Ask the Expert: Evaluation of the “Scale-Out” Biomanufacturing Strategy — from Early Clinical Stage to Commercialization

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In a BPI Ask the Expert webinar on 2 November 2017, Jie Chen (vice president of CMC management at WuXi Biologics) spoke about scale-out biomanufacturing strategies.

Chen’s Presentation
Scale-out strategies allow for the use of disposable bioreactors in commercial manufacturing. A scale-out strategy offers unique advantages over traditional scale-up manufacturing:

  • Reduces risks to product quality and process performance as manufacturing scale increases
  • Allows for flexible process design and validation strategies
  • Accommodates a wide range of productivity levels and market demands
  • Assists in controlling costs.

Changing market dynamics are driving a need for innovative biomanufacturing facility designs, especially for contract service providers. New facilities are focused on multiproduct and “scale-out” designs that offer flexibility, scalability, efficiency, safety, and regulatory compliance.

How can 2,000-L single-use bioreactors produce ≥100 kg? In a scale-out strategy design, multiple 2,000-L disposable bioreactors operate to provide the same volume of cell culture material as a single 10,000-L production run in roughly the same time.

WuXi Biologics has put those ideas into practice. Our 460,000-ft2 facility is the world’s largest mammalian cell culture biomanufacturing facility using disposable bioreactors: two 1,000-L perfusion and 14 2,000-L fed-batch. The facility can make >1,000 kg of protein products per year.

WuXi Biologics discovery, development, manufacturing, and testing capabilities are located at three sites around Shanghai, China. The company has ~2,500 employees who serve clients from the United States, Europe, Asia, and China. WuXi Biologics is a contract development and manufacturing organization (CDMO) that has supported one biologics license application (BLA) and filed >60 global investigational new drugs (INDs) for its clients.

During scale-up, process development efforts to maintain comparable product and process performance while eliminating impurities can be time and resource intensive. During large-scale cell culture, the physiological microenvironment of a selected production cell line is determined by media/feed strategy as well as bioreactor design and operation. Most impurities originate from cell culture processes. Scaling-up a cell culture process changes that microenvironment and can in turn greatly influence product quality and process characteristics. A scale-out strategy can ensure that product quality is consistent throughout clinical and commercial stages because the microenvironment never changes. Similar concepts apply to downstream processing.

Process validation using a scale-out strategy can offer many potential advantages. Traditionally, a bioprocess could be validated only at its desired commercial scale — limiting flexibility if postmarket approval product demands change. By contrast, a scale-out strategy makes it possible to validate processes at different scales at the same time using a “bracket” design: A process could be validated at both 3 × 2,000-L and 6 × 2,000-L scales over the course of three to four conformance runs, for example.

Each product has its own market demand lifecycle influenced by, e.g., competition, patient population, and disease outbreak. A scale-out strategy designed with a flexible process validation package would allow drug sponsors to adapt and manage that life cycle efficiently and effectively.

Downstream processing is a major contributor to biomanufacturing cost, especially for monoclonal antibody products that require expensive protein A resin. WuXi Biologics is working with vendors to design and implement continuous downstream processing (including protein A capture) for its perfusion and fed-batch facilities.

Hybrid disposable–stainless-steel systems can provide synergistic cost control. The overall cost of a hybrid scale-out facility compared with one using traditional stainless-steel for scale-up could be similar (even better) if initial facility construction and validation costs are considered. With encouragement from regulatory agencies for new technology adaptation, the road is paved for scale-out approaches and continuous processing technologies.

Question and Answer
How are timeline-related costs lower for changeover using scale-out mode rather than traditional scale-up? Let’s compare a single-use bioreactor with a stainless-steel bioreactor: The former bioreactor needs about a day to change over; the latter needs two to three days on average because of the necessary clean-in-place (CIP) step. If it takes two to three days between production rounds through the course of the year, you probably can save almost one entire production round with disposables.

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Watch the full presentation of this webcast — with slides and further discussion.