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Where to Next with Continuous Processing?

June 6, 2019

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In the market trends driving the need for continuous processing, I proposed that one approach to improving patient access to medicines could be through implementation of continuous processing in the manufacture of these therapeutics. Within the biotech sector productivity, which can be measured in terms of numbers of therapeutic doses produced per year per m2 of facility footprint, can be improved without compromising product quality by implementing continuous processing operations.

 

Today multiple suppliers offer commercial process solutions for continuous cell culture, continuous clarification, continuous chromatography, continuous virus inactivation and continuous filtration and their effectiveness is documented in the technical literature1-4. A benefit associated with continuous manufacture is improved product quality due to the very nature of a continuous process where consistency and robust operation is built in. Notwithstanding the process economic benefits that continuous operations may bring5 there is still a concern that the transition from batch operations to continuous or hybrid processes will bring regulatory challenges that need to be addressed. We do hear supportive presentations given by associates from the regulatory agencies around the world at international bioprocessing conferences that have a continuous thread and regulatory publications are available6. Earlier in 2019, BiosanaPharma got approval to start a phase I clinical trial for a biosimilar version of omalizumab, the first monoclonal antibody produced with a fully continuous biomanufacturing process7. This was pivotal moment in the acceptance of continuous manufacturing in the Biopharmaceutical sector and hopefully will be the beginning of a new era in commercial bioprocessing.

 

So, what’s next? We have the tools; the technology is proven and early adopters are active.

 

One thought provoking area relates to the paradigm shift associated between process development and clinical manufacture. In traditional batch processing, the process development stage is typically carried out with benchtop/pilot scale non-GMP compliant equipment and clinical manufacture is carried out on GMP compliant small-scale production equipment. At first sight, a similar approach could be taken using continuous processing and there is no reason why it should not work. But, consider that the productivity of an effective continuous process will be higher than the batch process so it is quite easy to process more than 100g of product per day in a relatively small footprint continuous facility, using what may effectively be considered laboratory or pilot scale equipment8. Based on this scenario it should be possible to produce 500 - 1000 g of therapeutic product within a week from a facility of this size and in many applications this may provide sufficient material to enter clinical phases I and II. Imagine clinical manufacture at effectively process development scale! This potentially changes the paradigm currently associated with early stage product manufacture. What’s next, most likely small-scale GMP compliant continuous processing equipment that can be used both in the process development (PD) laboratory but also in the manufacturing suite. Having two identical systems one located in PD and the other in manufacturing should enable seamless technology transfer and assure comparability between each stage of development as the 2 processes are identical! Intuitively this seems the way to go.

 

As we look to the future, the opportunities for process intensification through integration of unit operations, becomes a reality4. By matching the volumetric flow rates from the output of the preceding unit operation to the inlet flow rate of the subsequent unit operation, it should be possible to connect the 2 unit operations together. We often speak of fully integrated end-to-end processes and there is some latitude now as to what that actually means but ultimately one might envisage a 'black box' where the inlet is cell culture and the outlet is drug substance. This may be several years away and there are intermediate scenarios that may be implemented on the journey but in principle it could be done. We have the major technology building blocks already but it is the ancillary 'glue' that we need to complete the offering. What is this 'glue'? It includes all appropriate in-line analytics to measure the critical process parameters and selected critical quality attributes, it includes the data collection, analysis and storage of the analytic data. It includes the process control and automation of the individual unit operations within the continuous process train. It includes all the feedback control from the in-line analytics to maintain the process in a steady state. Clear linkages here to Industry 4.0, IoT and AI. Even with these elements we need to consider risk management and risk mitigation strategies including surge tank requirements, spare filters and chromatography columns etc. in case of any failures or downtime of the system and we need to consider fluid management, both reagent preparation and waste collection and disposal.

 

So quite a lot to think about but rather than be viewed as obstacles or problems to be solved, we should see them as opportunities for the future. These aspects will be discussed in future blogs.

 

So finally, there is a question I’m frequently asked. “Is continuous processing limited to monoclonal antibodies?” From my perspective, the answer must be no! For any modality that can be purified using batch downstream processes the transfer to continuous mode should be straightforward. Whether it is a monoclonal antibody, a recombinant protein, a vaccine or a gene therapy vector they should all be potential candidates for continuous manufacture. Is continuous manufacture a commercially viable option for each modality? That I do not know. You need to do some basic experiments and some economic modelling to determine if the process should remain batch, be fully continuous or a hybrid. As perfusion cell culture becomes established in the routine manufacture of biotherapeutics so there will be an implicit requirement to continuously purify product in real time soon after it is expressed by the host cell. We need to be ready and prepared to meet this opportunity!

 

More to follow next time.           

 

 

References: 

 

1 High Cell Density Perfusion Culture has a Maintained Exoproteome and Metabolome, Zamani, L. et al. (2018) Biotech. J. 13 1800036

2 Scale-up of continuous multicolumn chromatography for the Protein A capture step: From bench to clinical manufacturing, Ötes, O et al. (2018) J. Biotech. 281 168-174

3 Continuous In-Line Virus Inactivation for Next Generation Bioprocessing, Gillespie, C. (2019) Biotech. J. 14 1700718

4 Single pass diafiltration integrated into a fully continuous mAb purification process, Rucker-Pezzini, J. et al. (2018) Biotech. Bioeng. 115 1949-1957

5 Modeling the Downstream Processing of Monoclonal Antibodies Reveals Cost Advantages for Continuous Methods for a Broad Range of Manufacturing Scales, Hummel, J. et al. (2019) Biotech. J. 14 1700665

6 The Current Scientific and Regulatory Landscape in Advancing Integrated Continuous Biopharmaceutical Manufacturing, Fisher, A. et al. (2019) Trends in Biotech. 37 253-267

 BiosanaPharma. BiosanaPharma gets approval to start phase I clinical trial for a biosimilar version of omalizumab, the first monoclonal antibody produced with a fully continuous biomanufacturing process, Press Release (February, 2019)

8 Implementation of an end-to-end continuous bioprocessing platform using novel technologies, Levison P. (2017) Presentation at: Integrated Continuous Biomanufacturing III, Cascais, Portugal     

 

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Peter Levison – Executive Director Business Development

Dr Peter Levison holds a PhD gained in the Dept. of Biochemistry, University of Manchester. He has an MBA awarded through the Open University Business School, Milton Keynes. Peter is a member of various professional bodies.
Dr Peter Levison holds a PhD gained in the Dept. of Biochemistry, University of Manchester. He has an MBA awarded through the Open University Business School, Milton Keynes. Peter is a member of various professional bodies.
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