How Continuous Manufacturing is Advancing Bio/Pharma Production

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The forward movement of the bio/pharmaceutical industry is driven by fast-paced advancements in manufacturing technology innovations. As manufacturing technology advances, so does the shift to continuous manufacturing (CM), a process that enables real-time monitoring, improved scalability, and enhanced quality control. As the industry increasingly adopts CM, it is undergoing a transformative shift.

In the current environment, one of the most significant applications of CM is in the production of RNA-based therapeutics, including messenger RNA (mRNA), self-amplifying RNA (saRNA), and circular RNA. In an interview with Aaron Cowley, chief scientific officer at ReciBioPharm (1), Cowley noted how industry leaders have spearheaded the development of CM platforms for RNA manufacturing with funding from FDA. These CM platforms hold the promise of significantly increasing production efficiency while maintaining rigorous quality standards.

Influence of the COVID-19 pandemic

In particular, the COVID-19 pandemic sharply highlighted the necessity of having rapid and scalable RNA manufacturing to meet global vaccine demand at the time. Traditional batch manufacturing poses bottlenecks that hinder timely drug availability. In comparison, CM integrates all unit operations into a seamless and continuous process and allows for real-time release and significant reduction in production timelines (2).

One of the key advantages of CM in RNA therapeutics is its ability to maintain small-scale yet high-throughput production. And, unlike monoclonal antibodies or conventional biologics that require thousands of liters in bioreactors, RNA production runs at much smaller scales—typically a few hundred milliliters to several liters per batch (3). CM becomes an ideal approach to tackling production of RNA-based products because it facilitates rapid adaptation and scale-up while at the same time minimizing waste and inefficiencies.

A significant innovation in CM for RNA therapeutics is the integration of in-vitro transcription (IVT) into a continuous process. Traditionally, IVT reactions are performed in batch mode, in which RNA synthesis is followed by downstream purification and formulation. But the continuous integration of IVT with purification and fill/finish operations allows for real-time monitoring and control, which leads to enhanced product consistency and yield (4).

“Being able to have eyes on the process and the product as it goes along, the full train of manufacturing, and be able to release that real time—is the overall goal that we are after,” said Cowley in the interview (1), explaining that if another pandemic comes along there won’t be a bottleneck in manufacturing, and that an RNA-based vaccine, for example, will be available and the manufacturing process will still be able to produce extra material.

Highly potent APIs

On the small-molecule side, there is a trend toward higher potency and smaller dosing of APIs as, for the past 20 years, development and innovation in the pharma industry have focused on patient safety, meaning product quality, while also addressing cost efficiency and promoting greater sustainability, says Guia Bertuzzi, product manager of processing equipment for oral solid dosage (OSD) at IMA Active, the specialized division of the Italian company IMA Group.

“Modernizing the pharmaceutical industry requires both a more robust drug formulation design and better control of the production process, ensuring the highest quality and availability of the drug throughout its entire life cycle,” Bertuzzi states, adding that, “This concept strongly aligns with the adoption of the quality-by-design (QbD) approach, which prioritizes quality in drug development, as recommended by regulatory authorities. Furthermore, it paves the way for CM and other emerging technologies.”

Bertuzzi points to how CM fully supports the growing trend toward low-dose OSD forms and the increasing need for process containment and accuracy in quality control. “By definition, CM systems are designed for high-containment processes: they are typically compact, closed systems with a smaller process surface compared to batch manufacturing systems of equivalent productivity,” she explains. “Additionally, CM enables the integration of different production technologies in series, allowing for an uninterrupted material flow, from raw materials to the final pharmaceutical form, within a closed system that eliminates the need for product transfers between equipment, thereby minimizing the risk of product leakage.”

Because the CM process is continuously monitored in real-time with advanced instrumentation and an advanced control philosophy (i.e., process analytical technology [PAT]), the critical quality attributes (CQAs) of the product is also instantly monitored, allowing for increased sampling frequency without requiring physical sample collection, Bertuzzi states.

