XCELLEREX (WWW.GELIFESCIENCES.COM)

On Tuesday, 16 June 2015, Thomas C. Ransohoff (vice president of BioProcess Technology Consultants) chaired a midday roundtable titled, “Stretching for the Trifecta: Innovative Strategies for Speeding Development, Lowering Costs, and Enhancing Quality.” He brought together a panel of four industry experts:

Thomas C. Ransohoff (BioProcess Technology Consultants)
Conventional wisdom says that biopharmaceutical companies must choose only two of these three goals: high quality, speedy development/ manufacturing, and low cost. But increasingly, Ransohoff pointed out, the industry is being asked to meet all three goals simultaneously. Two main drivers are forcing companies to shorten timelines: new regulatory pathways (e.g., biosimilar pathways, breakthrough therapy designation) and competition, especially in the most promising discovery areas (e.g., oncology). Meanwhile, increasing price pressures are accompanying the emergence of biosimilar competition — driving the biologics industry to cut costs. Luckily, suppliers are offering the technological means to do so.

Ransohoff emphasized that, for drug products, quality is a critical parameter that can’t be compromised. The industry has changed, he said, since the “process defines the product” era. Modern biologics can be characterized, making it possible to define a product and build quality into the process used to make it: the quality by design (QbD) paradigm. He said that delivering quality, speed, and cost requires leaps forward in technology and business strategy.

But implementing new ideas can be a challenge. A regulated industry must be both risk averse and conservative in its approach to new technologies. Associated costs and time lags can be significant, so companies want as much assurance of success as possible. The biopharmaceutical industry invests relatively little in new technology development, Ransohoff explained, and that may have to change.

Joanne Beck (Shire Pharmaceuticals)
Beck focused on general business approaches to getting diverse products into clinical testing (and to market) as fast as possible. She said that Shire’s pipeline is very diverse in technology platforms: from gene therapies to messenger RNA replacement to antibodies, enzymes and other nonantibody proteins, and even small molecules. Product candidates come from both internal research and development (R&D) and external licensing.

Beck described what she called a “fairly typical” biologics development approach using mammalian cell culture — including Chinese hamster ovary (CHO) and human-derived cells — in single-use bioreactors, with continuous centrifugation for harvesting. Bacterial fermentation projects are outsourced through a “hybrid model” with some analytical work performed internally. Viral-vector production is also external.

Few Shire products lend themselves to purification or formulation platforms. Protein engineering (e.g., for solubility) options are limited, as well. Because many proteins can be very insoluble/hydrophobic, the company uses some nontraditional excipients and employs a specialized formulations group to develop difficult products such as gene therapies. Analytical support must be high throughput and high resolution for such a broad range of therapeutic modalities, Beck said. And IT interfacing is important as well, with data coming from different platforms (internal and external), different manufacturing plants, and so on.

“Our optimal business model,” she explained, “is to outsource as much as possible so that we do not have to build and run a lot of internal capacity.” For small molecules, she said, everything is outsourced. “We would like to apply that same approach to gene therapy and mRNA replacement therapy.” The company is not ready to hire staff and build new facilities for as-yet unproven platforms “until we have proof-of-concept and we have gone through successful phase 2–3.” But few contract development organizations have experience with such products, making it necessary for Shire to develop its own expertise. Experience in related areas helps. For example, she pointed to previous vaccine work with Merck & Co. translating to a new gene therapy partnership. With monoclonal antibody (MAb) expertise widely available, Shire can completely outsource its MAb projects.

Beck described her company’s switch from stainless steel and roller bottles to single-use bioreactors, which sped up validation and qualification. Shire looks for similar expansion agility in its partners after making an early decision about whether a project will be outsourced. The hybrid model is useful when some internal expertise (e.g., in high- resolution analytics) can be developed before transferring to a contract manufacturer.

“The idea that you can just outsource a biologic is not realistic,” Beck cautioned. Regulators hold sponsor companies responsible for everything, which requires continuous oversight. She reiterated Ransohoff’s point about quality: “Implementing the principles of QbD up front is extremely important, whether a program is internal or external.” All data must feed into internal QbD documentation to provide critical process and product understanding as well as process control.

Parrish Galliher (GE Healthcare)
Galliher described how innovation in biomanufacturing can help companies achieve their cost, quality, and speed goals. He said the industry is in the midst of a “new era of innovation,” with increasing expression titers, single-use technologies, and process intensification overall. He pointed to improvements in facility use, flexibility, and agility; reductions in variability, failures, and waste; and increases in operating efficiencies.

Galliher considers both disposables and high-titer production to be prerequisite to modern biopharmaceutical operations. So he focused on some other technologies instead. Regulatory agencies, he said, understand the need for innovations, especially those that companies can use to better maintain product quality in manufacturing (e.g., single-use technology to eliminate cross contamination).

Manufacturing strategy determines what other innovations a company should implement. Important criteria include a product’s dosage and market size, operation scale, production titers, cost targets, in-house experience, insourcing/outsourcing options, geographical location, and expansion plans. Companies must make decisions based on available capital.

Process intensification includes continuous operations and variations thereof involving technologies such as perfusion. With most such cultures, Galliher explained, filtration is used to clarify permeate for chromatographic purification. He showed an example reported by Johnson & Johnson subsidiary Crucell in The Netherlands, with 60–70 million cells/mL perfused through a single-use bioreactor system.

