A Decade of Production

Single-use technology has arguably been the biggest “story” of the past 10 years in bioprocessing. And for many people, implementation of disposable elements began soon after the turn of the century with a bioreactor (1, 2), first developed by Wave Biotech in 1996, now a mainstay of many upstream process development laboratories and sold by GE Healthcare. BPI identified the significance of such technologies early on, making them the subject of a supplement in its second year.

By the fourth installment of what became an annual tradition, there were even more disposable bioreactor options available than I could pack into an overview article (3), as I heard from a few readers after it was published. A 2009 update by two Swiss academics narrowed the field to two main categories: static and dynamic bioreactors (4). Among the latter, mechanically driven (rotating, shaken, stirred, and wave-mixed) options outnumbered the pneumatically or hydraulically mixed options, and hybrid systems were already being seen. Skimming the tables of contents in our most recent supplements covering single-use technology, you’ll see that disposable bioreactors are well entrenched these days.

Cell-Line Engineering

As our popular 2009 wallchart showed, animal cell culture and microbial fermentation dominate the field of biopharmaceutical protein expression. Another big story in our first decade of publication relates to cell line engineering. After a manufacturing capacity shortage was projected in the late 1990s, upstream process engineers took it upon themselves to address the problem (5). Resulting improvements in production titers and product quality are still reverberating throughout the industry, where the new “bottleneck” is seen in downstream processing. And the achievements of cell-line engineering continue to this day.

Culture Media

Concern about transmissible spongiform encephalopathies around the turn of the century didn’t begin the trend toward eliminating animal-sourced materials from bioprocessing, but in addition to some viral contamination incidents since then, it certainly pushed it along. As a result, media supplementation and optimization have not only risen to prominence, they’ve played a significant role alongside cell-line engineering in the unprecedented production improvements over the past decade.

We’ve covered the topic of media from all angles, including historical overviews (6) and how-to papers (7), detailed case studies and technical reports. One of my favorite stories to follow began as a mere “vendor voice” early in our second year (8), exciting to me partly because it was our first article from Australia. I was pleased to see that particular supplement later licensed by Novozymes, then SAFC. And I revisited the story once again while working on 2011’s special Asia–Pacific issue (9).

Process Analytical Technology

Another early vendor voice article — in our very first issue — typifies the supplier side of an important regulatory trend (10). Though unheard-of in our first issues, quality by design (QbD) has become pervasive in bioprocessing. And process analytical technology (PAT) is evolving to support it. BPI has documented the industry’s steps along the way — from the appearance of Aber Instruments Ltd. in “Volume 1 Number 1” to Genentech’s evaluation of a PreSens system from Precision Sensing GmbH in January 2012.

Early on, BPI had a hard time convincing some people that these things would be important — just as our sales staff had to talk us editors into devoting an entire supplement to disposables in 2004! But with the 2011 release of the FDA’s new process validation guidance document, few doubters remain. Analytical instrumentation isn’t “too researchy for BPI,” an argument I’ve been making ever since the appearance of well-characterized biologicals over a decade ago. Now everyone knows it’s vital to the success of every product and every biopharmaceutical company.

The Best Is Yet …?

Transgenics is one subject on which I’ve been proven wrong so far. With my love of both animals and gardening — thanks, perhaps, to farmers on both sides of my family tree — I was keenly interested in this topic from the beginning. It represented the intersection of my two greatest passions: nature and science fiction. So understandably I was excited by the idea of animals or plants that could “better” produce what factories did.

The “capacity crunch” that eventually petered out had a lot to do with early industry and investor enthusiasm for transgenic animals and plants as potential protein expression systems. But as early as our second year, BPI was reporting on troubles as well as successes for the companies involved (11, 12).

The problems go hand in hand with other production-related trends mentioned here. Regulators want to see more process control (QbD/PAT) and fewer animal-sourced ingredients. Whole organisms are more difficult to control, and whole animals are . . . well, animals. Meanwhile, cell-line engineers and process engineers have made culturing cells more efficient, more productive, and even more environmentally sustainable (13). Alongside a daunting regulatory path, that does make transgenics a less attractive option than they once might have been.

However, that is not to say that the concept is dead — far from it. For example, Eric Langer reported on several vaccine makers that are betting on transgenic plants (14). And what I first saw in our 2004 protein expression supplement as a fairly obscure species of aquatic plant (11) has evolved into a powerful option thanks to the efforts of Biolex Therapeutics, Inc. As reported by Keith Everett earlier this year, the company has taken advantage of single-use technology to help address many of those process-related regulatory matters even while developing the expression technology itself. GTC Biotherapeutics (now a member of the LFB Group) has thus far seen the most success with transgenic animals. Its ATryn recombinant human antithrombin product was approved for the European market in 2006 and for the US market in 2009.

REFERENCES

1.) Wong, R. 2004. Disposable Assemblies in Biopharmaceutical Production: Design, Implementation, and Troubleshooting . BioProcess Int. 2:S36-S38.

2.) Fries, S. 2005. Evaluation of Disposable Bioreactors: Rapid Production of Recombinant Proteins By Several Animal Cell Lines. BioProcess Int. 3:S36-S44.

3.) Scott, C. 2007. Single-Use Bioreactors: A Brief Review of Current Technology. BioProcess Int. 5:S44-S51.

4.) Eibl, R, and D. Eibl. 2009. Disposable Bioreactors in Cell Culture—Based Upstream Processing. BioProcess Int. 7:S18-S23.

5.) Scott, C. 2006. 30 Years at the Heart of Biotechnology . BioProcess Int. 4:S2-S4.

6.) Scott, C. 2005. Developments in Media for Culturing Cells. BioProcess Int. 3:S16-S27.

7.) Johnson, T. 2005. Promises and Pitfalls of Cell Line Adaptation: Some Basic Protocols . BioProcess Int. 3:S52-S56.

8.) Yandell, C. 2004. An Analogue of IGF-I: A Potent Substitute for Insulin in Serum-Free Manufacture of Biologics By CHO Cells. BioProcess Int. 2:56-64.

9.) Scott, C. 2011. Australia: Gateway to the Asia–Pacific Region . BioProcess Int. 9:4-7.

10.) Carvell, JP. 2003. Monitoring “Live” Cell Concentrations in Real Time: Using RF Impedance to Optimize Fermentation and Cell Culture Processes . BioProcess Int. 1:70-75.

11.) Montgomery, SA. 2004. Chapter 4: Transgenic Animals — Walking Bioreactors . BioProcess Int. 2:S40-S51.

12.) Rosin, LJ. 2004. Chapter 5: Transgenic Plants — Bio-Farming for the Future. BioProcess Int. 2:S52-S61.

13.) Scott, C. 2011. Sustainability in Bioprocessing: Not Just an Afterthought . BioProcess Int. 9:25-36.

14.) Langer, E. 2011. New Plant Expression Systems Drive Vaccine Innovation and Opportunity . BioProcess Int. 9:16-21.