Biopharma’s Continuous Future

There is tremendous pressure on companies to reduce the cost of developing new medicines, while at the same time maintaining high standards for quality and safety. In addition, there is a shift towards flexible manufacturing methods that can readily be duplicated at multiple sites worldwide to enable companies to meet local market needs. It’s clear that changes are needed in the bio/pharma industry’s manufacturing models – and Martin Smith, Chief Technology Officer at Pall – believes that continuous processing may be the answer.

What trends are driving increased interest in continuous processing for biopharmaceuticals?

For biopharmaceutical manufacturing, process intensification has led to the higher product titers needed to make continuous manufacturing a viable option. Single-use technologies, which are ideally suited for use in continuous operations, are also being more widely adopted at the commercial scale.

Continuous manufacturing can help reduce manufacturing and environmental footprints, as well as manufacturing costs. Continuous processes are monitored on an ongoing basis to ensure that process parameters are maintained at optimal values, leading to more consistent processes and product quality. Smaller bioreactors run for longer times can provide the same quantities of product obtained from batch reactions in large reactors – and a smaller footprint often equates to reduced capital expenditures, allowing for reduced energy, water and raw material consumption, resulting in lower operating expenses. Continuous processes are also more automated, which minimizes human intervention and the potential for error.

There has also been discussion around mobile continuous processing, which could, for example, take place in remote regions of emerging countries or anywhere outside of traditional factory walls. Because of this, technologies that are brought to the market for continuous unit operations should consider both traditional and mobile settings.

Is continuous processing for everyone?

One factor that is preventing some companies from actively pursuing continuous processing is perceived regulatory uncertainty, but the FDA, in particular, has been an advocate of continuous manufacturing and has been very vocal about the advantages. Perhaps the biggest challenge to continuous processing is the industry’s existing infrastructure – and existing processes that are already cost effective are unlikely to be completely converted to continuous. However, there is an opportunity for companies to adopt a ‘hybrid’ system comprising both batch and continuous processes for operations where there is clear evidence that continuous will provide benefits.

In my experience, it is in newer, multi-product, flexible manufacturing facilities that continuous technologies are being more widely implemented, often in conjunction with disposable systems for biomanufacturing. One of the challenges we face at Pall is the wide variation in customer needs and expectations. It is a bit like the Wild West at times because there are multiple ways of doing things. We don’t know how it will all play out yet, but we are having many conversations about how the new technologies we are developing can provide the widest applicability range.

Despite the hurdles, the discussion around continuous processing is very vibrant and I’m seeing keen interest at the unit operation level. Most companies, including drug manufacturers and contract manufacturing organizations, have recognized the potential benefits and are at least exploring some aspects of continuous manufacturing. There is no example yet of a completely integrated end-to-end continuous bioprocess on the commercial scale, but people are definitely interested in technology solutions for continuous unit operations. Several biologic drug substances are already being produced using continuous processing (perfusion).

How are new technologies responding to the challenges of continuous processing?

There are three main challenges associated with the implementation of continuous processing. First is the need for cost-effective continuous technologies for some unit operations, such as large-scale filtrations in bioprocessing and continuous crystallization for small-molecule manufacturing. Second is the need for clearly demonstrated performance under cGMP conditions at the commercial scale. Third is the need for process analytical technology that can truly enable real-time analysis of manufacturing processes from end to end. The industry is making great strides in all of these areas, with new developments announced almost daily. Pall has actively expanded its portfolio of continuous bioprocessing solutions and has a number of new technologies under development, as well as some recently launched. For example, our Cadence Acoustic Separator (CAS), which is based on acoustic wave separation, was introduced in April 2016 and reduces the buffer volume required to perform large-scale depth filtration by 75 percent. We are also in the process of developing a state-of-the-art clarification solution suitable for use with perfusion processes. In addition to these technologies for specific unit operations, we are looking at technologies to manage waste, as well as being involved in discussions about managing plastic waste.

Gazing into your crystal ball, do you have any predictions for the future of continuous processing?

In the next 3 years, I believe that an increasing number of companies will, to some degree, adopt continuous manufacturing on a commercial scale. Within 5 years, we are likely to see the first examples of fully integrated, continuous biopharmaceutical manufacturing at production scale, and 10 years from now, I believe that continuous manufacturing will be accepted as the norm. I also expect to see continuous processes used for the production of more advanced biological products, such as cell and gene therapies, viral vaccines and virus-like particles. The processing dynamics of such medicines are very different to proteins and antibodies, and both the industry and equipment suppliers will need to develop very specific processes and technologies that can handle these sensitive products.

Is there a risk that late-movers will be left behind?

If a company has a novel drug then they will have a unique position in the marketplace regardless of how it is made. Having said that, it is becoming increasingly difficult for drug companies to get their products listed on insurance company formularies. Payers are expecting differentiated performance at a cost-effective price. Drugs that can’t meet both requirements won’t be successful in many markets. Therefore, accelerated manufacturing at lower cost is crucial. Early adopters of continuous processing are already realizing the benefits of continuous manufacturing and late adopters could see their product portfolios losing competitiveness.

The benefits of continuous manufacturing have been clearly demonstrated in many other sectors, but these advantages can reach to pharma too! Changes in our industry are driving the need for more efficient manufacturing strategies that consistently provide higher-quality drug products. We are currently seeing the advantages of process intensification and the first steps are being taken to couple unit operations, such as concentration and chromatography, together. As regulatory aspects and the questions surrounding process monitoring are addressed, we will see further movement toward integrated continuous processes.