October 1, 2014 (Vol. 34, No. 17)

William Downey

In July 2014, CMC Biologics announced that it had entered into a commercial supply agreement with Portola Pharmaceuticals to produce andexanet alfa, a potential first-in-class Factor Xa inhibitor antidote. 

One of the reasons cited by Portola Pharmaceuticals for entering into a supply agreement with CMC Biologics is the need for an accelerated development timeline.

“Extending our collaboration with CMC as a contract manufacturing partner through commercial launch will help us meet our accelerated development timelines for andexanet alfa, with the goal of going from IND to BLA in under four years,” said John T. Curnette, M.D., Ph.D., executive vp of research and development at Portola Pharmaceuticals.  As a result of this new supply agreement, CMC Biologics will double its manufacturing capacity at its Bothell, WA facility.

“The expanded collaboration with Portola enables a strategic expansion for CMC Biologics and underscores our technical competence in the manufacture of complex proteins and coagulation factors. We are excited to help bring this valuable new class of drug to market,” said Gustavo Mahler, Ph.D., global chief operations officer at CMC Biologics.

An Evolving CMO Landscape

The agreement between CMC and Portola reflects some of the trends that are reshaping the biopharmaceutical contract manufacturing industry.

To explore these trends, pharmaceutical and biotechnology executives were asked about their expectations regarding contract manufacturing organization (CMO) business opportunities, novel therapeutics, accelerated development timelines, partnering relationships, and flexible manufacturing. The executives’ insights have been summarized in a report entitled, “Biopharmaceutical Contract Manufacturing 2014: Improving Markets, Services, and Technologies.”

Participating executives included CEOs, vice presidents of technology and manufacturing, and operations directors. The major trends identified by the executives include smaller production batch sizes, greater use of single-use bioreactors and disposable technologies, consolidation of biopharmaceutical CMOs, and the adoption of specialized technologies by CMOs to serve niche market needs (Table 1).


Table 1

Smaller Batch Sizes

The industry trend most often noted by the executives is the shift to smaller batch sizes and the associated shift to smaller-volume bioreactor tank sizes for biopharmaceutical production. The major reasons for this shift to smaller batch sizes are twofold: 1) biopharmaceuticals will target smaller patient populations, and 2) manufacturing productivity improvements.

Many of the biopharmaceuticals in development are novel therapeutics that target smaller patient populations, which obviates the need for large-scale bioreactors. In addition to novel biopharmaceuticals, CMOs will continue to make productivity gains, which reduce the need for larger batch sizes. Improvement in operations, cell-line technology, and better downstream recovery rates make the need for large-scale bioreactor tanks less compelling.

Furthermore, a few executives also mentioned that they expect production configurations and practices to change whereby production from smaller bioreactors run in parallel will be preferred to production from a few large-scale bioreactors.

Below are selected comments from the pharmaceutical and biotechnology executives regarding the trend toward smaller batch sizes.

  • “Long-term, I see the movement of biologics into personalized medicine, which require smaller batch and run sizes. New biotech companies hesitate to build internal manufacturing capacity, which makes business more favorable for the contract manufacturing organizations.”
  • “I expect cell-line technology to continue, leading to two- to threefold further increases in titers. I also expect we will increasingly entertain perfusion or semicontinuous processes and smaller footprints. Also, as demand increases, I expect we will see more scaling out than up, such as smaller bioreactors run in parallel versus fewer larger reactors. It offers more flexibility to have four multiplexed 2,500 L reactors than one 10,000 L reactor.”
  • “We’re seeing volumetric capacity coming down dramatically due to cell-line productivity levels. Twenty years ago, a 10 g/L cell line would have been a pipe dream. Now it’s reality. There will probably be more niche biopharmaceuticals as well, with smaller volume requirements.”

Shift to Single-Use Bioreactors

Because of the shift to smaller batch sizes combined with larger-scale single-use bioreactors (SUBs), the pharmaceutical and biotechnology executives expect CMOs to expand their use of SUBs. The advantages of SUBs have been well documented, including lower up-front capital costs, greater manufacturing flexibility, and improved throughputs.

While the overall trend toward disposable technologies is positive, there continues to be some technical concerns about the unknowns associated with plastic disposable systems such as leachables and the environmental impact of using disposables compared to stainless steel. Despite these concerns, most pharmaceutical and biotechnology executives expect SUBs and other disposable technologies to continue to be adopted by CMOs in the coming years.

A few insightful comments regarding single-use technologies from the surveyed biomanufacturing directors are shown below.

