March 1, 2014 (Vol. 34, No. 5)

Jeanene Swanson

The global biologics market is expected to reach $239 billion by 2015, $90 billion above the corresponding 2010 figure, reflecting a CAGR of nearly 10%. This growth rate, calculated by BCC Research, pertains to key market segments such as recombinant therapeutic proteins, monoclonal antibodies (mAbs), and vaccines.

When confronted by such broad-based, consistent, and robust growth, it is natural to ask: How can it be sustained?

The answer, in large measure, is contract manufacturing. Through contract manufacturing, outsourcers not only hope to expand, they also intend to accelerate drug development while reducing costs.

Whether they are pharma giants or relatively modest pharma and biotech firms, outsourcers (or prospective outsourcers) have had to consolidate operations and slash internal research budgets. In many cases, they have been responding to pressures such as imminent patent expirations and increasingly restive investors, or they are simply committed to increasing profitability.

The hopes and expectations of biotechnology companies have been summarized in a recent report issued by High Tech Business Decisions, a market research firm based in San Jose, CA. This report, which focuses on large-molecule drug substance production, also outlines the kinds of services contract manufacturers are developing to cope with industry demand. These services include cell banking, cell-line development, process development, technology transfer, and regulatory support.

Enhanced Capabilities

“Overall, [biologics manufacturing has become] a lot more competitive and much more price-sensitive” over the past decade, says Peter Coleman, CEO of Cobra Biologics. Coleman adds that while Cobra is seeing a greater number of large pharmaceutical companies interested in its services, the firm is trying to remain sensitive to the spending constraints faced by smaller biotech and early-stage companies. With a shortage of funding, “most of [them] have limited cash, and they’re looking for a discount or a partnership.”

In reaction to investor demand to produce more with less, companies across all spectrums are demanding more of contract manufacturing organizations (CMOs). In response, CMOs are increasing their capacities for both mammalian and microbial production, as well as forming agreements and broadening scope to become bigger and serve a more global market.

“There’s a shift toward larger companies using more outsourcing,” High Tech Business Decisions CEO William Downey says, including but not limited to outsourcing their manufacturing production. This is important as it provides the CMO space with more business.

A particular expansion is happening in the molecular diagnostics/IVD market, reports Harrison Ransom, director of marketing and sales at Biosearch Technologies: “Small and large CMOs in the rapidly expanding molecular diagnostics arena are facing a new product development environment that is no longer accessible only to large pharma or biotech companies.”

Ransom adds that “there is a growing bounty of smaller medical device companies with a single-minded interest in discovering and developing new and powerful diagnostic assays. These companies…come to a CMO to handle everything from provision of bulk components to complete fill-and-finish of client-branded diagnostic products.”

Cobra Biologics uses microbioreactor technology for improved monitoring and process control.

In February 2013, Biosearch Technologies purchased the oligonucleotide manufacturing division of Danish company DNA Technology and German manufacturer VitraBio. The deal, it said, reflected its growing interest in the European biotech and diagnostic markets. In April 2013, Biosearch Technologies relocated its GMP manufacturing into a new, 30,000-square-foot facility in Novato, CA, with the intention of expanding development for medical devices and molecular diagnostics clients.

In November 2013, Royal DSM purchased Patheon for $195 million and combined it with DSM Pharmaceutical Products (DPP) to launch a joint venture—a “powerhouse” contract development and manufacturing organization (CDMO). With a value of $670 million and 23 locations around the world, the new company announced plans to “accelerate growth” and offer an array of services from finished dosages for drugs to manufacturing of APIs.

“By achieving scale and having flexibility with more sites and more technologies, we can be more successful in the CMO space rather than being a small player,” comments Guy Tiene, director of marketing and communications at DPP.

Another opportunity is to serve companies looking to outsource the process development and manufacture of their molecules, explains Stephen Taylor, Ph.D., vice president and commercial director at Fujifilm Diosynth Biotechnologies, but clients present diverse requirements. “For some clients, the projects are becoming more modular as they take a step-by-step approach to their programs,” says Dr. Taylor. “With others, however, we work quite literally from ‘gene to GMP.’ We need to be flexible enough to accommodate both approaches.”

High-throughput screening of cell lines during early cell-line development at Fujifilm Diosynth Biotechnologies.

Single-Use Technologies

Single-use technologies, or disposables, are on the rise as drug companies pressure CMOs to improve efficiency and cost savings. In fall 2013, DPP opened a new cGMP facility in Brisbane, Australia. Key advantages of the facility cited by DPP included an output capability of 500 kg and space to expand. DPP’s president and CEO, Lukas Utiger, stated, “With its flexible design and use of single-use technology, the facility represents the model for the future of biomanufacturing.”

