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Home By Application AutoChem Applications Chemical Process Development and Scale-Up

Chemical Process Development and Scale-Up

Creating Safe, Efficient Processes from Lab to Plant

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reactor vessels for chemical process development

What Is Chemical Process Development and Scale-Up?​

Chemical process development is focused on the development, scale-up and optimization of a chemical synthetic route, leading to a safe, reproducible, and economical chemical manufacturing process. The initial stages following the identification of a target molecule are laboratory-based.

Chemists focus on route scouting (e.g., investigating the best synthetic approach) and defining the process design space (e.g., establishing process conditions that ensure consistent, desirable results). Later stages focus on the scale-up of a high-quality product and aim to produce larger quantities of the molecule for additional purposes (e.g., clinical studies or chemical testing).​

Activities involved in chemical process development and scale-up focus on process understanding and control with the goal of supporting quality by design (QbD) objectives. Process variables that affect critical quality attributes and product yield are well-defined, measured, and understood. A design of experiment (DoE) approach and process analytical technology (PAT) is often used to aid in accomplishing these goals. DoE helps to screen and identify optimal values within the reaction space while PAT provides a means to continuously monitoring across the entirety of the chemical development process. 

Scale-up efforts encompass a range of activities involved in the transition from lab to plant including investigating potential process hazards, understanding reaction kinetics and thermodynamics, identifying and characterizing impurities, mixing and mass transfer studies, heat transfer, and removal studies as well as crystallization and polymorph control. 

Why Is Chemical Process Development Important?

Chemical process development is important because it is the means by which a synthetic route is transformed into a safe, sustainable, robust and cost-efficient chemical process, yielding a high-quality product. The activities involved span nearly the entire life cycle of a product.​

​In the discovery phase, scientists synthesize a small amount of a target compound. If preliminary studies look promising, larger quantities of the compound will be needed. As the molecule moves to development, scientists often find that the discovery route is not the best choice for larger-scale production due to challenges related to scale. For example, the discovery route might require expensive reagents, present challenging operating conditions or create potential safety hazards when performed at larger volumes. Process chemists will begin work on the development of a synthetic route that achieves the quantity, quality, safety, robustness, and cost objectives that are required for larger scale.

After the best route is selected, the focus is on optimizing and scaling up the route. Work will begin on simplification (e.g., can steps be combined, identifying a catalyst enabling the reaction to be performed under milder conditions, etc.). Scale-dependent variables such as dosing rates, mixing and mass transfer are investigated. There is a concerted effort to understand process limits and create an effective design space for the process. Part of defining process limits is investigating potential safety hazards and ensuring that exotherms generated by the reaction at scale are understood and effectively controlled. As an element in an effective quality by design (QbD) strategy, online process analytical technology (PAT) methods will be developed and deployed to ensure product quality via process reproducibility and stability. 

What Are the Challenges and Goals of Chemical Process Development?

The chemical development and the scale-up of processes pose many challenges for researchers and span a variety of topics including: 

risks from rising temperature white paper

Free White Paper: Risks from Rising Temperature

In chemical process development and scale-up, understanding temperature change and the associated heat that is accumulated by the reaction is critical to understand process safety. This white paper discusses how to assess the implications of changing temperature regimes in chemical reactions. Examples from both lab and pilot plant are used to answer the following questions:

  1. Why does thermal accumulation occur?
  2. When does thermal accumulation occur?
  3. Is accumulation important to consider, and how big is it?
  4. What is the impact of an incorrect calculation of accumulation?

 

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Chemical Process Development Technologies

Automated Synthesis Workstations with Real-Time Reaction Analysis

chemical process development laboratory instruments
  1. In-Situ Raman Spectrometer — in-situ analysis of multiphasic reactions, polymorphs
  2. In-Situ FTIR Spectrometer — in-situ reaction kinetics, mechanisms and pathways
  3. PVM Particle Size Analyzer — inline imaging and analysis of particle formation and growth
  4. FBRM Particle Size Analyzer — inline particle size analysis with FBRM® technology
  5. Automated Chemical Synthesis Reactor — precise and automated execution and documentation of process conditions
  6. Reaction Sampling System — automated, representative sampling
  7. Process Development Software, Modeling, and Simulation — scale-up efficiently with software for data analysis and control, modeling and simulation
jacketed reactor support

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Industry Examples

Industry Applications of Chemical Process Development Technology

A Continuous Flow Sulfuryl Chloride Based Reaction Provides Greater Process Safety and Selectivity​