Modular and flexible manufacturing systems

The flexibility of CM, meanwhile, allows for modular process design, which enables manufacturers to switch between different modalities without major overhaul of infrastructure. The ability to switch between modalities is particularly important in RNA manufacturing as RNA therapeutics expand beyond vaccines to include gene therapies, cancer immunotherapies, and rare disease treatments. Having the ability to modify purification steps—such as adjusting the number of chromatography columns (based on impurity profiles)—will ensure that different RNA therapeutics can be produced efficiently and on a single platform (5).

Future of CM and challenges

However, despite the advantages that CM has demonstrated so far, the transition from traditional manufacturing to fully CM processes will continue to present challenges. Small and medium-sized enterprises (SMEs) will particularly face obstacles, including high initial investment costs, integration complexities, and the need for specialized expertise—factors that remain barriers to widespread adoption.

“Adopting CM requires a significant initial effort, including cultural and organizational changes within most pharmaceutical companies,” Bertuzzi says. “A company looking to implement CM must adequately prepare and structure itself. Beyond simply acquiring and integrating machinery in series, production and quality must be designed with a QbD approach, incorporating a higher level of automation and ensuring seamless integration between various technologies. This necessitates a strong orientation toward digitalization.”

Continuous manufacturing has gained increasing recognition by regulatory agencies such as FDA and the International Council for Harmonisation (ICH), which acknowledge CM’s potential and have issued guidelines (e.g., ICH Q13) to facilitate implementation (6).

“The drive toward CM will undoubtedly intensify due to the recent publication of regulatory guidelines (ICH Q13, FDA Q13, etc.) by major global authorities. Additionally, ongoing global challenges—such as pandemics, wars, and raw material shortages—further highlight the need for more efficient and resilient manufacturing processes,” Bertuzzi emphasizes.

Overcoming the challenges to full CM adoption will require strategic collaborations between biopharmaceutical companies, contract manufacturing organizations/contract development and manufacturing organizations, and technology providers. These collaborations will be crucial moving forward. In addition, standardization of CM technology platforms, especially those that incorporate modular automation, AI-driven process control, and cloud-based data analytics, will further enable CM adoption (7).

“From an equipment vendor’s perspective, we are actively driving the transition toward CM, particularly for SMEs, by providing process engineering support to facilitate adoption and implementation,” adds Bertuzzi.

References

1. Spivey, C. Biopharma’s Progress with Continuous Manufacturing in mRNA (BIO 2024). BioPharmInternational.com, Sept. 27, 2024.
2. Plumb, K. Continuous Processing in the Pharmaceutical Industry. Chem. Eng. Res. Des. 2005, 83 (A6), 730–738.
3. Kempf, H.; et al. RNA Manufacturing and Process Development: Current Trends and Future Outlook. Trends Biotechnol. 2020, 38 (10), 1168–1180.
4. Karmakar, S.; et al. Continuous Manufacturing of RNA Therapeutics: Opportunities and Challenges. Biotechnol. Adv. 2022, 53, 107840.
4. Uhl, P.; et al. Flexible Manufacturing Strategies for RNA-Based Therapeutics. Mol. Ther. 2021, 29 (7), 1982–1997.
5. FDA. Guidance for Industry, ICH Q13 Continuous Manufacturing of Drug Substances and Drug Products (CDER, March 2023).
6. Konakovsky, S.; et al. Smart Manufacturing Approaches for Continuous Biopharmaceutical Production. Curr. Opin. Biotechnol. 2022, 74, 100–108.

About the author

Feliza Mirasol is science editor at Pharmaceutical Technology®.

Article details

Pharmaceutical Technology®
Vol. 49, No. 2
March 2025
Pages: 24–26

Citation

When referring to this article, please cite it as Mirasol, F. How Continuous Manufacturing is Advancing Bio/Pharma Production. Pharmaceutical Technology 2025, 49 (2), 24–26.