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Home By Application AutoChem Applications Continuous Flow Chemistry PAT for Pharmaceutical Continuous Manufacturing (PCM)

Pharmaceutical Continuous Manufacturing (PCM) with PAT

The Key to Successful Continuous Manufacturing

Pharmaceutical continuous manufacturing (PCM) is a process where raw materials continuously enter the production line, enabling the uninterrupted, high-quality production of finished products without hold times. All testing and processing steps are performed inline. This continuous approach contrasts sharply with traditional batch production methods, which currently dominate drug manufacturing.

Unlike batch manufacturing, which treats pharmaceutical production as a series of distinct, siloed events, continuous processes execute all reaction chemistry, testing, and final processing inline. Process analytical technology (PAT) is a critical component of successful continuous production, ensuring in-process quality and regulatory compliance.

Pharmaceutical continuous manufacturing PAT

PAT—The Key to Successful Continuous Manufacturing

Process analytical technology (PAT) continuously monitors critical process parameters (CPPs) and critical quality attributes (CQAs) in real time. This ensures process operations remain reliable and stable, supporting a Quality by Design (QbD) strategy. When performance variations occur, PAT enables rapid detection and identification of the source, allowing issues to be addressed before rework or product rejection.

By eliminating hold times associated with offline analysis, PAT significantly enhances efficiency. Continuous Process Verification (CPV) facilitates ongoing process evaluation, enabling real-time product release. Additionally, PAT contributes to increased capacity and cost reduction through more efficient use of energy and materials.

PAT is also crucial in process development. Developing effective continuous flow chemistry is a key step towards continuous manufacturing, and PAT methods are extensively used to determine and optimize flow chemistry conditions. One major advantage of continuous flow chemistry is process intensification via telescoping reaction sequences, where PAT plays a vital role. Kinetic modeling leverages the rich data provided by PAT to achieve substantial gains in efficiency and deepen understanding of complex chemistry.

PAT Supporting Pharmaceutical Continuous Manufacturing (PCM)

PAT Supporting Pharmaceutical Continuous Manufacturing (PCM)

PAT Supporting Pharmaceutical Continuous Manufacturing (PCM)

The FDA endorses continuous manufacturing through science- and risk-based approaches. METTLER TOLEDO offers advanced technologies designed to facilitate the successful implementation of continuous pharmaceutical manufacturing.

Continuous Flow Micro Cell

Real-Time Monitoring and Control for Continuous Flow Chemistry

Process analytical technology (PAT) constitutes a pivotal component within pharmaceutical continuous manufacturing (PCM) frameworks, facilitating real-time, in-situ surveillance and regulation of critical process parameters (CPPs). This capability underpins enhanced product quality assurance and process consistency by enabling timely adjustments and comprehensive understanding of process dynamics. METTLER TOLEDO inline PAT instruments exemplify this paradigm, providing robust, precise measurement solutions that seamlessly integrate into continuous processing environments. Advanced sensors and analyzers afford high-resolution data acquisition, supporting dynamic control strategies essential for optimizing process performance and ensuring compliance with stringent quality standards:
  • ReactIR™ – Real-time FTIR analysis within the process stream using versatile flow cell or probe configurations.
  • ReactRaman™ – Continuous inline and online Raman spectroscopy to monitor molecular changes via flow cell or probe setups.
  • DirectInject-LC™ – Real-time, online HPLC analysis through fully automated sampling and injection.
  • EasyViewer™ – In-situ microscopic image analysis of crystal formation and particle characteristics during processes.
  • Dynochem® – Kinetic modeling software covering various individual operations to accelerate chemical process development, scale-up, and optimization.

PAT-Enabled Automated Feedforward Control: An Application to the Continuous Manufacture of Apremilast.

