Quality without compromise: The promise of fully-connected continuous manufacturing

By Sundar Ramanan, PhD, MBA (3 mins read)

Advances in cell culture technology have led to high cell viability for longer duration with genetic stability and titers.? Advances in automation have led cycling chromatography columns to match the process duration of cell culture.? Coupling the upstream cell biology advances and the downstream automation advances has enabled fully-connected continuous processing of biotherapeutics to be possible.?

Fully-connected continuous processing of biologics offers several key quality compliance advantages over traditional fed-batch processes:

1. Lower Complexity in Construction, Commissioning and Qualification: Producing large quantities of biotherapeutics is often associated with scale-up to 20,000 or 50,000L bioreactors.? Using continuous manufacturing technology, the same product quantity can be obtained using a 500L or 2000L bioreactor.? This substantially reduces the manufacturing complexity for construction, commissioning, qualification, and validation during the set-up phase.
2. Contamination Prevention and Control by Design: Since the 500L or 2000L bioreactors are available in a single-use format, the need for clean-in-place (CIP) or steam-in-place (SIP) is eliminated.? Contamination from facility or personnel is eliminated.? In addition, cross-product contamination is also eliminated, leading to a better quality compliance state.? Therefore, a fully-connected continuous manufacturing format offers better microbial control at higher throughputs/productivities.
3. Better Product Quality Profile: In a traditional fed-batch process, the product once secreted by the cells continues to stay in the bioreactor for several days until harvest.? Longer exposure of the product to enzymes in the bioreactor can deteriorate the product quality via oxidation, deamidation, or glycation -- attributes often considered to be correlated with efficacy and safety.? In a fully-connected continuous manufacturing format, the product is constantly removed from the cells, thereby significantly reducing the opportunity for degradation, and resulting in a better product quality profile.?
4. Scale-up Risks Eliminated: As product demand increases, a traditional fed-batch process requires a whole new manufacturing train, which often necessitates the need for constructing a new plant with new equipment (scale-up).? However, in the fully-connected continuous manufacturing process, we extend the cell culture duration (scale-out to produce more product).? Given there are no other changes, typical quality compliance and product quality challenges associated with scale-up and technology transfer are eliminated.
5. Real-Time Release Testing (RTRT): In a continuous manufacturing format, the product and process parameters are continuously monitored.? Process-product characterization, coupled with in-line monitoring, mitigates the need for forward-process tests typically associated with a fed-batch process.? Therefore, real-time release testing is possible in the fully-connected continuous manufacturing of biotherapeutics.

Key Quality Considerations in the Fully-Connected Continuous Manufacturing of Biotherapeutics:

1. Batch Definition: A traditional fed-batch lot size is fixed by bioreactor volume.? However, in a fully-connected continuous manufacturing, time is the key parameter.? Therefore, a batch size can be defined as a range with a minimum and maximum time-duration (i.e., a range of mass-output, range of mass-input, or a combination).
2. Deviation/Non-conformance Management: One of the key risks in continuous manufacturing is the potential for a transient event, either planned or unplanned, to impact process parameters.? The impact of transient events on product quality should be adequately characterized, and automation design should consider isolating the product, mitigating exposure to transient out-of-range parameters.? This will ensure product consistency and assurance of quality that product produced at any moment in time has always been within the approved range.
3. Control Strategy: An integrated process and product control strategy ensures product quality is consistently maintained throughout the production process.? The critical process parameters (CPPs) impacting critical quality attributes (CQAs) are mapped via process and product characterization, and the product quality is intentionally improved by controlling the process parameters.?

?Conclusions:

Fully-connected continuous manufacturing of biotherapeutics offers several advantages over a traditional fed-batch process for better quality in terms of compliance (reduction in microbial risks, scale-up risks, product quality) as well as efficiency (faster commissioning of facility and real-time release testing).

To learn more about our fully-connected continuous manufacturing, reach out to us at ?? [email protected] or visit www.enzene.com