The Early Stage Development of Biopharmaceuticals

By: Dr. Nick Hutchinson

Biopharmaceutical companies are placing great focus on the way they perform process development activities at the earliest stages of the product lifecycle. It is a field in which considerable research and innovation is taking place as firms attempt to make best use of their resources and gain competitive advantage. To find out more about the way in which companies are adapting their early stage development approach I spoke to Dr Will Lewis, Head of Purification Research, Biopharm Process Research at GSK.

Dr Will Lewis
Dr. Will Lewis

Why is early stage development attracting such a lot of interest in the biopharmaceutical industry?

Dr Lewis: “Early stage development that is done well is a relatively small portion of development cycle costs and yet a number of the decisions made at this point are carried through into commercial manufacture. If done badly it can ultimately end up being very expensive because you either have to live with a sub-standard process or spend a lot of money correcting processing problems at a later stage.”

“It entails generating a deep understanding of the effects of the process on the molecule, as quickly as possible. In this way, we can accelerate a safe and efficacious molecule into the clinic to start it on its path to success or allow it to fail as quickly and as cheaply as possible. It is about de-risking the manufacturability of the molecule.”

What changes have you observed in the way companies perform early stage development?

Dr Lewis: “We have changed the way we see early process development by looking at the process holistically, rather than as discrete upstream and downstream disciplines. We call this a “one-stream approach” where we optimize the process at all points to give the best overall output. This means, for example, a strong emphasis on product quality throughout upstream process development in order to give the best possible start to the downstream process.”

“Historically, within the industry, the drug discovery teams and CMC teams operated in distinct silos. Now the industry is trying to bridge that gap and transfer what we learn both ways. Not only does early stage development now build upon knowledge generated in the drug discovery area but we also feedback our knowledge into discovery to help build the best molecules and reduce product attrition rates in the future.”

How does this link with the concept of product developability?

Dr Lewis: “Developability is using all your legacy knowledge to design and develop a molecule with the best chance of success. Developability for GSK is the start of the QBD process. We form a quality target product profile and build that into our future process development.”

“Starting at lead discovery, and throughout early stage development, we have a molecular design intent (MDI) process that is split into two sections. The first section has a strong in-silico and protein science effort and focuses on the molecule and desirable attributes to make it as developable as possible. We can use it in addition to biology data to help differentiate leads. The second part of the MDI process focuses on early process targets such as cell line quality, purity, and yield. All this information then forms the basis of a quality panel at candidate selection. We traffic light the molecule and process in order to understand and mitigate the associated risks. This gives our molecules the best chance of success in the clinic and beyond.”

“From an early stage this approach allows us to determine where more resource needs to be allocated to solve problems, or whether we are confident that we can accelerate projects. In extreme cases, we may decide to send molecules back for re-design.”

To what extent does adopting a platform process approach reduce the need to early stage development activities?

Dr Lewis: “I think originally that the industry envisaged that as it built platform methods, early stage development would considerably reduce in scope and effort. However molecular formats are constantly changing and there is no such thing as a vanilla mAb anymore, which in turn affects our ability to fit the molecules in our pipeline to a platform. This means we now need to view our platform as a first intent with a series of toolbox options to consider when the platform does not fit. We can streamline this approach by using a decision tree with a defined set of experiments and understanding the process parameters feasible at clinical manufacture. With a more diverse pipeline of products, this platform scoping early stage development work is more important than ever.”

Is this why the industry is currently so focused on high throughput screening of process conditions?

Dr Lewis: “High throughput screening plays a very important part in the problem solving process when we need to move away from the platform centre-points. It gives us a firepower we did not traditionally have to be able to rapidly adapt to new situations with very little material. It also means we can handle more projects at the same time, making us a lot more resource efficient.”

What advice would you give to bioprocess engineers adopting high throughput screening approaches?

Dr Lewis: “They should avoid the desire to take a scattergun approach – don’t try to do a lot more for the sake of it, just because you can. Use high-throughput in a targeted and defined way to solve a specific problem, being aware of its limitations and compromises. “

Dr Nick Hutchinson

 

About the author: Nick Hutchinson is a Technical Content Marketing Manager at Sartorius Stedim Biotech.

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