By John Sterling

At the just completed BioProcess International Conference in Boston, a number of sessions focused on the Bioprocess 4.0 trend toward continuous bioprocessing operations. Akshat Mullerpatan, PhD, scientist, purification process development, Sanofi, spoke to GEN about the topic, which he addressed in his conference presentation, “Transitioning from Batch to Fully Continuous Bioprocessing: Considerations for Process Development and Implementation.”

GEN: What are the advantages of batch processing and those of fully continuous processing, respectively?

Mullerpatan: For a multi-step drug manufacturing process, traditional batch format is advantageous to implement due to its relative simplicity, siloed nature of operations, and flexible cadence. Also, most companies have a pre-existing batch infrastructure and familiarity with batch processing. Continuous processing possesses advantages of high productivity, reduced footprint, lower capital and operating costs, and increased opportunity for single-use infrastructure and facility flexibility. Moreover, continuous processes can be operated in a closed and hands-off manner and have shorter processing durations.

GEN: Since there is a strong movement toward fully continuous, what are the disadvantages of batch processing that are driving this movement?

Mullerpatan: While several programs at Sanofi employ batch processing, there is a strong, continued effort to transition to more intensified, integrated, and continuous modes of processing. Batch processing is relatively rigid to demand-supply fluctuations, occupies a large footprint, and is difficult to scale up or down. The investment for batch facilities is high due to larger equipment size, high cost of consumables and expensive cleaning procedures. Being mostly manual, batch processing is resource-intensive and can suffer from lower productivity.

GEN: What are the key considerations that need to be taken into account to make the transition to fully continuous safe and effective for the production of complex bio therapeutics?

Mullerpatan: The transition from batch to fully continuous will look different for each company and change with the molecule and specific situation. There may be intermediate iterations of hybrid continuous processes depending on the specific use case. There are several variables such as the type of biological modality, mode of cell culture, stage of development and facility infrastructure that need to be considered while deciding the timing and extent of continuous implementation. At Sanofi, we are working to create a platform for integrated continuous purification which would be universally applicable to diverse modalities and different scales.

As the manufacturing processes transition to continuous formats, it will be important to ensure that product quality and process performance are comparable to that of the batch process. Further, as continuous processing begins to be considered for commercial-scale implementation, companies will need to evaluate existing facility constraints and perform the required modifications to enable this transformation.

GEN: Can you provide a brief roadmap on how to carry out this transition efficiently and successfully with these considerations in mind?

Mullerpatan: The roadmap for transition broadly includes two phases, i.e., development and implementation. To ensure successful transition, the development phase will need to begin with understanding the requirements and fundamental engineering principles to convert each unit operation from batch to continuous. If the conversion involves a change in format, the next step will be to characterize and ensure comparable outcomes between batch and continuous formats.

This would be followed by designing suitable process control strategies and stepwise conversion of each unit operation from batch to continuous. Each operation will then need to be optimized for control robustness and tested at the pilot scale in an integrated continuous format. Simultaneous with the execution of proof-of-concept development campaigns, technology transfer activities should be initiated for subsequent implementation in manufacturing settings. Facility fit assessments will help identify infrastructural and technological gaps which will need to be addressed in advance of implementing integrated and continuous processing in GMP.

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