Daniel C. Boone 2018-02-16 23:44:36
Editor’s note: Six Sigma is a set of techniques for process improvement. Engineer Bill Smith introduced it while working at Motorola in 1986, and Jack Welch made it central to his business strategy as CEO of General Electric. Six Sigma relies on a team effort to identify and remove waste and minimize the variability in manufacturing and business processes. Each Six Sigma project follows a defined sequence of steps and has specific value targets, for example: improve product quality, reduce process cycle time, reduce pollution, reduce costs, or increase customer satisfaction. Whether it’s the complexity of a bioprocess, the inherent variability in raw ingredients and suppliers, or the inefficiency of the harvesting process, implementing Six Sigma methods and process controls into microbial fermentation is a challenge. With increasing market demand for biologics, increased competition, and constant advances in biotechnology, the need for money-saving process control is more desirable than ever. Experience in fermentation can help in identifying potential sources of variability; however, a true demonstration of process control is species-specific and requires a deeper understanding of what’s happening at an ecological level. The expression “you can’t tell a player without his scorecard” applies directly to working with biologics. A firm understanding is needed of the ecological niche that’s occupied by the organism of interest. The organism that’s selected or engineered for production is often the fastest grower—and obviously produces the desired active ingredient—but an organism’s sensitivities to environmental stressors, which lead to variations in yield, are often not used in the selection process. Factors that contribute to process variability from organism to organism can be further understood by understanding the environment from which an organism is selected. Optimizing that environment will not only maximize yield; it will reduce variation as well. A production environment that closely correlates to the natural environment to which the organism has adapted will reduce the biochemical and physiological changes that would occur in the organism in a less natural production environment. Unfortunately, biochemical factors such as C:N ratios in substrate selection and environmental parameters such as temperature and airflow are often better understood than the variability caused by the interactions of secondary metabolites or environmentally induced stressors. Of course, the fermentation process itself can be the largest contributor to variability. Liquid fermentation is becoming an industry standard for production of the secondary metabolites used in the agricultural, chemical, pharmaceutical, and food industries. The advantages of liquid fermentation, from a process control standpoint, are improved automation of the environmental controls and the precision of the raw ingredients. If process control were the only influential factor in deciding which fermentation process to use, then liquid fermentation would be an easy choice. Solid fermentation is often selected as a fermentation process because it mimics the natural growing process of many organisms. Process control with solid fermentation can be a challenge due to the non-uniformity of the substrate, as compared to liquid fermentation, and the variability of the raw ingredients from the suppliers. Simplifying the substrate with as few raw ingredients as possible is necessary for process control, even if it means potentially sacrificing occasional high yields for batch continuity. Strengthening the quality control process with the raw ingredient suppliers is also a must. The associated processes—such as inoculation and incubation—can’t be ignored. Advances in technology have made the regulation of gas exchange and temperature during incubation much easier than in the past. However, variation still exists. Implementing Six Sigma for all these processes, from start to finish, has advantages. For instance, eliminating nonessential processes and ingredients allows better timing, focus, and control of the essential processes and ingredients. Conducting a design of experiments (DOE) on the formulations may help distinguish between essential and non-essential factors and lead to cost savings. Running through the process flow map and performing a failure mode effects analysis (FMEA) may uncover significant areas that need attention. When working with biologics, process control is not optional. It’s essential for predicting stable yields, no matter how challenging the process may be. Six Sigma methods are just as useful for microbial fermentation as they are for any other manufacturing process. A deeper understanding of an organism’s natural habitat will aid in reducing variation and make predictability more achievable in an inherently variable industry. ASABE member Daniel C. Boone, Process Microbiologist, BioWorks, Inc., Victor, N.Y., USA, firstname.lastname@example.org. Further Reading Ecology levels: From individuals to classrooms. Mountain View, Cal.: Khan Academy. Retrieved from https://www.khanacademy.org/science/biology/ecology/intro-to-ecology/a/ecological-levels-from-individuals-toecosystems Morales-Ramos, J. A., Rojas, M. G., & Shapiro-Ilan, D. (Eds.). (2014). Mass production of beneficial organisms: Invertebrates and entomopathogens. Amsterdam, The Netherlands: Elsevier Science.
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