resolve early scalable issues provides an attractive strategy for expediting early-stage process development. Under this mixed "batch-CFR" paradigm, the problematic step(s) can be optimized to a CFR early on in the process allowing the chemistry to be readily scaled from grams to kilograms. Manufacturers of continuous CFRs such as Corning (Corning, NY) make smaller scale reactors that can be used for optimizing the continuous-flow chemistry on a small scale and employing the smaller reactor to make the desired product on a scale of grams to about a kilogram. When larger-scale production is required, the chemistry is readily transferred to an identical larger reactor simplifying the technology transfer process from laboratory scale to plant scale. Consequently, the "Batch-CFR" approach has the potential to be more expedient and cost effective as it takes advantage of CFR technology's ability to scale existing chemistry that is not suitable or safe for larger-scale batch processing. CFR technology may also allow the CMO to scale reactions beyond the capacity of their fixed reactors as an alternative to doing a technology transfer to another facility with larger fixed reactors.

The contract manufacture will still likely use fixed equipment to process the continuous-flow reaction maelstrom. Although significant gains have been made in in-process monitoring and continuous crystallization, at the present time, it is more expedient for early-stage continuous flow reactions to be worked-up using traditional methodology such as filtration, extraction, solvent removal, and crystallization in fixed equipment. If the project moves to commercialization, particularly in the hands of a large pharmaceutical company, the process is more likely to become a fully optimized continuous process from start to finish. With a "Batch-CFR" process, this transition should be facilitated since the more challenging chemistry has already been adapted to CFR technology.

The decision by a CMO to implement CFR technology to resolve a process scale-up issue is a critical risk decision requiring buy-in from the sponsor client. The technology holds significant promise for efficient and cost-effective development of early-stage cGMP processes. The "Batch-CFR" approach provides a much greater probability for scaling the initial discovery synthesis directly, thereby requiring significantly less process research and development work. CFR technology, however, requires different strategic thinking and technical expertise compared with classical batch manufacturing. Because most drug-development professionals are classically trained, there is likely to be some natural resistance to implementing CFR technology in early-drug development. This mindset has been referred to as "batch mentality (5). However, with FDA and the pharmaceutical industry encouraging the shift to CFR technology, contract manufacturers are likely to follow suit.

James Hamby, PhD , is vice-president of business development at Ash Stevens, 18655 Krause Street, Riverview, MI 48193, tel. 734. 282.3370 Ext. 1144,


1. A. Pellek and P. Van Arnum, Pharm. Technol. 9 (32), 52–58 (2008).

2. B. Trout and W. Bisson, "Continuous Manufacturing of Small Molecule Pharmaceuticals: The Ultra-Lean Way of Manufacturing," 2009 MIT Global Operations Conference, Dec. 2, 2009, accessed Aug. 16, 2010.

3. "Chemisty in Flow Systems" in Beilstein J. Org. Chem. Thematic Series 4, 5 (15), A. Kirschning, Guest Ed., Apr. 29, 2009,, accessed Aug. 16, 2010.

4. X. Zhang, S. Stefanick, and Frank J. Villani, Org. Proc. Res. Dev. 8 (3), 455–460 (2004).

5. P. Thomas, Pharm. Manuf.,, accessed Aug. 16, 2010.


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