Continuous bioprocessing – the journey has started and the destination is clearer than ever

The biopharmaceutical industry faces the challenge of updating the manufacturing paradigm to increase productivity and improve patient access. Continuous bioprocessing holds tremendous potential, offering numerous advantages compared to traditional batch-based processing methods. The benefits include increased productivity and economics (1-4), reduced facility footprints, and heightened flexibility. The focus of continuous bioprocessing has been on monoclonal antibody (mAb) manufacturing, but the same benefits apply to recombinant proteins, plasma-derived therapies, vaccines, and gene therapies.

New manufacturing approaches and continuous-enabling unit operations have already been developed, and process intensification through continuous manufacturing remains an active area of interest for researchers, vendors, and biomanufacturers, as evidenced by recent conferences (5) and publications (6-8).

However, the widespread adoption of continuous bioprocessing is hindered by perceived technology limitations, regulatory gaps, and a lack of a defined process and how to achieve it. There are many different continuous manufacturing demonstrations and implementations; these range from combining two-unit operations to what may be described as fully (or “end-to-end”) continuous, where the continuous process starts at the bioreactor and continues to the formulation steps at the end of the process. Common frameworks for integrated and continuous biomanufacturing range from perfusion processes linked to a multi-column capture chromatography step through to fully integrated processes from the bioreactor to the final concentration.

To support the adoption of continuous processing, including control strategies and rationales, BioPhorum has worked to assess the continuous bioprocessing landscape and published a roadmap (9), developed a template for a risk-based approach to process parameter evaluation (10) and defined a consensus approach for devising a control strategy (11). This article summarizes the progress made by BioPhorum across these publications to support the adoption of continuous biomanufacturing in the pharmaceutical industry.

BioPhorum’s Continuous Downstream Technology Roadmap (9) outlined a vision for continuous therapeutic protein production in the biopharmaceutical industry. The paper discussed the technology and regulatory gaps in continuous downstream drug substance processing of therapeutic proteins using a model mAb process. An end-to-end gap analysis was performed on a typical continuous mAb downstream process that identified gap categories, such as unit operation technologies, single-use technologies, automation, modeling, and regulatory challenges, which are hindering implementation. Closing these gaps will turn the promise of continuous bioprocessing into a reality.

Traditional control strategies, such as sterilization and filtration, may not be feasible for continuous downstream processing due to the longer processing times and the need for aseptic control. Solutions include using closed-processing and sterile-welded components, designing flow paths for cleanability, and the aseptic control of all feed streams. However, there are gaps in bioburden control, such as the absence of in-line, real-time bioburden monitoring and little availability when implementing aseptic connects and disconnects.

Technology advances and their implementation strategies that consider regulatory requirements have allowed the adoption of a number of continuous biomanufacturing approaches: e.g. continuous multi-column chromatography (12), plug-flow viral inactivation, slow-flow (constant) viral filtration (13), and in-line concentration and dilution. These have allowed the generation of case studies to support the development and implementation of GMP solutions for continuous bioprocessing at clinical and commercial scales (14).

Batch processes typically use buffer preparations that are required for one process step, lasting around one day or less, after which the next lot is generated and processed. Continuous processes can last for weeks or months and buffer may be required to flow into process steps continuously, without idle time for tank cleaning and refilling. Buffer preparation for continuous processing may utilize batch dissolution of 1x buffer, continuous blending from stock solutions, or dilution from buffer concentrates. Potential buffer hold methods include twin hold vessels, buffer hold tank top-off, and continuous on-line buffer production. Using a continuous buffer preparation and delivery system, such as BioPhorum’s buffer dilution skid (15), can reduce the buffer hold tank footprint and the buffer preparation area requirement.

Continuous processing requires expanded on-line monitoring to see what is occurring in real time. The main challenges associated with on-line monitoring and instrument probes for continuous processing are sensitivity and robustness to maintain long-term process control. The success of monitoring techniques depends on the speed, accuracy, and integration ability of sensors, as well as instrument calibration, performance life, recalibration, and cleaning for in-line and on-line sensors.

BioPhorum published the first part of its consensus approach to process validation, which was a template risk assessment to define standard considerations for process control of continuous bioprocesses (10)  . While these challenges can be resolved by individual organizations, a process validation template approach for assigning critical or key process parameters (CPPs/KPPs) de-risks and accelerates adoption into the GMP environment. Potential CPPs and KPPs were identified based on the process knowledge and experience of BioPhorum members with considerations for control of these CPPs and KPPs in continuous operations outlined in the document and supporting worksheet tool.

The follow-on BioPhorum document (11) considers determining the process control strategy by simplifying the handoffs between unit operations within a continuous process. A control strategy can then be generated by combining the risk assessment (which identified the CPPs and KPPs) with the identified set of unit operation-linking schema. This will describe the process and subsequent test conditions to validate the continuous process, equivalent to the validation process of a conventional batch process strategy.

One of the key advantages of continuous processing is beginning the subsequent operation as soon as possible and not waiting for the previous unit operation to reach completion, as in batch processing. The fluid connections between unit operations and the flow of product are then critical for a continuous process. Our recent white paper (11) categorized and simplified these fluidic connections between unit operations. There are three classes of connection: direct connection, in-line conditioning, and indirect connection through a surge vessel. In addition, there are four main ways the product mass flow and volumetric flow interact across and between the unit operations. The respective flows can be constant or variable, leading to the four combinations determining the appropriate connection type.

The regulatory landscape taking shape for continuous mAb manufacturing will serve as a guide for other therapies (16), such as non-mAb recombinant proteins, plasma-derived products, vaccines, and gene therapies – all reducing the time to market and cost of manufacturing. BioPhorum’s continuous downstream paper (9) highlighted the current barriers to adopting continuous downstream GMP bioprocessing and identified areas where individual companies or the wider industry could innovate to drive adoption. Examples where gaps have been closed by BioPhorum’s industry initiatives include the generation of a blueprint for a buffer blending system to debottleneck buffer management and supply (15).

Publishing a template approach to identify CPPs and KPPs that are impacted by the additional complexity of continuous processing (10), and defining a common process schema for linking unit operations to simplify and standardize the approaches to defining and validating continuous process control strategies (11) have clarified control strategy approaches to continuous bioprocessing. These activities, in conjunction with technology developments since the roadmap’s publication, have led to building a better understanding of how to implement continuous processes into the GMP environment and are enabling faster adoption by the industry.

End‐to‐end collaboration to transform biopharmaceutical development and manufacturing:

Erickson J., Baker J., Barrett S., Brady C., Brower M., Carbonell R., Charlebois T., Coffman J., Connell-Crowley L., Coolbaugh M., Fallon E., Garr E., Gillespie C., Hart R., Haug A., Nyberg G., Phillips M., Pollard D., Qadan M., Ramos I., Rogers K., Schaefer G., Walther J., Lee K. ” Biotechnology and Bioengineering Volume118.9 pp 3302-3312.

The design basis for the integrated and continuous biomanufacturing framework.

Coffman J., Bibbo K., Brower M., Forbes R., Guros N., Horowski B., Lu R., Mahajan R., Patil U., Rose S., Shultz J. Biotechnology and Bioengineering Volume 118.9 pp 3323-3333.