From batch to continuous flow production: A current trend in the pharmaceutical industry

Continuous flow manufacturing (CFM), also known as microfluidics, is a growing trend in the pharmaceutical industry with key pharmaceutical companies such as Pfizer, Novartis, Merck, Eli Lilly, GSK, and Sanofi, investing in this technology (Burcham et al., 2018). Continuous flow manufacturing of active pharmaceutical ingredients (API) has been extensively studied by world-renowned academic research groups, with significant process improvements. Thus leading pharmaceutical companies to follow suit and adopt the technology (Plutschack et al., 2017). A report published by the World Economic Forum (WEF) in November 2021 called CFM one of the top 10 emerging technologies in the 21st century (Gérardy et al., 2018). In this article, we discuss the multiple advantages offered by CFM and its widespread adoption in the pharmaceutical industry.

What is continuous flow manufacturing?

Unlike traditional batch processing, continuous flow manufacturing allows pharmaceutical companies to manufacture drugs continuously and without interruption. The past century has seen API being produced using traditional batch technology, whereby discrete amounts of material are produced one step at a time - called a batch - before moving on to the next stage. On the other hand, the continuous manufacturing process involves continuously feeding materials into a reactor or machine where they are transformed and continuously collected. In this method, advanced technologies and automated systems are used to create a much faster more efficient, higher-quality manufacturing process (Figure 1). As well as being more environmentally friendly, the use of continuous-flow manufacturing reduces the risk of contamination and any potential human error (Booth et al., 2023). With its expanded use it is fair to say that this technology will become the standard manufacturing practice in the near future.

Figure 1: Integrated continuous flow manufacturing (credit: Shutterstock)

Advantages offered by continuous flow manufacturing

1. Process modernization: In comparison to step-by-step batch-based conventional processing, CFM offers a streamlined, integrated process. With this shift, batch manufacturing procedures such as setup, cleaning, and changeover are no longer necessary. This results in faster production cycles that are less labor-intensive, more efficient, and more economical (Porta et al., 2015).

2. Enhanced productivity: Continuous flow manufacturing offers substantial benefits, including reduced production cycle times which in turn enhances overall productivity. Manufacturers can maximize equipment utilization and throughput by eliminating batch-related downtimes. Consequently, labor requirements are reduced, resources are more efficiently utilized, and process efficiency is improved (Porta et al., 2015).

3. Improved quality standards: Process parameters can be monitored and controlled in real time with CFM. As a result, manufacturers can maintain consistent quality throughout the production process, which reduces variability and reduces the risk of defects or batch failures. Enhanced traceability is also enabled by the continuous flow of materials. As a result, quality issues can be identified and mitigated much more rapidly (Dallinger & Kappe, 2017).

4. Drug discovery and development: Significant advantages are seen in utilizing CFM in the drug development process and formulation development. Specifically pharmaceutical companies can reduce costs and save time, which in turn allows them to bring their drug products to the market faster. Secondly, rapid screening of various formulation iterations, drug delivery systems, and real-time product quality assessments can be tested when using CFM (Hughes, 2020).

5. Simplified scaling: Flexible scaling options with different batch sizes are allowed when using continuous flow technologies. Manufacturing processes can easily be adjusted to meet the changing demands of the market, enabling more efficient production, planning, and reduced risk of overcompensation. This advantage is valuable for companies to respond to fluctuating market demands, and optimize supply chain management. This, in turn, reduces cost and waste burdens typically identified in the pharmaceutical industry.

6. Regulatory challenges associated with technology adoption: Regulatory agencies have recognized the potential of utilizing continuous flow technologies in the pharmaceutical industry, particularly in improving product quality, reducing manufacturing costs, and improving supply chain resilience. However, in order to transition from batch manufacturing to CFM, specific challenges must be overcome. For seamless integration and regulatory approval, manufacturers must consider process validation, regulatory compliance, technology transfer, and data management.

7. Forward patient healthcare: The use of continuous manufacturing has the potential to positively impact patient outcomes. A reliable supply of critical medications can be guaranteed with faster production cycles and greater process efficiency. As an added benefit, continuous manufacturing would enable the production of personalized medicines and dosage forms tailored to individual patient needs, resulting in improved therapeutic outcomes and patient compliance (Figure 2).

Figure 2: Patient forward healthcare (credit: Shutterstock)

Adoption of continuous manufacturing by various pharmaceutical companies

In 2015, Orkambi, a Vertex Pharmaceuticals' cystic fibrosis (CF) treatment, became the first FDA-approved drug manufactured using continuous flow protocols under current good manufactured practices - cGMP (Kleinebudde et al., 2017), and in 2018, the company continued to use similar manufacturing processes for its second CF treatment, Symdeko. Similarly, in 2017, Eli Lilly & Company manufactured a cancer-treating agent, Prexaserib, under cGMP standards utilizing CFM (Cole et al., 2017). Eight continuous unit operations were conducted to produce the target at roughly three kilograms per day. A combination of advances in chemistry, engineering, analytical science, process modeling, and equipment design contributed to the success of the process

Following these successes, the president of the United States, Joseph R. Biden, signed an executive order aimed at ensuring economic prosperity and national security, by building resilient, diverse, and secure supply chains. This report lists investing in the development of new pharmaceutical manufacturing processes and specifically mentions the use of continuous-flow manufacturing technologies (Gérardy et al., 2018). Shortly after in 2021, Pfizer announced the release of the highly anticipated Pfizer-BioNtech Covid-19 vaccine, using CFM to accelerate the production of the drug. Pfizer developed a continuous technique enabling the control of the encapsulation of mRNA in lipid nanoparticles (LNPs), ensuring a rapid, stable formulation that is distributed and administered globally to this day (Figure 3).

