Continuous Processing To Enable Manufacturing Of Affordable Biotherapeutics

The dominant hurdle in realizing healthcare opportunities for a majority of modern day diseases like cancer is the apparent disparity between availability and accessibility. While biotech based treatment modalities like monoclonal antibodies have provided access to these hitherto untreatable diseases, affordability remains a challenge in most of the world.

Continuous processing of biotherapeutics has emerged as a possible solution to this conundrum. It offers the potential of significantly reducing the manufacturing cost without compromising the product quality. In comparison to traditional batch processes, continuous processes offer a number of benefits such as improved productivity, product homogeneity, and superior quality assurance. However, its practical implementation faces many hurdles. One of the key challenges is that of integration of the various unit operations, each of which differs from one other in terms of the feed conditions of the load, flow conditions and intermediate processing requirements.

In a series of recently published papers in Biotechnology Journal and Chemical Engineering Science, researchers from the Indian Institute of Technology Delhi (IITD) have reported on a new invention, a novel coiled flow inverter based reactor (CFIR). This device has been demonstrated to yield superior performance for processes that involve chemical reaction and require adequate mixing. Examples include protein refolding, protein precipitation, and viral inactivation steps.

By performing a series of case studies it has been established that this device offers not only superior mixing which results in improved product quality but more importantly facilitates implementation of continuous processing. The latter results in significantly higher productivity (10-20X), reduced buffer utilization, and absence of any hold steps. These advantages are estimated to result in a greater than 50% reduction in manufacturing cost of biotherapeutics. Being a modular unit, it can also be connected seamlessly with other unit operations in a continuous processing train.

Related to this invention, in a recent paper in Biotechnology Progress, our team reported on successful integration of CFIR with the downstream train for creation of an end-to-end continuous manufacturing process for Granulocyte Colony Stimulating Factor (GCSF), a biotherapeutic used by cancer patients to prevent infection and neutropenic (low white blood cells) fevers caused by chemotherapy. The case study successfully validated the proposed benefits of continuous processing including smaller facility footprint, higher productivity, fewer hold steps, and significantly higher equipment and resin utilization. 

Consistent product quality remains a key target for biopharmaceutical manufacturers, and widely recognized to be non-trivial to achieve due to complexities associated with biotherapeutic products and processes. It has been demonstrated by us and other researchers working on continuous processing that end-to-end continuous manufacturing processes yield consistent product quality.

We believe that the work provides an important step forward towards the actual implementation of continuous processing in the biopharmaceutical industry which can potentially reduce both capital and operational expenditure. This will, in turn, significantly bring down the cost of biopharmaceuticals making them affordable for a large section of society and thus improve the accessibility of health facilities across the globe.

References:

• Continuous precipitation of process related impurities from clarified cell culture supernatant using a novel coiled flow inversion reactor (CFIR), N Kateja, H Agarwal, A Saraswat, M Bhat, AS Rathore Biotechnology Journal 11 (10), 1320-1331
• Continuous refolding of a biotech therapeutic in a novel Coiled Flow Inverter Reactor, AK Sharma, H Agarwal, M Pathak, KDP Nigam, AS Rathore, Chemical Engineering Science 140, 153-160

These findings are described in the article entitled Integrated continuous processing of proteins expressed as inclusion bodies: GCSF as a case study, published in the journal Biotechnology Progress. This work was led by Anurag S. Rathore from the Indian Institute of Technology Delhi.