The Next Bioprocessing Revolution: Functional Additives

Since the first large-scale bioprocessors started churning out cell culture–derived products more than two decades ago, manufacturers have been working towards more and more ambitious production goals. Advancements in this industry include the development and implementation of optimized cell lines, medium and feeding strategies, disposable culture vessels, and in-process monitoring instrumentation. Manufacturers striving for everincreasing product yield have had to implement these technologies in ways that ensure regulatory standards are met and that product quality is uncompromised. Now that many bioproduction technologies and processes are reaching maturity, manufacturers are seeking out the next level of refinements.

The next stage in bioprocess refinement
Commonly seen in production processes is the failure of cell lines to sustain specific productivity throughout the manufacturing time course, with drops typically observed as the culture period progresses. Manufacturers have implemented a variety of strategies to achieve sustained productivity, including (1) selecting or engineering cell lines with better performance profiles, (2) use of culture vessels that allow very fine control of temperature, pressure, agitation, pH, and dissolved oxygen to maintain optimal conditions, and (3) measuring viable cell levels and various metabolites during culture in an effort to define corrective supplements and treatments that would increase cell densities and the amount of protein being produced without significantly increasing the levels of inhibitory factors [1,2].

While culture modulators such as high-pH, singlecomponent additions and the addition of growth factors, hydrolysates, sodium butyrate, etc. can yield improved titers, there is some concern that these supplements: 

• Pose additional safety risks to production staff
• May compromise the steady state of the bioreactor
• Could adversely affect the quality of the end product
• Could jeopardize the regulatory compliance of the process

For most established fed-batch processes, increases in productivity have been largely achieved through systematic optimization of media formulation and the development of feeding regimes that support higher cellular biomass and cell-specific production of the molecule of interest [2]. As an extension of successful fed-batch strategies (such as the use of matched media and feeds), the next stage in bioprocess refinement involves the development of highly concentrated functional additives that can be added to each bioreactor run in the smallest amount necessary to give good titer increases. Ideally, these functional additives would have neutral pH and be formulated using standard cell culture media components so that no additional risks to personnel, bioreactor steady state, or product quality would be imposed.