Vaccine makers are leading the way — that's something you don't hear every day. For many years, vaccines were seen as “old-school” and less profitable than other biologic products — and they were the business of just a few huge companies. But thanks to recombinant technology, it's a real Cinderella story: Advancing technologies led to what's being called the “vaccine renaissance.” And now, vaccine companies may have something to teach their biopharmaceutical brethren.

In April 2004, BPI may seem to have been speaking too soon with its “Vaccine World” supplement, in which I wrote of cell-culture–based vaccine manufacturing as though it were a done deal (1). It made perfect sense to me (as a technically inclined but not economically inclined sort of person), especially for the new vaccine products that were being developed (2). In the same special issue, two former BPI editors pointed to another aspect of the vaccine business that was driving it in new technical directions: the conflicting economics of serving both developed and developing markets (3).

Now, six years later, BPI is looking at the biotech industry's response to those technical and economic challenges. Immunotherapeutics are becoming a reality, many new vaccines are on the market and in development, and a number of companies have jumped into the arena. New product and process technologies have made this possible, and they're helping companies address the needs of emerging global markets. As vaccine makers discover how to shift manufacturing closer to the people who most need the products they make, the rest of the biopharmaceutical industry is realizing that a similar approach might work for them, too. For makers of monoclonal antibody (MAb) and other protein therapeutics, it's not so much about speed (new vaccines need to be in doctors' hands as soon as possible after an infectious outbreak occurs) as about cost: If a biologic can be made at lower cost, then it should be able to sell for less, and that could open up some markets that were unable to afford it before.

Fully automated roller-bottle culture for virus production at IDT Biologika, which received the 2008 ISPE Facility of the Year Award in operational excellence for its state-of-the-art manufacturing site in Dessau-Rosslau, Germany. (Click to enlarge)

In a world where the expense of life-saving treatments is increasingly under scrutiny — while the necessary capital to keep moving forward is in shorter supply — biopharmaceutical companies must find new ways of doing almost everything. Technology, geography, and regulation combine to offer some shelter in this perfect storm of adversity: Regulatory agencies around the world have been working to harmonize their requirements for good manufacturing practice (GMP) and product testing, in particular through the efforts of the World Health Organization (WHO) and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Biologics in the 21st century are better understood and characterized than ever before, making equivalency easier to demonstrate. Methods of risk assessment and management are helping companies make process decisions and justify them clearly. And relatively new players on the world economic stage are demonstrating their interest and ability for biotechnology. Yes, all that makes biosimilars inevitable — but it also allows innovator companies more flexibility in their own manufacturing.

The New Frontier

Enabling technologies for those advances run the gamut from analytical methods for product characterization to high-titer expression and optimized production methods to platform technologies for downstream processing, as well as widely available disposables, emerging automation options, and overall process control. Together, these can help vaccine and biopharmaceutical makers get around historical facility constraints such as extensive hard piping and clean-in-place/steam-in-place (CIP/SIP) systems, large facility footprints, and legacy processes and systems that are hard to update. Just 10 years ago, the idea of a portable manufacturing process — as has already been explored by many vaccine manufacturers — would have been ludicrous. But the first decade of the 21st century has been a time of true revolutionary change in the biopharmaceutical industry.

Design Space and Process Control: New regulatory ideas and initiatives are often greeted with skepticism and trepidation in the biopharmaceutical industry. Case in point: the 21 CFR Part 11 final rule that first appeared in the late 1990s (4,5). In fact, the word validation was once considered a big question mark (Could it even apply to biologic processes?). Even the improved comparability rules of the late 1990s had some people looking askance (Didn't they offer a glimpse into a future of generic competition? Short answer: Yeah, pretty much.) — and rightly so. The concepts of risk management, design space, process analytical technology (PAT), and quality by design (QbD) have been no different (6,7,8,9,10,11,12).

All difficulties of implementation and applicability aside, QbD and all its supporting acronyms have taken comparability to the next level. This new paradigm not only illuminates a pathway toward biosimilars, but it also provides a framework within which biopharmaceutical companies can optimize and transfer their processes in reaction to the kinds of financial and market forces that have traditionally buffeted the industry. PAT and risk management techniques provide the means by which a design space may be established, which defines the boundaries for making changes without affecting product quality, safety, or efficacy. Such changes may involve raw material sources, cell culture media, downstream technologies, manufacturing scale, and yes, facility location. Improved reliability and specificity for process control enables companies to keep everything on track.

Doing More with Less: Late in the 20th century, questions of manufacturing capacity presented biotech researchers with a challenge they met head-on. Particularly successful were those involved in cell-line engineering (13,14,15,16,17,18). So successful were they that the baseline expectation for product expression titers in mammalian cell culture went from 100 mg/L or so to 1 g/L — and by now it's not uncommon to see expression levels as high as 10 g/L, with some production groups reporting up to 20 g/L. Just that initial tenfold increase conversely reduced the necessary bioreactor size for producing a given amount of therapeutic protein. With newer designed cell lines, you could switch from a 1,000-L bioreactor to a 100-L one. And that's only the beginning. Changes in growth media improved animal cell culture even more (19,20,21).

Those upstream improvements were so dramatic that downstream process engineers began to face the daunting challenge of handling radically different types of process streams without detrimental effects to the protein of interest (22,23,24,25). By 2009, they'd broached and were offering real answers to the question of the downstream bottleneck, and many of those answers involved single-use technology (25,26,27,28,29,30).

Single-Use Technology: The final piece in the puzzle is single-use bioprocess technology. Since October 2004, our annual supplement series has charted the progress of disposable bioprocess systems and the biopharmaceutical companies that have implemented those products in their biomanufacturing processes — from “the disposables option” through questions of implementation, development of best practices, and full acceptance (31,32,33,34,35,36,37,38). The “FAQ” box lists many reasons why disposables have steadily increased in popularity. Companies such as the members of the Bio-Process Systems Alliance (BPSA) continue to innovate and work with bioprocessors to create new systems and components that provide biomanufacturing flexibility and widen the range of options available for development and manufacturing of biotherapeutics.