Thursday, September 12, 2013

Single-Use Stirred Tank Bioreactors: Enabling Flexible Biomanufacturing

Author: Brandy Sargent, Editor, Cell Culture Dish,  Brandy will be joining us this year at BioProcess International as a guest blogger on September 16-19, 2013 in Boston, MA.  If you'd like to join us at BioProcess International, as a reader of this blog, register to join us and mention code BLOG13JP to save 20% off the standard rate!

Stainless Steel Stirred Tank Bioreactors have been used for several years in biomanufacturing and have proven their effectiveness across several biomanufacturing platforms. Of all production platforms, CHO cells are the most prevalent in stirred tank reactors, but they have also been successfully used with other platforms including insect cells, yeast, E. coli, plant cells, Pseudomonas, hybridoma, vero and others. While stirred tank bioreactors are traditionally associated with suspension culture, the use of microcarriers and associated technologies have allowed adherent cell lines to be effectively cultured in stirred tanks and stirred tanks have also had some success in stem cell manufacturing.

The traditional model for manufacturing biopharmaceuticals is to build a manufacturing facility focused on fixed stainless steel stirred bioreactors usually in sizes ranging between 100 – 25,000 liters. These facilities require high initial capital investment and large overhead. Initial capital investment includes cost of setting up the bioreactors, detailed facility design including piping and infrastructure for media delivery, plus water and steam necessary for Clean in Place (CIP), Steam in Place (SIP) and Water for Injection (WFI) requirements. The challenge with this traditional design is that these facilities have large manufacturing capacity, but little flexibility. They usually focus on manufacturing a handful of biopharmaceuticals requiring large volumes. However if demand changes, cell culture improvements result in higher titer, or any other alterations to volume requirements, excess capacity can quickly become a problem.

Due to some of the challenges experienced with traditional fixed biomanufacturing facilities there has been a desire to create more flexible spaces. Improvements in cell culture and downstream processing have made manufacturing more productive resulting in higher titers and product quality. In some cases reducing the overall number of cell culture liters required to meet a biopharmaceutical’s demand. As a result, facilities that were used to operating at capacity could find they now have costly capacity excess to fill.

Single-use Stirred Bioreactors Designed for Flexibility
The development and subsequent improvements to single-use stirred bioreactors have offered a more flexible and cost effective alternative to their stainless steel fixed counterparts. Single-use stirred bioreactors offer several advantages that makes them an attractive option in designing flexible facilities:

Reduced Start Up Time and Capital Investment
Single-use stirred bioreactors offer a reduction in installation time. They don’t require extensive piping systems or infrastructure to support media delivery, clean in place, or steam in place requirements. The overall capital investment is also reduced due to the simpler facility design, smaller facility footprint and lower cost for equipment. In addition, many single-use stirred bioreactors offer “ready out of the box,” efficiency, which provides lower set up hurdles prior to use.

Process Flexibility
Single-use stirred bioreactors offer optimal process flexibility, particularly when combined with other single-use technologies. The ability to move these bioreactors around offers tremendous flexibility in facility layout and process flow. This allows the bioreactors to move to other areas within one facility based on need or even to other manufacturing locations. Because these are mobile and disposable, they do not need to be dedicated to one product type. For example, they could be used to manufacture one product for a clinical trial material campaign in one area, then moved to another area and used for commercial product manufacturing. Each different product may utilize different cell lines, media or other manufacturing requirements, but single-use bioreactors can be repurposed and utilized in different scenarios.

Single-use stirred bioreactors also support different production modes including fed batch, perfusion or continuous processing. Just like their stainless steel counterparts, they have been proven across many different biomanufacturing platforms and have consistently performed comparably with fixed stainless steel bioreactors.

Manufacturing Efficiency
One of the biggest advantages for single-use stirred bioreactors is the reduction or elimination of cleaning, sterilization and validation requirements. This reduces product changeover time and thus promotes increased manufacturing efficiency and improves scheduling of product manufacturing. Disposable systems also reduce the risk of product cross contamination, thus eliminating costly manufacturing shut downs. As mentioned in process flexibility, because these bioreactors are not fixed or dedicated, they can be moved around to create a manufacturing configuration that is most efficient.

Single-use stirred bioreactors coupled with new automation systems, offer a truly all in one solution. With the ability to have advanced control over processes, including data management, temperature, RPM, pH, DO, gas and liquid flow rates, weight and pressure, these systems offer a number of parameters to be set automatically and can even aid in troubleshooting. They also make evaluating data convenient with export options.

Flexible Scaling to Meet Product Demand
Single-use stirred bioreactors offer many choices as to size and scale (<1L - 2,000L), so that lot sizes can be matched with the current product demand. If product demand changes, then the scale of the single-use bioreactor can also be adjusted to keep pace, which greatly reduces costly capacity excess or drug shortages. This also enables the move toward smaller market or orphan drug products that have smaller product demand.

Cost Savings
Single-use stirred bioreactors can offer a reduction in cost of goods by reducing overall utility costs, reducing or eliminating manufacturing steps (cleaning and validation, for example), reduction in labor requirements, and as mentioned earlier, scalability to more closely match demand.