EasyMax HFCal Measures Heat Release and Aids in Batch Optimization

de Souza, J. M., Berton, M., Snead, D. R., & McQuade, D. T. (2020). A Continuous Flow Sulfuryl Chloride-Based Reaction—Synthesis of a Key Intermediate in a New Route toward Emtricitabine and Lamivudine. Organic Process Research & Development, 24(10), 2271–2280. https://doi.org/10.1021/acs.oprd.0c00146

The authors discuss the development of a continuous flow approach to synthesizing a key intermediate in the oxathiolane core used to manufacture the anti-retrovirals Emtricitabine and Lamivudine. The intermediate is formed using a two-step sequence: sulfuryl chloride is reacted with a menthyl thioglycolate to produce a sulfenyl chloride compound which is then trapped by vinyl acetate and chlorinated further. Batch scale-up revealed that the sequence featured a strong exotherm and that reaction conditions had a significant effect on reaction yield, byproduct formation and product purity. For example, excess levels of a dichloroacetate byproduct formed when temperature, mixing and residence time were not precisely controlled. Implementation of a continuous flow approach enabled greater control over temperature and mixing rate, resulting in improved selectivity and scale-up safety. ​

Heat flow calorimetry played an important role in the decision to pursue a continuous flow approach. An EasyMax HFCal system was used to measure the heat released during batch-scale as 242 kJ/mol during the sulfenyl chloride step and 438 kJ/mol during the vinyl acetate addition step. From this, the authors predicted adiabatic temperature rises of 102−133 °C and 138−207 °C, respectively. Continuing with a batch approach given such strong exotherms would require developing challenging process equipment/conditions such as an active reactor cooling strategy, changing reagent dosing rate, etc. 

Integrated Continuous Manufacturing Pilot Plant

​In-Situ FTIR, FBRM, NIR and Raman Used as PAT  ​

Testa, C. J., Hu, C., Shvedova, K., Wu, W., Sayin, R., Casati, F., Halkude, B. S., Hermant, P., Shen, D. E., Ramnath, A., Su, Q., Born, S. C., Takizawa, B., Chattopadhyay, S., O’Connor, T. F., Yang, X., Ramanujam, S., & Mascia, S. (2020). Design and Commercialization of an End-to-End Continuous Pharmaceutical Production Process: A Pilot Plant Case Study. Organic Process Research & Development, 24(12), 2874–2889. https://doi.org/10.1021/acs.oprd.0c00383

Integrated continuous manufacturing (ICM) has gained interest as a way to combat challenges posed by traditional batch-processing in the pharmaceutical industry (e.g., inefficient manufacturing techniques, quality control issues, and supply chain vulnerabilities). This article reports on the development and operation of an end-to-end integrated continuous manufacturing (ICM) pilot plant for the streamlined production of small-molecule active pharmaceutical ingredients (APIs) and tablets of a marketed generic drug. The plant performs unit operations across six main processing areas: feeding, dissolution, and clarification bypass; reactive crystallization; filtration and resuspension; drying; extrusion molding-coating and solvent recovery. ​

Process analytical technology (PAT) was used to aid in system function and adhere to a QbD-based design strategy. ParticleTrack FBRM and ReactIR 15 in-situ probes were used in the reactive crystallizer to measure chord length distribution and to determine reactant concentration and reaction yield. PAT was also used in the resuspension unit to determine chord length distribution of the API crystals and reactant/solvent content in the resuspended slurry. In-situ NIR and raman methods were used to measure residual solvents, content uniformity of the API in the polymer melt and crystal form/crystallinity.  

Continuous Crystallization, Milling and Annealing System

Automated Reactors and In-Situ PAT Probes Aid in Providing Targeted Crystal Size Distribution

Meng, W., Sirota, E., Feng, H., McMullen, J. P., Codan, L., & Cote, A. S. (2020). Effective Control of Crystal Size via an Integrated Crystallization, Wet Milling, and Annealing Recirculation System. Organic Process Research & Development, 24(11), 2639–2650. https://doi.org/10.1021/acs.oprd.0c00307

