Visions of Biopharma

David Gemmell looks at possible biopharmaceutical facilities of the future

IN THE final article in our biopharmaceutical series, we will briefly discuss conceptual designs for facilities of the future. Over the course of the last four articles, we have assessed different key technologies used in both traditional and novel biotherapeutic manufacturing processes. TCE issue 972 discussed the rise of continuous bioprocessing. Many of these next-generation technologies will be essential to meet future bioprocessing requirements.

Many large biomanufacturers are investing in stainless steel high-capacity facilities with large 20,000 L bioreactors.¹ There will likely always be a place for traditional large-scale manufacturing, especially of older molecules or those with very wide patient populations or markets. This article will focus on the trends expected for cutting-edge manufacturing processes focusing on small batch volumes with higher throughputs.

Facilities of the future

There are significant changes expected when it comes to next-generation bioprocessing. Industry is actively looking into manufacturing capabilities which can be deployed into developing countries so a “manufactured-in-
country-for-country” strategy could be applied.²

By creating simplified designs and incorporating some of the closed-processing concepts we have discussed in previous articles (TCE issues 971–972) one could achieve a much smaller facility which does not rely heavily on traditional steam and water utilities for the purposes of sterilisation and cleaning.

By using pre-sterilised single-use components such as filters, bags, transfer assemblies etc the turnaround time is greatly decreased, and cross-contamination risks are mitigated. These benefits have been discussed before, but one advantage which hasn’t been highlighted yet is the sheer mobility of these technologies. By utilising smaller skid-based unit operations with higher throughputs but overall smaller batch volumes, facility designers can create highly flexible concepts which have a modest physical footprint and significantly reduced cleanroom HVAC requirements. This can lead to huge savings, as HVAC systems are typically the most expensive utility system to operate.

Ballroom concept

One of the leading concepts is to create a large area which can be arranged in different ways. This is what has been known as the “ballroom” concept.³ Depending upon the physical hardware selected this could be segregated into fixed stainless steel upstream capabilities followed by flexible single-use downstream purification operations or entirely single-use (SU). Depending upon the manufacturing philosophy, the upstream could be cycled so that a bioreactor was always being harvested and fed into a purification train. This allows upstream and downstream unit operations to be arranged as required.

The use of smaller unit operations designed for flow-through purification can provide high throughputs. A facility operating connected flow-through processes, in single-use, could manufacture different products and purify them swiftly. Once the batch was processed, the entire room would be stripped down, re-arranged with different unit operations and set up for the next distinct product. This kind of flexibility is highly valuable. It allows manufacturers to quickly pivot to market demands and emerging outbreaks around the world.

Modular facilities

Designing modular facilities which can be shipped to any location and immediately assembled can provide much-needed local manufacturing capabilities to support vaccination programmes near to viral outbreaks. These could take the form of self-contained shipping container sized units as discussed previously, or they could be individual modules designed to be assembled into a much larger facility. This concept is especially useful for deployment in developing countries which are less likely to have sophisticated manufacturing facilities to roll out vaccines. In theory, the ability to rapidly build identical facilities in different locations would minimise the difficulty of tech transferring products into/out of different sites and allow manufacturers to move between sites in the wake of pandemics.

Automation and robotics

Another key facet of the facility of the future is the incorporation of automated systems, robotics, and entirely digital ways of working. The automated receipt and storage of raw materials alongside digital certificates of quality, sent in advance, allow for minimal on-site quality control labs for testing incoming materials. Connected digital inventory control, robotic handling, and automated manufacturing schedules all will increase facility productivity and reduce processing time. Operators and engineers using mobile digital technologies such as augmented reality glasses and other digital tools will minimise setup issues and allow enhanced process control which will be undertaken on a holistic basis. No longer will unit operations be controlled individually; a connected process will be vital for maximising process efficiencies.

Biopharmaceutical vendors have already launched software suites designed to enhance processing by allowing different unit operations to be connected digitally and for critical information to be collected and displayed in meaningful ways.⁴

Science fiction or distant future?