Single-use Bioreactors Offer Solutions to Manufacturing Challenges
There are several specific manufacturing challenges to which single-use bioreactors and even entire single-use systems are well suited. Below I have listed some examples.

More Products, Smaller Volumes
There has been increasing need to produce more products at smaller volumes. This has occurred for several reasons. First, product yield increases has reduced the need for 10,000 – 25,000 liter batches and allowed for the opportunity to manufacture multiple products in the same facility. Traditionally turnaround time and cleaning, sterilization, and validation would have made it challenging to produce many products at the same facility. However with single-use systems, cleaning, sterilization and validation are greatly reduced or eliminated, thus enabling multiple products produced in the same facility at smaller lot sizes.

Another industry area where single-use bioreactors can be very effective is in biosimilar manufacturing. Biosimilars will have new technologies available that the original biopharmaceutical manufacturer did not, including single-use systems. Speed to market plus reduced cost will be key drivers in the success of biosimilars. In terms of speed, single-use bioreactors clearly have the advantage by offering reduced installation time, no piping infrastructure required, and easy set up with “ready out of the box” type operations. In addition they offer more attractive economics with lower start up costs and lower water for injection use requirements.

Clinical Trial Material
There has also been a great deal of interest in the ability to manufacture clinical trial material with limited investment. When drugs enter clinical trials it is unclear at that time how the drugs will do or if they will eventually earn approval. The attrition rate for investigational drugs is quite high, so logically companies do not want to make significant capital investments in manufacturing these products prior to approval. The flexible manufacturing offered by single-use bioreactors is perfectly suited to address these needs. Clinical trial manufacturing campaigns can be initiated to manufacture the necessary product and then can be switched to manufacture a different drug or could be taken offline until future need arises.

With product globalization, there is a desire to manufacture medicines closer to the populations that they will be supplied to. This also provides some security with respect to facilities going offline. If one facility goes offline due to contamination, natural disaster, etc., the entire product supply chain will not be disrupted. With flexible manufacturing options, more single-use bioreactors could come online to address any temporary shortages. Ideally model single-use system facilities could be designed with the goal of replicating these facilities in multiple countries or regions.

Employing Single-use Systems Facility Wide
While single-use stirred bioreactors are a primary enabling strategy to achieving the goal of flexible manufacturing, there are a variety of single-use technologies, which when combined, create entire single-use systems that can support the entire biomanufacturing process from upstream to downstream. Single use products like disposable mixers and filters can aid upstream preparation of cell culture media. In manufacturing, single-use bioreactors and single-use mixers offer many advantages in terms of reduced cleaning, sterilization and validation up to the 2,000 liter scale. Finally downstream can take advantage of single-use filtration, centrifugation and chromatography options, many of which are still in development and improving rapidly.

A recent study titled “Fast Track API Manufacturing from Shake Flask to Production Scale Using a 1000-L Single-Use Facility” by B. Minnow, et al., and published in Chemie Ingenieur Technik, describes how Rentschler Biotechnologie set up a “fast and flexible multipurpose manufacturing facility in the 1,000L scale”. The completely single-use facility was awarded Facility of the Year in 2012 by the International Society for Pharmaceutical Engineering. The facility was able to reduce manufacturing costs, timelines and experienced increased flexibility for clinical manufacturing. Scale up was from shake flasks to 1,000L production scale.

In the study, a CHO DG44 DHFR line producing a monoclonal antibody that was optimized for high titer was thawed and initially expanded in shake flasks. Further cell expansion was performed in 50L and 200L XDR single-use stirred bioreactors (Xcellerex). The final production reactor was a 1000L XDR single-use stirred bioreactor (Xcellerex). A 28 day (vial thaw to harvest) fed batch process was used in the study.

The scale-up was performed based on calculating the specific volumetric power input, which allowed a direct transfer from small culture volumes to the production scale. A seeding volume of 700L was used.

The study demonstrated that fast track protein production could be achieved in less than 12 weeks from cell bank to final bulk drug product. The authors of the study stated the following in the conclusion. “With these experiments a fast track concept for the manufacturing of active pharmaceutical ingredients in single-use bioreactors combined with a robust and reliable process was shown. This led to a short manufacturing timeline from clone to product. A well-known and also simple scale-up strategy was applied and the calculated specific volumetric power input was used as key scale-up parameter. Additionally, results regarding product quality and titer as well as reproducibility in key process parameters are highly comparable. Finally, it was concluded that the applied scale-up method is feasible for single-use bioreactors in production scale as well as for non single-use bioreactors in laboratory scale.”

With the many pressures facing biomanufacturing today including cost effective manufacturing, stringent regulatory requirements and effective capacity management coupled with the many different product demands, it is not surprising that companies are looking for more flexible manufacturing options. In particular, single-use bioreactors and platforms enable fast-track manufacturing strategies. Single-use stirred bioreactors and single-use system based facilities are key in enabling these processes and moving manufacturing forward to meet new biopharmaceutical manufacturing challenges.

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