The authors report the development of a novel, continuous system designed to produce an API product with a target crystal size distribution. The system integrates crystallization, wet milling and annealing functions resulting in a continuous process, effectively narrowing crystal size distribution. PAT was integrated into the crystallizer and annealing vessels to support the system and related QbD objectives. ReactIR with an ATR-FTIR probe was used in both vessels to monitor the liquid phase concentration and provide information regarding supersaturation state. ParticleTrack FBRM probes were used in both vessels to provide insight into nucleation and crystal growth and to control nucleation in support of achieving the target crystal size. An OptiMax automated lab reactor was used as the crystallizer and the annealing vessel was controlled by a RX-10 jacketed reactor automation system to manage temperature and agitation rate. ​

The article's findings show that careful selection of mill configuration and milling speed aide in modifying the crystal size while retaining size uniformity. They also demonstrate the importance of finding the optimum annealing temperature to narrow size distribution. Desupersaturation profiles obtained via ReactIR showed that additional solids were dissolved after elevating the slurry temperature and that increased milling speed yielded smaller particles, thus facilitating desupersaturation.  ​

Process Safety in the Pharmaceutical Industry

Thermal and Reaction Hazard Evaluation Processes and Techniques

Allian, A. D., Shah, N. P., Ferretti, A. C., Brown, D. B., Kolis, S. P., & Sperry, J. B. (2020). Process Safety in the Pharmaceutical Industry—Part I: Thermal and Reaction Hazard Evaluation Processes and Techniques. Organic Process Research & Development, 24(11), 2529–2548. https://doi.org/10.1021/acs.oprd.0c00226

This article reports the findings of an in-depth survey given to several pharmaceutical companies within the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), with the goal of fostering collaboration and understanding of the participating companies’ procedures and assessment regarding process safety.​

​The results presented summarize general issues around different tools used to assess thermal hazard risks and questions regarding staffing and tech transfer of process safety data/information across all stages of chemical process development. The article additionally provides insight into how different assessment strategies are employed at different stages of development (e.g., early, mid and late phase).