The ultimate goal of the industry is to move to a “personalised medicine” approach. The basis of this concept is very simple, if not extraordinarily expensive with current technology. A patient would undergo some form of analysis from a blood sample, or other quantitative assessment. The sample would be fed into an analytical platform and using artificial intelligence, assessments would be generated. A bespoke biological therapy would be conceptualised, verified and manufactured by a small self-contained bio-processing unit. The analysis is certainly beyond any real-world technology at the moment but the manufacturing is perhaps a little closer to reality.

This device would contain a miniature upstream and downstream manufacturing process which would generate single doses of the drug product, using next-level automation, artificial intelligence driven analysis or drug development and drawing from a digital library of ailments, biological information and medical records.

While this level of technology is a staple of the science fiction genre, there are promising signs that it could one day be a real-life capability. Vaccine manufacturing processes using mRNA are currently being miniaturised; this has huge potential beyond vaccine manufacture.⁵ One could argue that this concept would have limited usefulness, as the economies of scale will always apply, and most people will not need individual treatments. While this is true, there are unique use cases such as remote or mobile deployment options such as future space stations, remote colonies on distant planets or perhaps more terrestrial options such as deployment on large ships or submarines. While the humble beginnings of this are being conceptualised at the moment, the reality of this medicinal vending machine is still very far away.

We are critical

Chemical engineers are, and always have been, at the forefront of technological development. Whether it was distilling crude oil into lighter more useful fractions, splitting the atom, and harnessing the energy produced or separating drinking water from pollutants. In the last century, one could argue that some of the biggest technological developments have been biological. Before the 1940s, a simple cut could have potentially fatal ramifications, but when Alexander Fleming discovered penicillin and it was developed and industrialised, this changed dramatically. Now it is produced in large-scale fermentation processes designed and controlled by chemical engineers.

The biopharmaceutical industry gave diabetics synthetic human insulin, and specific therapies to treat chronic disease and genetic disorders. Biofuels allow opportunities to lessen the environmental impact of the fossil fuel industry. Biological organisms such as fungi are being researched to potentially degrade waste held in landfills or floating in our oceans. Biological computing systems have the potential to greatly outstrip the performance of conventional systems.

Nature has always developed remarkably elegant ways to solve problems. We, as a species, as technology developers, are in our infancy compared to the millennia of iterative evolution levied by the natural world. However, scientists and engineers working closely together, drawing inspiration from biological systems, will bring the advanced technologies of the future closer with each passing day.

The UK is investing millions into biotechnology research and development. Many foreign companies are investing in the UK too; one such example is the mRNA vaccine development centre.⁶ The opportunities for chemical engineers have never been greater. There are also more bio-processing university courses at UK institutions than ever before. Now is the time to draw from our existing bioindustry experience and the wonders of the natural world and apply those techniques in a controllable, reproducible manner for the betterment of society.

References

1. Fujifilm, Fujifilm to Invest USD 1.6 Billion to Enhance and Expand its Global Offering of Cell Culture Manufacturing Services (2022), https://bit.ly/3JHZAKa
2. Adepoju, P, New Initiatives to Advance mRNA vaccine production in Africa (2022); Nature, https://go.nature.com/3QxgL3u
3. ISPE, Biopharma Facility Design: Lessons Learned on the Dance Floor, https://bit.ly/3QejMpk
4. Merck, Merck Accelerates Readiness of Bioprocessing Facility of the Future (2020), https://bit.ly/3BTFUkK
5. Blankenship, K, Tesla teams up with CureVac to make ‘RNA microfactories’ for COVID-19 shot, Musk says, (2020), https://bit.ly/3vOdXqI
6. Department of Health and Social Care, Moderna to Open Vaccine Research and Manufacturing Centre in UK (2022), https://bit.ly/3A9twM4

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Acknowledgments: Michael Burns, Paul Beckett, Stuart Rolfe and Carole Inglevert for helping to write this article.

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This is the fifth  and final article of a series discussing how chemical engineers contribute to the biopharmaceuticals industry. To read the full series, visit:  https://www.thechemicalengineer.com/tags/chemical-engineers-and-the-biopharmaceuticals-industry/