  • “There will be greater integration of 2,000 L disposable bioreactors, higher-producing cell lines (not much higher than available today), and higher capacity chromatography resins. This is what the CMOs dream of.”
  • “The long-term trends for the biopharmaceutical contract manufacturing industry and market are an increased use of single-use technologies, more flexible and multiproduct facilities, and an increased use of platform methods and technologies that increase the speed to the clinic.”
  • “There will probably be an increase in the use of disposables, although I am not totally convinced. We deal with a lot of companies who say that they are moving away from disposables back to stainless steel.  There is concern about plastics, extractables, and leachables, such as slippage agents, which are fatty acid amides that help make plastic surfaces easier to separate. There is a suspicion that a suspension from the slippage agents may leach into product.

“Overall, there is an impression that plastic disposable systems are not environmentally friendly, and this is a growing consensus, despite the flexibility of plastics and being able to throw the system out and start again very quickly compared to stainless steel. At least with stainless steel, you know where you stand.”

Industry Consolidation

The third most mentioned trend noted by the executives is further consolidation among CMOs. Recent consolidations in the biopharmaceutical contract manufacturing industry include Wacker Biotech’s purchase of Scil Proteins Production, KBI Biopharma’s acquisition of Merck & Co.’s microbial process development and manufacturing operations, Gallus Biopharmaceuticals’ acquisition of Laureate Biopharmaceutical Services, and DPx Holdings’ subsequent announcement to acquire all shares of Gallus Biopharmaceuticals, LLC.

These acquisitions have increased the capacity and capabilities of the acquiring CMOs, as well as offering a way for CMOs to provide its clients with greater offerings and improved scale of operations. Such advantages were cited by Thomas Maier, Ph.D., managing director at Wacker Biotech, when his company acquired Scil Proteins, a microbial CMO with an EMA-approved and FDA-inspected facility located in Halle, Germany.

“Our customers highly appreciate this strategic move as we doubled our process-development capacities and added strong refolding expertise to our established technology portfolio for the secretion of proteins by E. coli,” said Dr. Maier. “With a commercial product in our 1,500 L facility and an ongoing approval for our 300 L facility, Wacker Biotech is now offering unique microbial services from ‘scratch to commercial batch.’ ”

Mergers also offer CMOs an opportunity to gain synergies from greater scope of operations. As noted by one executive, “I see more consolidation among CMOs to get bigger and diversify their offerings. Companies will have both mammalian and microbial manufacturing and synergy in what they have to offer. For technical development, they are tackling a difficult issue. Bioreactor productivity has increased, but downstream purification has not kept up. I expect these new technologies, as they are developed, will differentiate CMOs in the future.”


A key trend cited by pharmaceutical and biotechnology industry executives is the consolidation of CMOs. Just one event contributing to this trend was the recent purchase of Scil Proteins Production by Wacker Biotech. Wacker picked up Scil’s patent portfolio as well as the acquired company’s manufacturing site in Halle, Germany. When the acquisition was announced in November 2013, Wacker executives asserted that Scil’s protein refolding expertise would complement Wacker’s protein secretion know how, reinforcing Wacker’s role as a full-service provider of microbially manufactured biologics. If proteins cannot be produced in an active form in bacterial cells, the inactive proteins can be made active by means of refolding.

More Specialty Technologies

Finally, many of the pharmaceutical and biotechnology executives expect CMOs to offer more specialized technologies in the future. The executives expect smaller CMOs to follow a strategy that focuses on specialized services with the goal of being experts in specific areas or technologies. Specialization should improve service levels to smaller biotechnology companies and improve industry-wide profitability.

The move toward more specialization is summarized by one executive as follows: “Manufacturing will become more niche oriented. Smaller CMOs will specialize. Even large CMOs will specialize. This is needed for more unusual products that are coming to market nowadays. I see large CMOs purchasing smaller specialized CMOs (such as fill-and-finish, high expression cell lines) and offering their specialties, while the large CMO focuses on bulk manufacturing.”

An example of a CMO specializing to serve a niche in the biopharmaceutical contract manufacturing market is noted by Pascal Bolon, Ph.D., biologics sales and marketing manager at Eurogentec: “[Our company] invests in and develops new, cutting-edge manufacturing technologies to become the number-one supplier. This includes plasmid DNA manufacturing, glycosylation-free protein manufacturing in Pichia, and manufacturing of chemically modified proteins.

“In the field of GMP plasmid DNA production, we have developed a strong track record. We are working on late-clinical phase projects and early-phase projects that require large-scale production as a result of large doses.”

Conclusion

Pharmaceutical and biotechnology companies are relying more and more on CMOs for the production of their biopharmaceuticals, both in clinical and commercial phases.  Demands by CMO clients for faster and more flexible production of biopharmaceuticals is driving some of the major industry trends. Smaller batch production sizes, the greater use of SUBs and disposable technologies, more CMO consolidation, along with more diverse service offerings and greater specialization by smaller CMOs to serve niche markets are the major industry trends seen by the pharmaceutical and biotechnology executives.

William Downey is president of High Tech Business Decisions, which recently published Biopharmaceutical Contract Manufacturing 2014: Improving Markets, Services, and Technologies.