We recently finished our Ask the Expert discussion on Single-Use Technology for Microbial Fermentation. This week we had many interesting questions about incorporating single-use systems into microbial fermentation manufacturing. Topics covered included scale-up processes, fed batch in E. coli, oxygen transfer, cooling capability, volume capacity and cost benefits. Single-use in flexible manufacturing facilities and in vaccine manufacturing were also discussed.

Microbial fermentation processes are used for biomanufacturing of various drugs and vaccines, such as hormones, antibody fragments, and pneumococcal vaccine. Stirred-tank fermentors up to 100,000 L scale have traditionally been used in such microbial processes and their success has formed the general engineering foundation and principles of the design of bioreactors. The majority of today’s fermentation processes are performed in bioreactors constructed of traditional materials such as stainless steel. However, there is an increased interest in disposable technology to gain flexibility, save batch change-over time, and minimize cleaning and cleaning validation efforts.

To date, single-use stirred-tank bioreactors for mammalian and insect cell cultures have been successfully used in scales up to 2,000 L working volume and are installed in both clinical and commercial drug manufacturing facilities. However, for bioreactors to be utilized in microbial fermentation some engineering challenges needed to be addressed. For instance, fermentors had to be designed to handle very high metabolic rates and the high oxygen demands of some microbial cultures. By applying general bioengineering principles and designs, high oxygen transfer rates can be achieved also in disposable fermentors. Augmented designs and operational methods compensate for the low heat transfer rates in these systems. Although pressurizable single-use stirred-tank fermentors are within the realm of the technical feasibility, this feature might not be necessary as sufficient oxygen transfer can be achieved through a variety of mechanical and process control designs and techniques.

This Ask the Expert Session was sponsored by GE Healthcare Life Sciences and hosted by Ken Clapp. Mr. Clapp is the senior global product manager for single-use stirred-tank bioreactors and fermentors. He holds a Bachelor’s degree in biology with a specialization in sub-cellular biology. He received a Masters degree in biological engineering, focused on biological control systems, mathematical modeling and instrumentation. Early in his career he worked as a media chemist, produced antigens and antibodies in large scale, and developed hollow-fiber based bioreactors. Over the past 25 plus years, Kenneth has worked in a variety of roles with bioprocess equipment manufacturers, including field service, sales & marketing, applied research & development, quality assurance, automation, manufacturing and operations management. He has been involved with and responsible for bioprocess equipment capital projects, spanning multi-vessel benchtop systems through large-scale, multiple train production facilities.

For more information on the use of single-use in microbial fermentation, please see: Cell Culture Dish – “Single-use Technology for Microbial Fermentation

Below is a sneak peek of the discussion. For a full transcript of the discussion, please see – Ask the Expert – Single-Use Technology for Microbial Fermentation.

Question:

It seems that single-use is a good option for new processes, but for existing processes what points would you consider when deciding whether to change to single-use?

The Answer:

Single-use technology is a good option for new and existing processes. There may be more to evaluate for existing processes because is it already operational. Consider that single-use technology shortens the turnaround time thereby, effectively, increasing equipment utilization. The industry remains very competitive and saving time had direct benefit to the bottom line. Also consider the amount of time and, if nothing else, the water associated with cleaning a fermentor between runs. Water is a valuable resource with daily headlines trumpeting its scarcity. Consider, too, footprint…and not just the footprint at the fermentor. Single-use fermentors do no rely on piping skid adjacent to the vessel; nor do they require clean or plant steam sources.

Question:

We are looking to manufacture a few different products mammalian and microbial in the same location. We have looked at a few of the flexible facility models for mammalian cell culture. Do you believe that a similar approach using single-use in microbial fermentation and single-use for mammalian would be effective? If so, are there any aspects of planning that you would recommend considering?

The Answer:

Very definitely…the flexibility imparted to fermentation, like in cell culture, is analogous. If I interpret your question further, might I also say that dual-purpose systems, systems capable of either cell culture or fermentation by switching reactor bags and some accessories are available. This type of dual-purpose product provides another level of flexibility, especially for development and pilot operations. With respect to implementing a flexible manufacturing environment, a comprehensive approach to the owner’s business is recommended, if not required. Single-use technology provides a catalyst for implementing changes necessary to be competitive today and into the future where biologics production is concerned. Single-use technology suppliers, especially for the unit operations become a much deeper “partner” in the business. The more information that can be shared, the better the supplier is able to support business continuity, for things like facility layout/design, operational efficiency, supply chain integration, just-in-time materials delivery and many more. As mentioned in an earlier topic response, footprint, utility requirement and water consumption all change for the better. Personnel skills and training may need augmentation. The technology really provides an excellent opportunity to align a manufacturing entity with specifics of today’s biomolecule while equipping them with ability to handle the changes so often associated with our industry.

Question:

Is there technology to support a fully single-use system for microbial fermentation? I mean are there any parts that still need to be cleaned and validated?

The Answer:

With respect to the process contacting parts, which is the bioreactor/fermentor bag, there is nothing to clean as nothing gets reused from that assembly. This is one of the main benefits of single-use bioprocess technology as a whole. And, specifically, for fermentation, single-use technology eliminates cross-contamination previously associated with O-rings, gaskets, diaphragms and mechanical seals. The process piping from the stainless steel equivalent has been replaced by elastomeric tubing. No cleaning necessary, just discard similar to other process waste.