June 28, 2017

Hybrid Bioprocessing: A Q&A with Andrew Sinclair

Process Development Forum speaks about hybrid bioprocessing with Andrew Sinclair, President and Founder of BioPharm Services

How would you define hybrid bioprocessing?
Hybrid processing is not a very precise term and it used indiscriminately. In my view, it's where within the manufacturing process, there are a combination of single-use (SU) materials and re-usable materials in contact with the process and associated fluids. This often refers to piping, housings, containers and vessels, but not exclusively. In reality, claimed SU manufacturing is hybrid bioprocessing. In the therapeutic protein space, there has not been a truly SU facility at commercial scale.

What could be the main reasons and/or the main drivers that hybrid bioprocessing are being used? Is there a difference between upstream and downstream?
If we look at the key benefits that are attributed to what are described as single use facilities but are in fact hybrid; they have lower costs, smaller footprints less support infrastructure, but they still have some reusable equipment. The key benefits are derived from decoupling process equipment from building (i.e. having no interstitial piping other than provision of basic service utilities). Removing clean-in-place (CIP) and sanitization-in-place (SIP) from the equipment are primary drivers for simplification, the reduction in size in vessels so that everything fits into single floor facility. With the improvements and the rise of SU equipment bioreactors, containers, and physical transfer, a lot of the complexity is removed and even with some reusable equipment, we can still achieve the facility simplification.

There is a definite difference between upstream and downstream. Why?

First is scale. In most cases, upstream is managing the largest volumes. Bioreactors tend to be very complex when incorporating CIP and SIP, so the SU bioreactors address the complexity of CIP and SIP and remove the supporting infrastructure requirements. By limiting to 2,000 L, the manufacturing area is contained to one level. Hence, it often makes good operational sense to scale out rather than go to stainless-steel (SS) bioreactors. 

With downstream, volumes reduce significantly after harvest. The scale of the equipment reduces, so once vessels are converted to SU, a lot CIP and SIP complexity is removed even with reusable equipment. 

Is there an impact on process economy when using hybrid bioprocessing? Is there a difference between upstream and downstream?
The main benefits attributed to SU are achieved in hybrid systems by selectively tackling those areas that give rise to SIP, CIP, and multi-floor manufacturing. There is a difference between upstream and downstream. For the reasons discussed above, upstream scale out is often attractive as an option to scale up into SS. For downstream, it's less important and staying in a reusable SS format can often be cheaper when it comes to the process. For support infrastructure as it relates to hold vessels for buffers etc, it is nearly always good to incorporate as much as possible taking account of the practicalities

Continuous bioprocessing is getting a lot of attention at the moment. Do you see hybrid bioprocessing play a role there as well?
There are two components to this: the upstream and the downstream. In the upstream arena, people often refer to perfusion as a variant of continuous. This is a mature technology and the economics are well understood. Where the productivity of the cell line is equivalent in fed batch and perfusion, then the balance favors fed batch based on efficient media utilization and easier development. Perfusion has potential, but so does fed batch. The bias is toward fed batch with membrane techniques being used to increase cell density. Reduced media pricing would shift the balance toward perfusion-based processes.

The situation in downstream is different. The technology is not mature and it is at the early stages of implementation. It has the potential for a step change though in my view, it will require innovative thinking around, automation, PAT, and online release to realize its full potential. 

It is often stated that continuous requires perfusion upstream and continuous downstream. This is not the case. Manufacturing modes can be envisaged where fed batch bioreactors feed a continuous downstream operation, and this currently looks to be an attractive option.

Read more Q&As here

Tags: continuous, stainless steel, single-use, hybrid manufacturing