The Art of Bioreactor/Fermenter Scale-Up (or Scale-Down)

by Dr. Deb Quick

Effective bioreactor or fermenter scale-up/down is essential for successful bioprocessing. During development, small scale systems are employed to quickly evaluate and optimize the process, but larger scale systems are necessary for producing commercial quantities at a reasonable cost. But how does one effectively transfer the process between scales so that the process performs the same?

In an ideal world, the physiological microenvironment within the cells/microorganisms will be conserved at the different scales, but with no direct measure of that microenvironment the scientist identifies relevant macroproperties to measure and control to ensure comparability. There are many macroproperties and operating parameters that define the process at each scale, and while the goal is to keep as many of those parameters constant between the scales, it simply isn’t possible to keep them all the same.

When using the same operating parameters at small and large scale is impractical, there are several correlations that are commonly used: mass transfer coefficient (kLa [the volumetric transfer coefficient, 1/hr] or OTR [oxygen transfer rate, mmol/hr]; volumetric power consumption (P/V, agitation power per unit volume); agitator tip speed; and mixing time.

Matching the kLa at different scales is generally considered the most important factor in scaling cell culture and microbial processes. The second most common approach is to match the power consumption. For both of these correlations, there are often multiple combinations of operating parameters that provide the same kLa or the same power consumption at the different scale. And herein lies the art of bioreactor and fermenter scale-up/down. Selecting the best combination of parameters to match process performance at different scales is an art. There is no magic combination that works best for all cell types and products.

To establish comparability at different scales, you’ll make your life significantly easier if you start with the same vessel design at the different scales, but this luxury is rarely reality. More often, the development lab has significantly different equipment than the manufacturing facility. But even with different reactor designs, comparable performance can be obtained at different scales through appropriate experimentation.

• First, you’ll need to understand your equipment at all scales: measure the kLa and P/V of the different scales over a wide range of air flows, agitation rates, working volumes, and backpressures. It’s best to perform the testing in your process media, if possible. If you can find the time, it’s useful to evaluate different mixing schemes at small scale - different impeller styles and positions, baffles, and sparger styles and positions (particularly valuable if you already know the differences in these features between small and large scale systems available to you).
• Second, you’ll need to understand how your product responds to the different operating parameters. Those dreaded statistically designed experiments (DoE) are particularly useful for understanding the effects and interactions of the many parameters that can be changed. Performing DoE experiments at small scale with your product to evaluate the effects of aeration, agitation, and volume will not only help you with scale-up, but will also provide useful information for setting acceptable ranges for the operating parameters at large scale. As with the kLa studies, it’s useful to study different mixing schemes at small scale if time allows. One set of experiments that is highly useful but rarely performed is the evaluation of the process performance at the same kLa (or P/V) obtained using different operating parameters.

Understanding your equipment and how your product responds to various operating conditions is the key to effective process scale-up and scale-down. Despite the historical and ongoing need for scaling bioprocesses up and down, there is no strategy that works in all situations. The art of successful scale-up lies in thoughtful experimental design and thorough data analysis in order to obtain the information that allows equivalent performance at all scales.

Re-educating Leah

By Leah Choi

Four grueling years of chemistry, biology, math, and physics barely prepared me for life after college. As I entered America’s workforce on November 13th, 2006, I was equipped with nothing more than a general knowledge of what was to come.

Within my first few weeks at RMC Pharmaceutical Solutions, I quickly realized my inadequacies. GMP? GLP? NDA? IND? The acronyms alone could have driven me to near insanity. Likewise, I had spent four years at the University of Colorado learning the theory behind chromatography even putting it into practice on an ancient gas chromatography system. Yet this was no match for the advanced chromatography systems used in today’s biotech industry. To complicate matters further, I did not fully understand the intricacies of working in a regulated environment. What did it mean to follow a standard operating procedure? To evaluate and qualify the design, installation, performance, and operation of an instrument? What did it mean to document deviations? To perform a corrective and preventative action? Each new client and each new project presented a fresh set of unfamiliar issues. I often questioned if I would ever be able to bridge the gap between the theories of my college education with the applications of my working world.

Am I an isolated incident or do current biotechnology educational programs lack the necessary curriculum to develop entry-level employees? According to a recent survey conducted by AAPS (American Association of Pharmaceutical Sciences) and published by the National Institute of Pharmaceutical Technology and Education (NIPTE), 35% of respondents believe that current training for entry-level pharmaceutical development scientists is inadequate, 60% believe that there is a shortage of suitable candidates and nearly 70% asserted that there is an inadequacy in the number of US colleges focusing on industrial needs. According to this survey, academic programs training the majority of pharmaceutical product development scientists have declined substantially in recent years due to the emphasis in professional pharmacy programs on patient care rather than product knowledge. Additionally, these programs lack research funding in basic physical sciences supporting development and manufacturing.

