(111f) Synthesis and Steady-State Optimization of a Continuous Pharmaceutical Process

Gerogiorgis, D. I., Massachusetts Institute of Technology (M.I.T.)
Barton, P. I., Massachusetts Institute of Technology

Continuous Pharmaceutical Manufacturing (CPM) attracts ever-increasing attention nowadays, because of the expanding profitability gap experienced by most pharmaceutical companies; the latter is due to increasing R&D and operating costs and decreasing drug prices (Behr, 2004). Despite the strict licensing requirements for product purity and stability, and the established batch manufacturing processes, the FDA has spearheaded CPM initiatives, recognizing that CPM has a strong potential to improve product quality and suppress operating costs (Plumb, 2005). Comparative studies have confirmed this potential experimentally (Betz et al., 2003). Corporations are thus encouraged to focus on introducing modern process engineering design principles, advances in instrumentation and control, and data management systems (FDA, 2004). The vast majority of Active Pharmaceutical Ingredients (APIs) are currently produced by batch processes, whose reconfiguration implies long, expensive clinical trials and revalidation. Nevertheless, novel APIs provide ample opportunity to explore the CPM paradigm, addressing systematically the optimal design and operation of continuous pharmaceutical production lines. Microsystems technology offers a convenient, efficient, cost-effective way to conduct a wide variety of organic synthesis reactions (Jensen, 2001) and ensuing separations (Kralj et al., 2007); its advantages include miniaturization (space and fixed investment cost savings), high heat and mass transfer coefficients, scaleability, quick screening, rapid manufacturing and customization. Accelerating CPM R&D (from laboratory to pilot-plant and production scale) can be substantial.

Organic synthesis is the cornerstone of CPM process development and flowsheeting, since  demonstrating a robust and efficient chemical reaction pathway is essential for proof of concept. In contrast to standard batch process prerequisites (high conversion, yield and API purity), CPM processes can in principle be flexible and viable at much lower conversions and yields, as long as (a) continuous flow without solid precipitation and (b) efficient separations are both ensured. Batch pharmaceutical manufacturing often relies on conventional, recipe-oriented R&D, conducted in long campaigns of arduous, expensive and time-consuming laboratory experiments.

Advances in unit operations engineering can also positively impact CPM processes, by improving efficiency as well as reducing solvent emissions and environmental footprint. Nanofiltration (Lin & Livingston, 2007), steady-state recycle (Kennedy et al., 2004) and continuous granulation (Vervaet et al., 2005) are examples of proven technologies which have been shown to enhance the upstream (API production) and downstream (drug formulation) part of many pharmaceutical production lines, accelerating the transition to CPM processes. Concurrently, breakthroughs in Process Analytical Technology (PAT) (Munson et al., 2006), novel sensors (React-IR) and actuators (micro-pumps) provide in-depth understanding of chemical kinetics, enabling first-principles modeling and efficient multivariate process control.

The present study focuses on plantwide synthesis and optimization of a new upstream process which is aimed at the continuous production of a novel Active Pharmaceutical Ingredient (API). The conceptual flowsheet comprises 3 organic synthesis reactions and 3 separations, considering microsystems (microreactors, microseparators) for the respective steps, due to the plant capacity. Kinetic parameter estimation (based on yield data from CPM experiments conducted at MIT) and thermodynamic modeling enable accurate reactor and LLE extractor design, respectively. Conceptual synthesis allows for solvent integration (Ahmad & Barton, 1999); for costly solvents, this can improve process economics, in contrast to wasteful and exensive batch processing. Steady-state upstream process optimization allows the determination of optimal stream flows and liquid-liquid extraction solvent utilization, based on a number of explicit process design constraints: plant capacity (API throughput), effluent purity, and residual solvent (EMEA, 2001). Cost estimation indicates there is an appreciable margin for cost reduction over batch processes.


Figure. The proposed upstream flowsheet of a novel continuous pharmaceutical process for API production.


Ahmad, B.S., Barton, P.I., Process-wide integration of solvent mixtures, Comput. Chem.
23(10): 1365-1380 (1999).

Behr, A., New developments in chemical engineering for the production of drug substances,
Eng. Life Sci. 4(1): 15-24 (2004).

Betz, G., Junker-Purgin, P., Leuenberger, H., Batch and continuous processing in the production of pharmaceutical granules, Pharm. Dev. Technol. 8(3): 289-297 (2003).

European Medicines Agency (EMEA), Impurities: Residual solvents, VICH Topic Report GL18 (plus annexes) (Web: http://www.emea.europa.eu/pdfs/vet/vich/050299en.pdf) (2001).

U.S. Food and Drug Administration (FDA-CDER), Innovation & continuous improvement in pharmaceutical manufacturing. (Web: www.fda.gov/cder/gmp/gmp2004/manufSciWP.pdf) (2008).

Jensen, K.F., Microreaction engineering: is small better?, Chem. Eng. Sci. 56(2): 293-303 (2001).

Kennedy, J.H., Belvo, M.D., Sharp, V.S., Williams, J.D., Comparison of separation efficiency of early phase active pharmaceutical intermediates by steady state recycle (SSR) and batch chromatographic techniques, J. Chromatogr. A  1046(1-2): 55-60 (2004).

Kralj, J.G., Sahoo, H.R., Jensen, K.F., Integrated continuous microfluidic liquid-liquid extraction, Lab Chip 7: 256-263 (2007).

Lin, J.C.T.,
Livingston, A.G., Nanofiltration membrane cascade for continuous solvent exchange, Chem. Eng. Sci. 62(10): 2728-2736 (2007).

Munson, J., Stanfield, C.F., Gujral, B., A review of process analytical technology (PAT) in the
US pharmaceutical industry, Curr. Pharm. Anal. 2(4): 405-414 (2006).

Plumb, K., Continuous processing in the pharmaceutical industry - Changing the mind set, Chem.
Eng. Res. Des.
83(A6): 730-738 (2005).

Vervaet, C., Remon, J.P., Continuous granulation in the pharmaceutical industry, Chem. Eng. Sci. 60(14): 3949-3957 (2005).