Myths, Advantages & Challenges of Continuous Manufacturing

By Abhishek Mathur, PhD, MBA (3 mins read)

Continuous manufacturing represents an innovative and progressive alternative to the conventional fed-batch processes, particularly in the production of complex biologics. It entails seamless and uninterrupted processing from initial cell culture to the final drug substance. This innovative approach streamlines the entire production chain, eliminating the need for batch-to-batch transfers and minimizing downtime, thereby enhancing the efficiency and reducing costs. Integration of upstream and downstream operations into a continuous flow also ensures consistent product quality while accelerating time-to-market for life-saving medications.

Five reasons to choose Continuous Manufacturing:

1. Enhanced efficiency & productivity: Continuous manufacturing enhances efficiency and productivity by streamlining unit operations, reducing downtime between batches and optimizing resource utilization. Our patented EnzeneX? continuous manufacturing platform has demonstrated increased upstream processing productivity by ~10-fold, and downstream processing productivity by 25-50%, over a traditional fed batch process.
2. Enhanced product quality: Continuous extraction of the product from the bioreactor (followed by purification) minimizes the product's contact with harmful metabolites and proteolytic enzymes, which would otherwise accumulate in a conventional fed-batch process. This feature allows for a significant reduction in protein aggregation and degradation (clipping, oxidation, deamination, glycation), resulting in higher product quality, even for proteins that are less stable or challenging to express (fusion proteins, bi/multi-specific antibodies, cytokines).
3. Reduced area footprint & emissions: Smaller equipment and single-use bioreactors reduce facility size and carbon footprint (up to 50% as observed with EnzeneX?).
4. Flexible design: Clinical phase GMP supply in as low as 30-50L scale and modular design with variable bioreactor capacity accelerates development with scale-on and scale-out approaches.
5. Cost-effective manufacturing: Lower operational costs combined with high productivity translates into ~50% reduction in overall cost per gram of manufacturing for the product.

Addressing misconceptions:

Addressing the misconceptions and myths surrounding continuous manufacturing is essential for fostering greater acceptance and a well-informed understanding of the technology. A few of the common myths are addressed below.

• Continuous manufacturing is difficult to implement: ?NOT TRUE. Though setting up or transitioning to continuous manufacturing may require initial investment and process optimization, modern technologies and advancements have simplified implementation significantly. Companies can seek guidance from experts and can pilot with CDMOs who have matured workflows and validated technology, to evaluate and eventually facilitate the transition smoothly.
• Continuous manufacturing does not allow for flexibility for small to large-scale production: ?NOT TRUE. Contrary to the common belief, continuous manufacturing offers operational flexibility due to its modular design enabling scalable approaches such as scale-on and scale-out strategies. It allows for the process to have the flexibility around the process duration while enabling it to go for longer durations (‘scale on’) without impacting the product quality. This flexibility allows manufacturers to adjust production capacity as needed, making it suitable for both large and small operations.
• Continuous manufacturing is not cost-efficient: ?NOT TRUE. Some believe continuous manufacturing to be more expensive than fed-batch. Although the initial setup or transition to a continuous manufacturing facility may entail higher initial costs, continuous manufacturing ultimately yields lower operational expenses, shorter cycle times, and enhanced productivity. These benefits lead to significant long-term cost reductions, making continuous manufacturing a financially viable option for most companies.
• Continuous manufacturing is not regulatory compliant: ?NOT TRUE. Continuous manufacturing adheres to regulatory standards set by agencies, ensuring compliance with strict guidelines for drug substance production, thereby enhancing product safety and quality. In March 2023, US FDA published specific guidance for industry Q13 ‘Continuous Manufacturing of Drug Substances and Drug Products’ that provides further clarifications on scientific approaches and regulatory considerations specific to continuous manufacturing processes.
• Continuous manufacturing has limited applicability: ?NOT TRUE. There is a misconception that continuous bioprocessing is only suitable for certain types of biologics or specific production volumes. In reality, modularity of continuous systems allows for seamless adaptation for various biopharmaceutical products and production scales, offering versatility across different applications.

Challenges with Continuous Manufacturing:

Innovative technologies present unique challenges, and Continuous Manufacturing is no exception. Below are some of the challenges associated with it.

• Integration of upstream & downstream processes: Seamless integration of upstream and downstream processes in continuous manufacturing workflows can pose logistical and operational challenges. It’s not trivial and needs deep technical expertise.
• Operational challenges: Implementation of the perfusion filtration devices (e.g. ATF) in the process flow could result in greater protein retention inside the bioreactor, and subsequent reduction in the product yield. Further, clogging of filtration devices could also presents operational hurdles, potentially disrupting production and necessitating timely interventions to maintain process efficiency and product quality.
• Bioburden control: In continuous manufacturing, where the production process operates without interruption, maintaining sterility and preventing bioburden buildup is crucial to ensure product quality and safety.
• Risk Management: Identifying and mitigating risks associated with continuous manufacturing, such as process interruptions or equipment failures, is essential to ensure uninterrupted production.

Overcoming these challenges through innovation

EnzeneX? is our patented and commercially validated continuous manufacturing platform, that resulted from the outcomes of numerous trials and iterations aimed at establishing a reliable and efficient continuous bioprocessing workflow.

During the development and implementation of EnzeneX?, we proactively addressed challenges of aforementioned nature and devised strategies to overcome them. The insights gained during this process have positioned Enzene as one of the very few players with a successful and commercially validated end-to-end connected (upstream and downstream) continuous manufacturing platform.

The advancement of continuous manufacturing has sparked a transformative revolution in the production of costly biologics. This pioneering technology holds great promise in enhancing product accessibility and boosting productivity and efficiency in biologics manufacturing.

Utilizing compact equipment, continuous manufacturing technology significantly reduces the facility footprint by up to 70% compared to conventional fed-batch plants. Ultimately, this approach effectively addresses the primary challenges encountered in the production of biologics today.

To learn more about continuous manufacturing, reach out to us at

?? [email protected] or visit www.enzene.com