WuXi Biologics hopes to start with a clean slate

By Dr Nick Hutchinson

Biopharmaceutical companies around the world are reconsidering their approach to process design due to rapid technological changes that are facilitating the implementation of continuous bioprocesses. The industry has tended to perform the manufacture of stable molecules such as monoclonal antibodies with batch process and the production of labile molecules such as enzymes and hematologic factors with perfusion cultures. Yet new technologies for cell retention and cell culture greatly facilitate the implementation of perfusion cell cultures for manufacturing both stabile and labile biologics. The need for highly consistent product quality and for products to reach the clinic quickly also influences the process design decision.

WuXi Biologics has installed two 1000 L single-use bioreactors at their facility in Wuxi city as part of their perfusion platform for production of biopharmaceuticals. I caught up with Dr Weichang Zhou (Senior Vice President, Biologics Development and Manufacturing, WuXi Biologics Inc.) at Sartorius Stedim Biotech’s ‘China Bioprocess and Integrated Solution Innovation Forum’ in Suzhou, which was held in September, 2016 and asked him about the decision to develop a perfusion-based platform.

A flexible alternative to 6-pack biomanufacturing facilities

“China does not necessarily need to build a large facility with, for example, 6 x 15,000L bioreactors. Despite the fact that it is not as mature a market as the US or EU, we have the opportunity to learn from the past and improve upon it by installing the latest technologies”, Dr Zhou told me.

Dr Zhou has provided strategic leadership to many multifunctional biologics CMC teams over the past twenty years and across three continents. Amongst his assignments, he served for approximately five years as Senior Director of Commercial Cell Culture Development at Genzyme, a SANOFI Company, well known for its leadership in the field of continuous bioprocessing.

“These large facilities that are designed for batch processing require a massive investment and take a long time to build. There is considerable risk for companies constructing them. Technology developments are allowing process intensification and an increase in productivity that enables us to operate facilities with a smaller footprint even taking into account any additional infrastructure they may require,” continued Dr Zhou.

Of course, perfusion culture itself is not a new technology. Companies have historically used perfusion processes for labile proteins that would degrade if allowed to remain within a batch bioreactor for a few days. To what extent, these days, might firms consider perfusion processes for non-labile proteins?

“There comes a point when you require a certain amount of protein, such as an antibody, and the productivity achieved through continuous processing will result in a lower cost of goods and more consistent product quality profiles. However, this is not the only reason for implementing perfusion. The point is that if you only have a fed-batch platform your facility is limited to producing stable proteins. If you have a continuous platform, you can produce either labile recombinant proteins or stable molecules such as monoclonal antibodies. A continuous platform is more flexible in this respect. In the US and EU, sometimes companies have no choice because platforms were built around specific products but in growth markets we can learn this lesson. We are not so constrained by legacy infrastructure,” said Dr Zhou.

Fed-batch cultures versus Perfusion: which is more challenging to operate?

“Switching from fed-batch operation to perfusion culture might be challenging because people need to adopt a new mind-set and learn new skills. However, the relative degree of complexity of either approach is really a question of perspective. We are not comparing apples with apples. If you ask folks that have operated fed-batch processes for many years, they might see perfusion as being complex because of the control needed to maintain a steady state. But maybe if you ask people from companies who have operated perfusion processes for a long time you might get an alternative view. They might point out that with steady state processes you do not need to worry about product quality variation so much, or there is less need for frequent changeovers. Fed-batch processes are more dynamic and can be less predictable. Cells can die very quickly during this type of culture. Culture performance profiles can vary from batch to batch and between different scales. With a perfusion culture, it is much easier to predict today what will happen tomorrow. WuXi’s data from many of these cultures operated at 60 days or longer shows they are highly reproducible and consistent. “

Do Continuous Bioprocesses Reduce Cost of Goods?

During the Sartorius European Upstream & Downstream Forum 2016 held in Gottingen, Germany, Andrew Sinclair (President & Founder, Biopharm Services) observed that the usage and cost of cell culture media could increase when switching to perfusion culture even if the bioreactor size was reduced. I asked Dr Zhou whether WuXi Biologics’ experience was that operating continuous cultures reduced cost of goods.

“The cost of goods will always depend on the productivity of your process and the amount of protein you need to produce to fulfil market demand. WuXi is able to achieve a productivity of over 2 g/L of antibody per day, with continuous harvesting over an extended period. To achieve this level of productivity in fed-batch mode is very challenging. With fed-batch cultures, you will eventually reach a limit. You can rarely go beyond 10-15 g/L without having a negative impact on product quality,” responded Dr Zhou.

“Continuous bioprocessing reduces downstream costs. You can avoid many of the expenses associated with clarifying cell cultures if you seamlessly integrate the upstream with the capture step. Running the capture chromatography step in continuous mode allows a significant reduction in column size because the resin utilization is much higher (Figure 1). Less resin is needed because of the increase in the number of cycles that will be run and modern Protein A resins have lifetimes of up to 200 cycles. This is especially useful when making clinical material as it means there is no need to purchase and store large resin volumes,” he added.

Continuous Bioprocessing in China

To conclude our discussion, I invited Dr Zhou to comment on the opportunities and challenges of continuous bio-manufacturing in China.

“There is a pressure from patients to develop a biopharmaceutical industry within China. Because of smartphones, people receive news of the latest regulatory approvals of novel biologics instantly and they want access to the same medicines for themselves, their friends or families. People feel pressured to move the industry forward aggressively and they are getting a lot of attention from the press and from investors. There is a danger that if you move too quickly you will make mistakes and not plan well enough for the future.”

“The biotech industry in China is less mature than in the US, which has had over 30 years to develop. There are less than 15 MAbs approved in China compared to more than 60 in the US or other advanced countries. However, you will see many more biologics in the clinic in the near future. Many have finalised their CMC packages and are now awaiting approval by the Chinese FDA for entering clinical trials”, he told me.

“High quality technical people are in great demand in China. It is easy to underestimate the amount of talent you need to develop a biologics manufacturing process and to run a facility. Firms have to consider how they will build a multi-discipline team, not just at the strategic level but also at the executional level. Those people that invest in a high quality team will deliver a high quality product in the end.”

“WuXi Biologics has done just this. It wants to be a world leader in the continuous bioprocessing space”, Dr Zhou concluded.

The Development & Transfer of Perfusion Processes

Do perfusion processes take a long time to develop and does this affect a company’s speed to clinic?

“Maybe if you have to design a whole new platform. Developing a perfusion process can be very fast if you already have a platform with the people and the infrastructure you need. With a perfusion platform, you do not have to do such a high level of development. The benefit of being able to operate at a smaller scale, say 500 or 1,000 liters, allows you to reduce your initial investment and build your facility much sooner.”

“You can also apply the McDonalds principle to increasing production capacity. Rather than building one very large facility and transporting product all over the world, you can simply build more modules of the same design in different geographical locations. That way you have the same scale and it provides greater flexibility,” said Dr Zhou.