Hsieh, H-W, Griffin, D.J. Nambiar, A.M.K., Sarkar, N., Ismail, H.Y., Saigal, K., Shen, D.E., Goudas-Salomon, N., Wimalasinghe, R., Zeng, A., Thiel, O.R. and Beaver, M.G. (2024). PAT-Enabled automated feedforward control: An application to the continuous manufacture of Apremilast. Org. Process Res. Dev., 28(7), 2844–2853. https://doi.org/10.1021/acs.oprd.4c00155

Scientists at Amgen developed a continuous manufacturing process for the final step in the synthesis of apremilast. This work describes a closed-loop controller utilizing two ReactIR PAT systems to monitor incoming feed concentrations. By adjusting the feed flow rate based on real-time data, the system maintains optimal yield during continuous production. This lab-scale setup simulates a manufacturing platform and demonstrates the value and requirements of PAT-based closed-loop control in continuous processes.

Continuous Flow Reaction Of Highly Exothermic Reaction

Integrated Continuous Crystallization–Spherical Agglomeration (CCSA) Process for the Intensified Manufacturing of Atorvastatin Calcium

Parvaresh, R., Ferdoush, S., Kshirsagar, S., Gonzalez, M. and Nagy, Z.K. (2024). Integrated continuous crystallization–Spherical agglomeration (CCSA) process for the intensified manufacturing of atorvastatin calcium. Crystal Growth & Design, 24(12), 5355-5364. https://doi.org/10.1021/acs.cgd.4c00587

This article details a two-stage continuous MSMPR system integrating continuous crystallization with spherical agglomeration to improve atorvastatin calcium (ASC) crystallization. Three interconnected vessels carry out sequential steps: the first holds ASC/methanol mother liquor, the second crystallizes ASC, and the third performs agglomeration using ethylene chloride. FBRM probes provide real-time particle formation and agglomeration monitoring. Decoupling nucleation and growth from agglomeration enhances particle size and morphology, improving downstream processing efficiency and enabling the elimination of certain steps like granulation. The intensified process allows customization of product properties for maximum bioavailability and processing efficiency.

FTIR Spectroscopy for Flow Chemistry

FTIR Spectroscopy for Flow Chemistry

Journal Articles to Review Before Developing Your Continuous Process

Acid Catalyzed Transfer Hydrogenation

Acid Catalyzed Transfer Hydrogenation

Continuous-flow Catalytic Asymmetric Hydrogenations: Reaction Optimization Using FTIR Inline Analysis

Reaction Analysis Guide

Real-Time Reaction Analysis Guide

A Guide Reviewing the Advantages and Importance of Real-Time Reaction Analysis—A Key Element in Any PAT Strategy

Flow Chemistry as a Powerful Tool to Enable the Scale-up of APIs

Webinar: Flow Chemistry as a Powerful Tool to Enable the Scale-up of APIs

This webinar reviews how a continuous flow process was developed as a safe, cost-effective, and scal...

Flow and Batch Chemistry Monitoring

Flow and Batch Chemistry Monitoring

Charles Goss presents examples illustrating how GlaxoSmithKline (GSK) monitors flow and batch chemis...

The Power of PAT at Scale in an API Pilot Plant

The Power of PAT at Scale in an API Pilot Plant

James Marek and Eric Moschetta of AbbVie present "The Power of PAT at Scale in an API Pilot Plant".

continuous flow chemistry for api manufacturing

Continuous Flow Chemistry for API Manufacturing

Presented by Dr. Frederic Buono of Boehringer-Ingelheim, this on-demand webinar reviews continuous f...

Continuous Flow Chemistry Using PAT

Development of Continuous Flow Chemistry Using Online PAT Analysis

Eric Fang of Snapdragon discusses how continuous flow chemistry is applicable across the entire valu...

Continuous Flow Process Optimization and Control Using Multiple Orthogonal PAT

Webinar: Continuous Flow Process Optimization and Control Using Multiple Orthogonal PAT

In this webinar, we will introduce a modular system created using a standard Vapourtec platform coup...

What is continuous manufacturing in pharmaceuticals?

