Implementation of Continuous Manufacturing Strategies for Protein Therapeutics

Sponsored by: WuXi Biologics
Answers by: Hang Zhou, Ph.D., Director of Cell Culture Process Development, WuXi Biologics & Sherry Gu, Ph.D, Vice President of CMC Management, WuXi Biologics

Introduction

There continues to be growing interest in continuous processing of biological therapeutics with the primary driver being reduction of drug costs through more efficient manufacturing processes.  Together, drug developers, contract manufacturing organizations and process equipment suppliers continue to make significant advancements towards the goal of making continuous biologics manufacturing a reality from the initiation of cell culture to the production of bulk drug substance.  Compared to traditional batch technologies, continuous bioprocessing can offer more flexibility and in some cases improve product quality in addition to lowering the costs of production. Continuous cell culture technologies can be used in the manufacturing of both stable and unstable biological molecules. The US FDA has been supportive of the implementation of continuous manufacturing using a science- and risk-based approach.

This week WuXi Biologics’ offer Hang Zhou, Ph.D, Director of Cell Culture Process Development and Sherry Gu, Ph.D, Vice President of CMC Management as two industry experts in applied continuous manufacturing approaches to address any questions you may have related to the adaptation or implementation of continuous manufacturing strategies for protein therapeutics.  WuXi Biologics has developed a continuous processing platform for biologics manufacturing using single-use bioreactors and have been successful in the development of multiple continuous unit operation steps both at small development scale and for large-scale GMP manufacture (1,000 L perfusion cell culture).

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Question 1

For lot release, what do you consider a lot?

In the past there was concern over definition of a batch or lot but it is no longer an issue. A batch from a continuous process can be defined by batch duration and/or certain product amount. For early phase clinical production, one perfusion culture run is usually released as one lot – thus, harvest collections … Continued

Question 2

Do you run continuous downstream too? How do you connect your upstream and downstream?

Yes. There are various advantages to continuous downstream manufacture. It can be implemented together with continuous upstream to realize an integrated continuous process. For fed-batch culture, continuous downstream allows lower one-time resin expense due to use of smaller sized columns and higher resin utilization efficiency. The critical technologies that allow for continuous downstream processing are … Continued

Question 3

What product limits have you found with continuous with either product type or demand?

We don’t see many product related limits when using a continuous process scheme compared to a traditional fed-batch process. In fact, continuous manufacturing can accommodate a wide variety of molecules – including mAbs, fusion proteins, growth factors, recombinant enzymes, etc. – many of which could not be produced in other cell culture modes (such as … Continued

Question 4

What are the main reasons that cause you to choose a continuous manufacturing vs. conventional?

There are several major drivers for implementing continuous bioprocessing. First of all, there are increasing needs for flexibility and speed to meet market demands. Continuous bioprocessing will allow the use of modular and smaller facilities with smaller and/or single-use bioreactors in order to meet rapidly changing and unpredictable market demands in diversified and segmented market … Continued

Question 5

Have you applied PAT and do you find it is easier or more difficult in continuous? Are you able to monitor process conditions and make adjustments real time?

We’ve evaluated various PATs on continuous processes including auto-sampling systems and online probes and analyzers. Implementation of PAT is usually easier for continuous processes since we typically can develop and thus expect steady state conditions. We found PATs quite useful especially those that monitor key process parameters in real-time and others that help to identify … Continued

Question 6

Do you have to do much optimization on your perfusion culture?

For products (e.g.,monoclonal antibodies) that in general tend to behave similarly in production we typically do minimal process development work for early stage programs (e.g., prior to IND or for production of Phase I/II clinical trial material) but rather we leverage our well-established continuous “platform” process.  For example, our platform comprises solid knowledge of our … Continued

Question 7

Can you provide a timeline of your continuous manufacturing runs?

Timelines from cell expansion through continuous cell culture and potentially continuous downstream purification can vary widely pending on a multitude of factors that include actual product demand, the scale of bioreactors, the expression levels of the product and if continuous downstream is utilized, production timelines are impacted by pooling/holding strategy, the number of cycles required … Continued

Question 8

I know this is a complex question but can you give a high level about cost and if you see cost savings and where.

Continuous manufacturing is quite flexible and can be utilized at various production scales and configurations. Regardless of the case-by-case cost structure of every process, we will try to identify a few key factors that could significantly affect the cost of a continuous manufacturing process, in comparison to conventional processes. Generally speaking, continuous upstream processes can be … Continued

Question 9

What is the typical time from target to manufacturing?

As I understand the question, you are inquiring about the timeline of a novel lead therapeutic from preclinical development to initiation of the first clinical manufacturing run. If a good platform process development strategy has been established, the overall timeline won’t be significantly different from that of a fed-batch process. Specifically, in cell line development … Continued