With so much on the line, what is currently being done to address these nationally recognized problems? Organizations such as NIPTE have implemented plans with hopes of providing the “highest caliber entry-level scientists/engineers for the pharmaceutical and biopharmaceutical industries”. These plans include training students in degree programs using shared curricula materials, summer training programs and industrial internships via a network of industrial and institutional collaborators. The curriculum is based on “the precepts of interdisciplinary approaches strongly advocated by the National Academy of Sciences and constructivist learning theories important in the development of modern engineering and science higher education”. Presently, only ten universities have signed onto this plan: Duquesne University, Illinois Institute of Technology, Purdue University, Rutgers University, University Puerto Rico San Juan/Mayaguez, University of Connecticut, University of Iowa, University of Kansas, University of Kentucky, University of Maryland-Baltimore, and the University of Minnesota.

Other initiatives include the National Science Foundation (NSF) which currently provides $16.3 million in support of biotechnology programs through its Advance Technological Education (ATE) program. NSF regularly brings together scientists, educators, and other stakeholders to share their opinions on official issues such as biotechnology workforce development. Panelists share their opinions about how the biotechnology industry will grow during the next five years, the skills that technicians will require to meet workforce needs, and their experiences with promising educational practices. April 2008 conference recommendations include

1. instruction in written and verbal communication and “soft skill” such as team work and time management;

2. core curriculum courses that transfer and articulate from high school to two-year and four-year degree programs;

3. a strong theoretical understanding of the entire manufacturing process encompassing upstream and downstream process;

4. the introduction of immerging technologies in basic biotechnology courses; and

5. the redesign of standard microbiology and biology curricula to include applications in industrial and environmental biotechnology.

The limitations of ordinary degree programs spurred Montgomery College in Maryland to develop curriculum specifically aimed at preparing students for life after college. By soliciting information from industry personnel, coordinators of the program have developed and continually update courses that meet the current skill sets expected from entry level employees. Students acquire real life experience through internships engineered by the program. The success of this program depends highly on the continual collaboration between working professionals and academic faculty. Without a doubt, this synergistic dynamic allows both sides to benefit: educators gain valuable input for relevant curriculum while industry gains practical, productive entry level employees. Programs like these emphasize the absolute necessity for industry involvement.

I realize the learning curve is steep but not unconquerable. To all those recent graduates or better yet, those who are still in school the best advice I can give, is to get involved. Build your own bridge, by participating in professional groups and societies. Attend local events and seminars. Organizations such as the PDA (Parental Drug Association) AAPS (American Association of Pharmaceutical Scientists) and ISPE (International Society of Professional Engineers) often provide students with special benefits and discount memberships. As a PDA Student Member, you receive access to numerous benefits which provide you with the most current scientific and technical information. You receive access to Student Programs which provide grant funding and career growth resources, subscriptions to the PDA Journal of Pharmaceutical Science and Technology, including PDA Technical Reports which offer expert guidance and opinions on a variety of important scientific and regulatory topics pertaining to pharmaceutical and biopharmaceutical production.

Begin building contacts as early as possible. Make your first professional contacts at a career fair. Collect business cards and follow up. Professional social networking sites such as LinkedIn, Xing, Plaxo, and Spoke make these connections simple and instantaneous. Seek and invite professionals to speak at your school’s student group and find other means of collaborating with industry experts. Build a bond with someone who can act as a mentor. Having a mentor can be a great way to develop your career for the long term.

Take the opportunity to educate yourself on current topics and those of interest. Earlier this year, I was afforded the opportunity to gain valuable knowledge by earning a Certificate of Good Laboratory Practices/Good Manufacturing Practices from the University of Denver. We spent 10 weeks focusing on the regulations surrounding device manufacturing and use, specifically 21CFR820 and 21CFR58. My thirst for knowledge did not end there. In the same months I earned a Yellow Belt Training Certificate from the Colorado Association of Manufacturing and Technology. For six weeks my classmates and I studied yellow belt topics, specifically in the areas of Six Sigma Root Cause Analysis, 8D Problem Solving and Statistical Process Controls. Both of these courses were free, local and most importantly, offered helpful insights into contemporary subjects.

I commend unique programs and organizations such as NIPTE, NSF and Montgomery College for offering much needed curriculum that unites academia with industry. With increasing awareness and initiatives, my hope is that future graduates will be endowed with the basic education and ability to hit the ground running within this rapidly emerging industry.