Citations and References

Chemical Process Development and Scale-Up in Journal Publications

  • Yerdelen, S., Yang, Y., Quon, J. L., Papageorgiou, C. D., Mitchell, C., Houson, I., Sefcik, J., Ter Horst, J. H., Florence, A. J., & Brown, C. J. (2023). Machine Learning-Derived Correlations for Scale-Up and Technology Transfer of Primary Nucleation Kinetics. Crystal Growth & Design, 23(2), 681–693. https://doi.org/10.1021/acs.cgd.2c00192
  • De Oliveira, R. M. S. (2022, June 1). Process development to prepare sensitive active pharmaceutical ingredients enabled by flow chemistry and modeling. https://repositorio.ul.pt/handle/10451/54901
  • Fava, E., Karlsson, S., & Jones, M. L. (2022). Using Oxygen as the Primary Oxidant in a Continuous Process: Application to the Development of an Efficient Route to AZD4635. Organic Process Research and Development, 26(4), 1048–1053. https://doi.org/10.1021/acs.oprd.1c00279
  • Lomont, J. P., Ralbovsky, N. M., Guza, C., Saha-Shah, A., Burzynski, J., Konietzko, J., Wang, S. C., McHugh, P. M., Mangion, I., & Smith, J. P. (2022). Process monitoring of polysaccharide deketalization for vaccine bioconjugation development using in situ analytical methodology. Journal of Pharmaceutical and Biomedical Analysis, 209. https://doi.org/10.1016/j.jpba.2021.114533
  • Marçon, H. M., & Pastre, J. C. (2022). Continuous flow Meerwein-Ponndorf-Verley reduction of HMF and furfural using basic zirconium carbonate. RSC Advances, 12(13), 7980–7989. https://doi.org/10.1039/d2ra00588c
  • Marzijarani, N. S., Fine, A., Dalby, S. M., Gangam, R., Poudyal, S., Behre, T., Ekkati, A. R., Armstrong, B. A., Shultz, C. S., Dance, Z. E. X., & Stone, K. H. (2021). Manufacturing Process Development for Belzutifan, Part 4: Nitrogen Flow Criticality for Transfer Hydrogenation Control. Organic Process Research & Development, 26(3), 533–542. https://doi.org/10.1021/acs.oprd.1c00231
  • Morin, M. A., Zhang, W., Mallik, D., & Organ, M. G. (2021). Sampling and Analysis in Flow: The Keys to Smarter, More Controllable, and Sustainable Fine-Chemical Manufacturing. In Angewandte Chemie - International Edition (Vol. 60, Issue 38, pp. 20606–20626). John Wiley and Sons Inc. https://doi.org/10.1002/anie.202102009
  • Smith, J. P., Obligacion, J. V., Dance, Z. E. X., Lomont, J. P., Ralbovsky, N. M., Bu, X., & Mann, B. F. (2021). Investigation of Lithium Acetyl Phosphate Synthesis Using Process Analytical Technology. In Organic Process Research and Development (Vol. 25, Issue 6). https://doi.org/10.1021/acs.oprd.1c00091
  • Javier, S. R. (2021). Process development for the synthesis at industrial scale of active pharmaceutical ingredients. Dipòsit Digital De Documents De La UAB. https://ddd.uab.cat/record/243852
  • Allian, A. D., Shah, N. P., Ferretti, A. C., Brown, D. B., Kolis, S. P., & Sperry, J. B. (2020). Process Safety in the Pharmaceutical Industry—Part I: Thermal and Reaction Hazard Evaluation Processes and Techniques. Organic Process Research & Development, 24(11), 2529–2548. https://doi.org/10.1021/acs.oprd.0c00226​
  • Malig, T. C., Tan, Y., Wisniewski, S. R., Higman, C. S., Carrasquillo-Flores, R., Ortiz, A., Purdum, G. E., Kolotuchin, S., & Hein, J. E. (2020). Development of a telescoped synthesis of 4-(1H)-cyanoimidazole core accelerated by orthogonal reaction monitoring. Reaction Chemistry & Engineering, 5(8), 1421–1428. https://doi.org/10.1039/d0re00234h​
  • Ma, Y., Wu, S., Macaringue, E. G. J., Zhang, T., Gong, J., & Wang, J. (2020). Recent Progress in Continuous Crystallization of Pharmaceutical Products: Precise Preparation and Control. Organic Process Research & Development, 24(10), 1785–1801. https://doi.org/10.1021/acs.oprd.9b00362​
  • Meng, W., Sirota, E., Feng, H., McMullen, J. P., Codan, L., & Cote, A. S. (2020). Effective Control of Crystal Size via an Integrated Crystallization, Wet Milling, and Annealing Recirculation System. Organic Process Research & Development, 24(11), 2639–2650. https://doi.org/10.1021/acs.oprd.0c00307​
  • Ładosz, A., Kuhnle, C., & Jensen, K. F. (2020). Characterization of reaction enthalpy and kinetics in a microscale flow platform. Reaction Chemistry & Engineering, 5(11), 2115–2122. https://doi.org/10.1039/d0re00304b​
  • Dennehy, O. C., Lynch, D., Collins, S. G., Maguire, A. R., & Moynihan, H. A. (2020). Scale-up and Optimization of a Continuous Flow Synthesis of an α-Thio-β-chloroacrylamide. Organic Process Research & Development, 24(10), 1978–1987. https://doi.org/10.1021/acs.oprd.0c00079​
  • Lim, J. J., Arrington, K., Dunn, A. L., Leitch, D. C., Andrews, I., Curtis, N. R., Hughes, M. J., Tray, D. R., Wade, C. E., Whiting, M. P., Goss, C., Liu, Y. C., & Roesch, B. M. (2019). A Flow Process Built upon a Batch Foundation—Preparation of a Key Amino Alcohol Intermediate via Multistage Continuous Synthesis. Organic Process Research & Development, 24(10), 1927–1937. https://doi.org/10.1021/acs.oprd.9b00478​