Pharmaceutical continuous manufacturing (PCM) is a process where raw materials continuously enter a production line, enabling uninterrupted, high-quality production of finished goods without hold times. All testing and processing steps are performed inline, ensuring seamless operation.

What is the difference between batch and continuous manufacturing in pharmaceuticals?

Batch manufacturing treats pharmaceutical production as a series of separate, discrete events, whereas continuous manufacturing integrates all reaction chemistry, testing, and final processing inline into a streamlined process.

What are the advantages of pharmaceutical continuous manufacturing?

  • Eliminates hold times.
  • Enables rapid response to market changes.
  • Allows execution of complex or hazardous chemistries that are difficult in batch processes.
  • Consolidates production within a single facility, reducing bottlenecks.
  • Reduces operational costs.
  • Achieves higher quality and improved yield.

Why is the use of process analytical technology (PAT) important in PCM?

PAT is critical for pharmaceutical continuous manufacturing as it provides continuous, real-time monitoring, and measurement of Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs). This ensures process reliability and stability while supporting a Quality by Design (QbD) strategy. It enables instant detection of performance variations, identifies their sources, and allows proactive interventions, minimizing rework or rejection of the final product.

Continuous Process Manufacturing in Peer-Reviewed Publications

  1. Liu, P., Jin, H., Chen, Y., Wang, D., Yan, H., Wu, M., Zhao, F. and Zhu, W. (2024). Process analytical technologies and self-optimization algorithms in automated pharmaceutical continuous manufacturing,Chinese Chemical Letters, 35, 3, 108877. https://doi.org/10.1016/j.cclet.2023.108877
  2. Bass, T.M., Zell, D., Kelly, S.M., Malig, T.C., Napolitano, J.G., Sirois, L.E., Han, C. and Gosselin, F. (2024). Scalable Synthesis of 6-Chloro-1H-pyrazolo[3,4-b]pyrazine via a Continuous Flow Formylation/Hydrazine Cyclization Cascade. Organic Process Research & Development. https://doi.org/10.1021/acs.oprd.4c00047
  3. Clarke, A., Panchal, H., Yang, J., Bai, Y. Wu, Y., Sun, J. and Zhou, Z. (2024). Going with the Flow: Implementation of a New Continuous Process for a Selective Acetal Deprotection. Org. Process Res. Dev., 28, 8, 3094–3107. https://doi.org/10.1021/acs.oprd.3c00401
  4. Agrawal, S. Rawal, S.H., Reddy, V.R. and Merritt, J.M. (2024). Use of automation, dynamic image analysis, and process analytical technologies to enable data rich particle engineering efforts at the Drug Substance / Drug Product interface: A case study using Lovastatin. Chemical Engineering Research and Design, 205, 578-590. https://doi.org/10.1016/j.cherd.2024.04.032
  5. Reid, J., Haer, M., Chen, A., Adams, C., Lin, Y. C., Cronin, J., Yu, Z., Kirkitadze, M. and Yuan, T. (2024). Development of automated metabolite control using mid-infrared probe for bioprocesses and vaccine manufacturing. Journal of Industrial Microbiology and Biotechnology, 51. https://doi.org/10.1093/jimb/kuae019
  6. Qin, Y., Mattern, K. A., Zhang, V., Abe, K., Kim, J., Zheng, M., Gangam, R., Kalinin, A., Kolev, J.N., Axnanda, S., Dance, Z. E. X., Ayesa, U., Ji, Y., Grosser, S. T., Appiah-Amponsah, E. and McMullen, J. (2024). Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 4─Applications of Process Analytical Technology in Heterogeneous Biocatalytic Hydroxylation. Organic Process Research & Development, 28, 2, 432-440. https://doi.org/10.1021/acs.oprd.3c00419