Figure 3: Thermo Fischer Scientific, Monza production facility

Novartis is among the pharmaceutical companies that have followed suit. In collaboration with the Massachusetts Institute of Technology (MIT), Novartis demonstrated an end-to-end continuous flow production of Aliskiren hemifumarate tablets, a drug substance used to treat hypertension. The formulated tablets were produced in a fully continuous process, from the API starting material to the final drug product. Furthermore, they demonstrated the production of the API at a rate of 45 g/h, in a production facility with a footprint of approximately 18 square meters (Burcham et al., 2018).

Concluding remarks

Manufacturing API on a continuous basis could revolutionize the process of developing, manufacturing and delivering drugs to patients. The use of this technology has already led to a paradigm shift in the pharmaceutical industry, but it will likely take some time before the industry fully adopts these new technologies. Nevertheless, it offers significant benefits in terms of output efficiency, cost reductions, quality standards, and patient-centricity.

Bibliographic references

Booth, A., Jager, A., Faulkner, S. D., Winchester, C. C., & Shaw, S. E. (2023). Pharmaceutical company targets and strategies to address climate change: Content analysis of public reports from 20 pharmaceutical companies. International Journal of Environmental Research and Public Health, 20(4). https://doi.org/10.3390/ijerph20043206 Burcham, C. L., Florence, A. J., & Johnson, M. D. (2018). Continuous manufacturing in pharmaceutical process development and manufacturing. Annual Review of Chemical and Biomolecular Engineering 9, 253-281. https://doi.org/10.1146/annurev-chembioeng-060817-084355 Cole, K. P., Groh, J. M., Johnson, M. D., Burcham, C. L., Campbell, B. M., Diseroad, W. D., Heller, M. R., Howell, J. R., Kallman, N. J., & Koenig, T. M. (2017). Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions. Science, 356(6343), 1144-1150. https://doi.org/10.1126/science.aan0745 Dallinger, D., & Kappe, C. O. (2017). Why flow means green–Evaluating the merits of continuous processing in the context of sustainability. Current Opinion in Green and Sustainable Chemistry, 7, 6-12. https://doi.org/10.1016/j.cogsc.2017.06.003 Gérardy, R., Emmanuel, N., Toupy, T., Kassin, V. E., Tshibalonza, N. N., Schmitz, M., & Monbaliu, J. C. M. (2018). Continuous flow organic chemistry: Successes and pitfalls at the interface with current societal challenges. European Journal of Organic Chemistry, 2018(20-21), 2301-2351. https://doi.org/10.1002/ejoc.201800149 Hughes, D. L. (2020). Applications of flow chemistry in the pharmaceutical industry - Highlights of the recent patent literature. Organic Process Research & Development, 24(10), 1850-1860. https://doi.org/10.1021/acs.oprd.0c00156 Kleinebudde, P., Khinast, J., & Rantanen, J. (2017). Continuous manufacturing of pharmaceuticals. John Wiley & Sons. Neyt, N. C., & Riley, D. L. (2021). Application of reactor engineering concepts in continuous flow chemistry: a review. Reaction Chemistry & Engineering, 6(8), 1295-1326. https://doi.org/10.1039/d1re00004g Plutschack, M. B., Pieber, B., Gilmore, K., & Seeberger, P. H. (2017). The hitchhiker's guide to flow chemistry parallel. Chemical Reviews, 117(18), 11796-11893. https://doi.org/10.1021/acs.chemrev.7b00183 Porta, R., Benaglia, M., & Puglisi, A. (2015). Flow chemistry: Recent developments in the synthesis of pharmaceutical products. Organic Process Research & Development, 20(1), 2-25. https://doi.org/10.1021/acs.oprd.5b00325

Visual sources

Cover image: Neyt, N. C., & Riley, D. L. (2021). Application of reactor engineering concepts in continuous flow chemistry: a review. Reaction Chemistry & Engineering, 6(8), 1295-1326. https://doi.org/10.1039/d1re00004g

Figure 1: Integrated continuous flow manufacturing (credit: Shutterstock) (2023). [Illustration]. Retrieved June 13, 2023 from https://www.shutterstock.com/image-vector/thin-line-flat-design-internet-website-311573924

Figure 2: Patient forward healthcare (credit: Shutterstock) (2023). [Illustration]. Retrieved June 13, 2023 from https://www.shutterstock.com/image-photo/female-chemist-doctor-tapping-on-digital-2078558725

Figure 3:Thermo Fischer Scientific, Monza production facility. Retrieved June 13, 2023 https://www.pfizer.com/news/articles/shot_of_a_lifetime_how_pfizer_is_partnering_with_cmos_to_increase_covid_19_vaccine_production_and_reach_more_people