DSM is not the only company to move toward increased use of disposables. Fujifilm, notes Dr. Taylor, believes disposables have a role in producing next-generation mAb therapeutics, which are making use of the specificity of biologics. Not only is Fujifilm developing new mammalian cell lines and platforms for biologics production (the company has an alliance in place with Piramal Healthcare to deliver a one-stop solution for antibody drug conjugate developers), the company is also implementing single-use technologies to lower cost-of-goods.

To reduce time and costs in downstream mAb production, Fujifilm decided to try using disposables such as disposable downstream filters. According to the company, using disposables eliminated carryover, reduced cleaning requirements, and improved operator safety.

Fujifilm is building a new cGMP manufacturing facility in Billingham, U.K., where the company is headquartered. This manufacturing facility will primarily utilize single-use technologies, and it will initially offer 200 L and 1,000 L single-use bioreactors, with 2,000 L bioreactors already planned for 2014.

Investing in Efficiency

Increasing efficiency and reducing final cost of goods is key to optimizing biologics-based medicines. According to Downey, some trends he’s documented include improving cell-line development, raising titers (concentrations), gaining quicker turnaround times, and investing in high-throughput technologies. An example of a company picking up on these trends is Cobra Biologics. The company has invested in cell-line development and high-throughput technologies or robotics to improve titers and streamline production.

“It’s all about being fast, so we try to develop processes and expression systems that speed things up,” says Cobra Biologics’ Coleman. The company optimizes cell-line development with a process that utilizes ubiquitous chromatin-opening element (UCOE) technology to increase protein and antibody yields. This technology, the company asserts, can overcome a key obstacle to cell-line development by enabling quick isolation of high-expressing clones.

Cobra Biologics also makes use of an automated plate-handling robotic system (Cello™, from TAP Biosystems) for cell-line development, enabling large-scale, rapid clone selection. In addition, the company uses microbioreactor technology (Ambr, also from TAP Biosystems) for improved monitoring and process control. Microbioreactor technology, the company says, presents a significant advantage over shake-flask culture. Specifically, it allows data on the cells’ behavior and product characteristics to be collected before larger bioreactor studies.

Over at DSM, its XD® high-cell-density process reportedly yields an eight- to tenfold titer improvement, and a 500 L bioreactor can provide a DSM client with the same amount of drug product as a 5,000 L stainless steel bioreactor at an overall lower cost.

“We continue to see pressure on pricing across all aspects of our services, as clients aim to bring their products to market as cost-effectively as possible,” Fujifilm’s Dr. Taylor relates. “However, as these services are very labor intensive, we have had to look to smarter ways of working to speed up development, for example, by implementing LSS (Lean Six Sigma) techniques to ensure we perform these activities in a cost-efficient manner.

“We are also introducing high-throughput technology across our R&D and process-development groups,” says Dr. Taylor. “We see this as a way of maintaining high-quality outputs for our customers while reducing timelines.”

At its new manufacturing site in Billingham, Fujifilm also created a new mammalian cGMP cell banking facility. Clients can contract with the new cell-banking facility as part of a larger manufacturing program or as a stand-alone service. Launching the new cell-banking facility is part of a larger expansion of the mammalian cell culture capabilities at the site. In 2013, new process-development and scale-up capabilities were installed.

According to DSM, the company’s XD® high-cell-density process can yield an eight- to tenfold titer improvement.

Smaller, More Flexible Assets

While proteins, DNA, and viruses all fall under the biologics umbrella, DSM’s Guy Tiene says that viruses have gotten a lot of interest lately, especially as the government ramps up its search for economical ways to prepare for possible new flu outbreaks and to combat bioterrorist threats.

In fact, DSM is working with BARDA to implement a strategic plan that, according to BARDA, will facilitate the manufacture “vaccines, therapeutics, diagnostics, and nonpharmaceutical countermeasures against a broad array of public health threats, whether natural or intentional in origin.”

Tiene also notes that specialty treatments are gaining share as personalized medicine (along with the research behind it) comes into focus. Specialty treatments tend to focus on niches instead of traditional therapeutic categories, such as cardiovascular or allergy, which have very large patient populations. According to Tiene, a typical niche might involve the manufacture of a therapeutic for a specific cancer, where “volumes are not as large.”

“The increase in personalized medicines and orphan drugs will probably mean that CMOs will have to make fewer batches of different products,” Fujifilm’s Dr. Taylor concludes. “When taken in conjunction with higher titers that are now routinely possible, this points to a different model for manufacture, with smaller, more flexible assets.”