A Convergence of New Products and Technologies Changes the Game

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. ()

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.

The Future of BioManufacturing

The BPSA was formed in 2005 as an industry-led corporate member trade association dedicated to encouraging and accelerating the adoption of single-use manufacturing technologies for producing biopharmaceuticals and vaccines. Having recognized BioProcess International as an early proponent of disposables in biomanufacturing, the organization worked closely with us over the years since, and we have published several of its best-practices consensus guideline documents along the way. This member-led organization represents the industry to regulatory bodies and serves as a networking resource for its corporate members, seeking industry consensus at all levels. Its members are the major “movers and shakers” in single-use bioprocess technology.

What have they done? From a product category largely defined by plastic shipping/storage containers and bags used for mixing and containing powdered culture media and supplements upstream and chromatography buffers and formulation ingredients downstream, single-use innovators have greatly expanded their offerings. Added tubing, adapters, connectors, ports, filters, automation, chromatographic membranes, and sensors have extended disposables into applications as diverse as small-scale seed culture, full-scale fermentation, separation and purification, and formulation and filling. Companies such as Xcellerex and Celliance (now Millipore) have touted their ability to perform an entire biomanufacturing process using disposables almost exclusively (39,40). To that end, Xcellerex recently integrated SciFlex and SciPure downstream processing products from SciLog into its FlexFactory biomanufacturing platform.

Other Technological Advances: Other suppliers are making a difference, too. Pharmadule fabricates modular pharmaceutical and biopharmaceutical facilities for speedy project implementation. For high-performance inline photometric analyzers helpful in process monitoring and control, companies turn to optek-Danulat. Integration of a Groton ARS automated reactor sampler with a DASGIP bioreactor and YSI biochemistry analyzer provides automated, online real-time feedback control, which illustrates the potential of automation in bioprocessing. In a recent application note, Groton reported that controlled feeding of select amino acids increased protein production by >30% in and of itself (41). It’s a concept already being implemented by Genentech and Biogen-Idec.

Another means of producing therapeutic proteins in larger quantities using smaller bioreactors is to begin with a powerful cell line. Now famous expression systems include Crucell’s PER.C6 human cell line (reporting ≤27 g/L titers); the Pseudomonas fluorescens bacteria-based Pfēnex system (an alternative to the traditional Escherichia coli used in bacterial fermentation, with increased metabolic diversity and higher cell densities and product yields without requiring antibiotics, 42); and Lonza’s glutamine synthetase (GS) system for mammalian cells, which is regularly providing 5 g/L in many applications.

I’ve provided only a bare sampling of technologies that are converging to change bioprocessing as we know it. What are the results of this convergence?

A Truly Global Industry: In a January 2009 conference presentation, Howard Levine of BioProcess Technology Consultants described his vision of the biomanufacturing facility of the future (43). First, he said, future facility designs will have to accommodate high-titer (>10 g/L) processes. “Smaller bioreactors will produce similar quantities to today’s larger bioreactors.” The ratio of production floor space to processing floor space will decrease. “Facilities of the future will require greater downstream process space and capabilities to better handle the high-titer bioreactor output.”

The difference between pilot and commercial-scale plants is diminishing. It may be possible to perform continuous production in one location. Smaller facility requirements may enable smaller companies to construct and manage their own facilities more cost effectively than before. Increased use of disposables will further reduce capital investment and operating cost of manufacturing facilities.

Picture a single monoclonal antibody (MAb) manufacturing facility with six 2,000-L bioreactors (possibly disposable ones) running 12-day fed-batch CHO culture at 15 g/L to provide a 30-kg harvest. With an 80% purification yield, that’s 24 kg of MAb per batch, harvested every two days. Each year, this facility could perform 167 harvests (over 334 days), providing four tons of product annually. Each bioreactor would be served by a dedicated purification train. Levine estimates such a facility would cost less than US$100 million to build and ultimately translate to a cost of goods sold (COGS) at $70/g MAb. That’s a vast improvement over what was possible even at the end of the 20th century.

But “despite all this,” Levine says, “outsourcing may still be the better option.” A contract facility like the one described above could conceivably serve six drug sponsors making products for its local market (wherever it happens to be located) much cheaper than any one of those companies could do so on its own. To take advantage of the labor, utility, and/or shipping savings of making it where you sell it, some may build their own facilities in faraway locales — but many are finding that savvy contract manufacturing organizations (CMOs) have set up shop overseas already in anticipation of the industry’s true globalization. Outsourcing to them might help drug sponsors get around the challenges associated with overseas operations, as I discuss in Chapter 4.

So how are vaccine manufacturers leading the way into this future? Relatively new vaccine companies such as Bavarian Nordic (which is headquartered in Denmark with operations in Germany, the United States, and Singapore) are using modern cell culture practices to make vaccines for multiple markets (44). They know that new technologies have made it possible for them to enter into the expensive world of biologics manufacturing. This helps them work within short project timelines to minimize contamination risk in highly flexible facilities:

The 2009 response by vaccine manufacturers to the H1N1 pandemic revealed the convergence of three technological developments. First is a revolution in technology: Vaccines are being developed for diverse and unprecedented applications through a number of entirely new approaches. Second is the recent adoption of cultured cell-based production for a growing number of vaccines, such as influenza. And third is the rapid acceptance of single-use technology in bioproduction overall. (45)

That influenza outbreak illustrates the speed with which vaccine makers often need to go from zero to 60 mph in production. That need, along with the varied finances of patients internationally, led them to consider first the idea of making products where you sell them. Novavax uses insect cell culture and disposables in a manufacturing concept that can be fully transplanted to where it’s needed. On its website, the company states that smaller facilities can be “distributed to regions that need a local supply of influenza vaccine.” This is important in pandemic influenza response, when vaccine access is be limited and countries may have a desire to be self-sufficient within their borders rather than depending on foreign suppliers and importation issues. In collaboration with GE Healthcare, Novavax has made in-country vaccine manufacturing possible.

Combined with numerous advances in vaccine technology itself, this has brought out the renaissance of an industry once known for low profit margins and limited opportunity. As technologies converged to make that happen, biopharmaceutical companies have taken notice. When it comes to saving money while maintaining product quality and efficacy, they’ve always been interested — but the modern business environment is transforming that interest into an imperative.

Vendor companies are taking steps that will enable biopharmaceutical manufacturers to consider the options described in this special issue. Many are opening distribution and service centers in far-f lung regions of the world from Asia to Australia, the Middle East, the Indian subcontinent, and eastern Europe. Companies choosing to “make it where they sell it” will be able to buy “locally” even as they think globally.

About the Author

Author Details
Cheryl Scott is senior technical editor of BioProcess International, 1574 Coburg Road, #242, Eugene, OR 97401; phone/fax 1-646-957-8879; [email protected]; www.bioprocessintl.com.

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