  • Hu, C., Testa, C. J., Wu, W., Shvedova, K., Shen, D. E., Sayin, R., Halkude, B. S., Casati, F., Hermant, P., Ramnath, A., Born, S. C., Takizawa, B., O’Connor, T. F., Yang, X., Ramanujam, S., & Mascia, S. (2020). An automated modular assembly line for drugs in a miniaturized plant. Chemical Communications, 56(7), 1026–1029. https://doi.org/10.1039/c9cc06945c​
  • Power, M., Alcock, E., & McGlacken, G. P. (2020). Organolithium Bases in Flow Chemistry: A Review. Organic Process Research & Development, 24(10), 1814–1838. https://doi.org/10.1021/acs.oprd.0c00090​
  • de Souza, J. M., Berton, M., Snead, D. R., & McQuade, D. T. (2020). A Continuous Flow Sulfuryl Chloride-Based Reaction—Synthesis of a Key Intermediate in a New Route toward Emtricitabine and Lamivudine. Organic Process Research & Development, 24(10), 2271–2280. https://doi.org/10.1021/acs.oprd.0c00146​
  • ​Testa, C. J., Hu, C., Shvedova, K., Wu, W., Sayin, R., Casati, F., Halkude, B. S., Hermant, P., Shen, D. E., Ramnath, A., Su, Q., Born, S. C., Takizawa, B., Chattopadhyay, S., O’Connor, T. F., Yang, X., Ramanujam, S., & Mascia, S. (2020). Design and Commercialization of an End-to-End Continuous Pharmaceutical Production Process: A Pilot Plant Case Study. Organic Process Research & Development, 24(12), 2874–2889. https://doi.org/10.1021/acs.oprd.0c00383​
  • Cao, Y., Du, S., Ke, X., Xu, S., Lan, Y., Zhang, T., Tang, W., Wang, J., & Gong, J. (2020). Interplay between Thermodynamics and Kinetics on Polymorphic Behavior of Vortioxetine Hydrobromide in Reactive Crystallization. Organic Process Research & Development, 24(7), 1233–1243. https://doi.org/10.1021/acs.oprd.9b00384​
  • Dimitri Skliar, Jeffrey Nye, Antonio Ramirez, “Use of Process Analytical Technology (PAT) in Small Molecule Drug Substance Reaction Development”, 2019, https://doi.org/10.1002/9781119600800.ch42​
  • Skliar, D., Nye, J., & Ramirez, A. (2019). Use of Process Analytical Technology (PAT) in Small Molecule Drug Substance Reaction Development. Chemical Engineering in the Pharmaceutical Industry, 937–955. https://doi.org/10.1002/9781119600800.ch42​
  • ​Yang, Q., Sane, N., Klosowski, D., Lee, M., Rosenthal, T., Wang, N. X., & Wiensch, E. (2019). Mizoroki–Heck Cross-Coupling of Bromobenzenes with Styrenes: Another Example of Pd-Catalyzed Cross-Coupling with Potential Safety Hazards. Organic Process Research & Development, 23(10), 2148–2156. https://doi.org/10.1021/acs.oprd.9b00126​
  • Yu, M., Strotman, N. A., Savage, S. A., Leung, S., & Ramirez, A. (2019). A Practical and Robust Multistep Continuous Process for Manufacturing 5-Bromo-N-(tert-butyl)pyridine-3-sulfonamide. Organic Process Research & Development, 23(9), 2088–2095. https://doi.org/10.1021/acs.oprd.9b00254​
  • Strotman, N. A., Tan, Y., Powers, K. W., Soumeillant, M., & Leung, S. W. (2018). Development of a Safe and High-Throughput Continuous Manufacturing Approach to 4-(2-Hydroxyethyl)thiomorpholine 1,1-Dioxide. Organic Process Research & Development, 22(6), 721–727. https://doi.org/10.1021/acs.oprd.8b00100​
  • Maher, A., Hodnett, B. K., Coughlan, N., O’Brien, M., & Croker, D. M. (2018). Application of New Technology to a Mature Piroxicam Crystallization Process To Gain Process Understanding and Control, via Industrial–Academic Collaboration. Organic Process Research & Development, 22(3), 306–311. https://doi.org/10.1021/acs.oprd.7b00347​
  • Yang, Q., Cabrera, P. J., Li, X., Sheng, M., & Wang, N. X. (2018). Safety Evaluation of the Copper-Mediated Cross-Coupling of 2-Bromopyridines with Ethyl Bromodifluoroacetate. Organic Process Research & Development, 22(10), 1441–1447. https://doi.org/10.1021/acs.oprd.8b00261​
  • Taylor, B., Fernandez Barrat, C., Woodward, R. L., & Inglesby, P. A. (2017). Synthesis of 2-Oxopropanethioamide for the Manufacture of Lanabecestat: A New Route for Control, Robustness, and Operational Improvements. Organic Process Research & Development, 21(9), 1404–1412. https://doi.org/10.1021/acs.oprd.7b00170​
  • Leitch, D. C., John, M. P., Slavin, P. A., & Searle, A. D. (2017). An Evaluation of Multiple Catalytic Systems for the Cyanation of 2,3-Dichlorobenzoyl Chloride: Application to the Synthesis of Lamotrigine. Organic Process Research & Development, 21(11), 1815–1821. https://doi.org/10.1021/acs.oprd.7b00262​
  • Federsel, H. (2009). Chemical Process Research and Development in the 21st Century: Challenges, Strategies, and Solutions from a Pharmaceutical Industry Perspective. Accounts of Chemical Research, 42(5), 671–680. https://doi.org/10.1021/ar800257v
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