  7. Vasilev, M., Gangu, A.S., Gajula, P., Kaetzel, N.D., Natarajan, V., Desai, B., Sirasani, G., Qu, B. and Senanayake, C.H. (2024). Development of Continuous Flow Processes to Access Pyrrolo[2,1-f][1,2,4]triazin-4-amine: An RSM for the Synthesis of Antiviral Drugs. Organic Process Research & Development, 28, 5, 1556-1566. https://doi.org/10.1021/acs.oprd.3c00184
  8. Brown, C.J, McGinty, J., Islam, M.T., Rajoub, N., Arjmandi-Tash, O., Ottoboni, S., Shahid, M., Urwin, S.J., Lee, Y.S., Chong, M.W.S., Papathanasiou, F., Prakash, A.S., Prasad, E., Spence, B., Sefcik, J., Robertson, J. Smith, R., Litster, J.D., J. Price, C.J., Nordon, A., Adjiman, C.S. and Florence, A.J. (2024). Integrated Continuous Process Design for Crystallisation, Spherical Agglomeration, and Filtration of Lovastatin. J Pharm Innov 19, 9. https://doi.org/10.1007/s12247-024-09815-z
  9. Kaldre, D., Stocker, S., Linder, D., Reymond, H., Schuster, A., Lamerz, J., Hildbrand, S., Püntener, K., Berry, M. and Sedelmeier, J. (2023). Development of a Continuous Flow Grignard Reaction to Manufacture a Key Intermediate of Ipatasertib. Org. Process Res. Dev. https://doi.org/10.1021/acs.oprd.3c00235
  10. Lathrop, S.P., Mlinar, L.B., Manjrekar, O.N., Zhou, Y., Harper, K.C., Sacia, E.R., Higgins, M., Bogdan, A.R., Wang, Z., Richter, S.M., Gong, W., Voight, E.A., Henle, J., Diwan, M., Kallemeyn, J.M., Sharland, J.C., Wei, B. and Davies. H.M.L. (2023). Continuous Process to Safely Manufacture an Aryldiazoacetate and Its Direct Use in a Dirhodium-Catalyzed Enantioselective Cyclopropanation. Organic Process Research & Development, 27, 1, 90-104. https://doi.org/10.1021/acs.oprd.2c00288
  11. Armstrong, C., Miyai, Y., Formosa, A., Kaushik, P., Rogers, L. and Roper, T.D. (2023). Leveraging first-principles and empirical models for disturbance detection in continuous pharmaceutical syntheses. J Flow Chem 13, 275–291. https://doi.org/10.1007/s41981-023-00266-0
  12. Lagerman, C.E., Marshall, G.D., McDonald, M.A., Harris, P.R., Grover, M.A. and Rousseau, R.W and Bommarius, A.S. (2023). Magnetic separation of immobilized biocatalyst enables continuous manufacturing with a solids-forming reaction. React. Chem. Eng., 8, 2323-2331. https://doi.org/10.1039/D3RE00214D
  13. Mallia, C.J., McCreanor, N.G., Legg, D.H., Stewart, C.R., Coppock, S., Ashworth, I.W., Le Bars, J., Clarke, A., Clemens, G., Fisk, H., Benson, H., Oke, S., Churchill, T., Hoyle, M., Timms, L., Vare, K., Sims, M. and Knight, S. (2022). Development and Manufacture of a Curtius Rearrangement Using Continuous Flow towards the Large-Scale Manufacture of AZD7648. Organic Process Research & Development, 26(12), 3312–3322. https://doi.org/10.1021/acs.oprd.2c00316
  14. Sacher, S., Castillo, I., Rehrl, J., Sagmeister, P., Lebl, R., Kruisz, J., Celikovic, S., Sipek, M., Williams, J.D., Kirschneck, D., Kappe, C.O. and Horn, M. (2022). Automated and continuous synthesis of drug substances. Chem. Eng. Res Des., 177, 493-501. https://doi.org/10.1016/j.cherd.2021.10.034
  15. Muhaimin, M., Chaerunisaa, A.Y. and Bodmeier, R. (2021). Real-time particle size analysis using focused beam reflectance measurement as a process analytical technology tool for continuous microencapsulation process. Sci Rep 11, 19390. https://doi.org/10.1038/s41598-021-98984-9
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