On the downstream side, some companies are combining steps for straight-through processing. Galliher showed an example from another J&J subsidiary (Centocor) that eliminated intermediary hold steps to connect unit operations and run semicontinuously, shortening overall cycle times. The company eliminated holding tanks and used in-line dilution of concentrated buffers to shrink its buffer storage needs.

Other companies are experimenting with continuous chromatography (e.g., using multiple columns) to reduce buffer and resin consumption. Another downstream innovation Galliher highlighted involves “plug-and-play” closed-processing systems such as prepacked chromatography columns and filter cartridges. They allow manufacturers to set up enclosed processes quickly, connect and operate them with reduced overall facility environmental control requirements. “They break down just as quickly for disassembly and turn-around.”

He also described facility design innovations, first showing a traditional plant with many cleanrooms, gowning rooms, and corridors. That alone can present a logistical challenge for moving disposables around. The more complicated a facility is, said Galliher, the longer it can take to operate and transition between projects. The “open ballroom” concept was designed specifically to accommodate disposables. But it would require a high level of closed processing to reduce virus-safety risk.

Other innovations Galliher listed include high-throughput screening, QbD strategies, and manufacturing- ready cell lines. He also mentioned lean manufacturing approaches to raw-material variability, improved efficiency, and failure reduction. For multiproduct facilities, innovations that create needed flexibility can improve cost of goods (CoG). Galliher described “synergized manufacturing,” wherein single-use technology is combined with closed and connected processing (maybe continuous) in a ballroom facility. In the future, he predicted, that could enable simultaneous multiproduct manufacturing and substantially improve CoG per product.

Lynne Frick (Pall Corporation) Frick presented the economics of “integrated continuous bioprocessing.” Without real benefits, she cautioned, money invested in innovation is wasted. She believes that single-use technology is key. Continuous processing allows companies to use less water and tankage in smaller facilities, with less support than batch processing requires. Together, disposables and continuous can reduce overall CoG.

Frick showed some continuous processing examples. With perfusion cell culture upstream, some companies may yet take a traditional batch approach to downstream processing. Or they might use continuous clarification/capture. Ultimately, the entire downstream process could be continuous. Process intensification can help companies reduce cost. For monoclonal antibodies (MAbs), Frick said, chromatographic capture is one of the most expensive and inefficient downstream unit operations. Reducing its volume requirements could help companies cut MAb purification costs.

Frick introduced some specific Pall technologies that illustrate her economic points: inline concentrators and simulated moving-bed (SMB) chromatography. Cadence inline concentrators are based on single-pass tangential-flow filtration (TFF) technology, removing water from process fluids to reduce their overall volume. That improves the economics of operations further downstream. BioSMB chromatography is similar to a continuous purification method used in other industries. Adapting it to the highly regulated biopharmaceutical industry presented sanitary challenges. Multicolumn configurations require many valves, which introduce contamination risk, so developers created a disposable valve block. Pall is also working on continuous viral inactivation, ultrafiltration/ diafiltration, and other technologies.

Next, Frick provided a CoG analysis of inline concentration using Biosolve modeling software from Biopharm Services. Her analysis was based on a generic MAb platform with a protein A capture step. To concentrate the process flow by 4×, she placed an inline concentrator after primary clarification, which dropped the CoG for depth filtration and sterile filtration by ~50% (whether a process is based on either continuous or batch chromatography). To normalize chromatographic results, analysts use “specific productivity” to express them in terms of product yielded per liter of chromatographic resin over time. With a three-column BioSMB technology, for example, Frick showed a doubling of specific productivity to 8 g/L/h, which could be very helpful with low-titer production processes (e.g., some perfusion processes).

Mark Brower (Merck & Co.)
Brower focused on real-time release and the evolving role of process analytical technology (PAT) in drug- substance manufacturing. He said that >50% of a biopharmaceutical company’s staff and facility are devoted to quality control (QC), an area where PAT could help reduce overall costs.

After economic analysis showed that large (50,000-L) stainless steel vessels were no longer economically viable, Merck discovered that hybrid processes (using both disposables and stainless steel) provided substantial reduction in CoG and total cost of facility ownership. Next, the company looked into continuous processing, which also reduced costs — but only with real-time drug-substance release. Merck wants a future continuous process platform that can accommodate new types of unit operations, Brower said, and further reduce CoG.

He showed a fed-batch bioreactor example with continuous culture feeding, centrifugation, depth filtration, column chromatography, and single-pass TFF. Yields and impurity clearance were similar to those of batch processes. Between the time-consuming start-up and shut- down of a given unit operation is a steady state that Merck has extended to multiple days, weeks, and even months. Rather than stopping a process to take samples for a QC lab, PAT allows the process to keep going.

Thus, Merck is engineering PAT into its manufacturing processes: high-performance liquid chromatography (HPLC); Fourier-transform infrared (FTIR), Raman, and near-infrared (NIR) spectroscopy; particle-size–distribution analysis; and inline sensors (e.g., for pH, temperature, and conductivity). The company models process parameters to help optimize manufacturing processes, then uses that knowledge to develop control strategies.

PAT can help a company monitor process consistency and product quality. Compendial release assays test product appearance, color, identity, and potency. Brower emphasized the importance of both process control parameters and release criteria for real- time product release. Merck believes that PAT streamlines real-time release from continuous processes. Because of the cost of implementing it, a company must distinguish between necessary assays and those that simply would be nice to include. Brower touted multiattribute methods as key. Citing raw materials as “critical inputs” and sources of process variability, he said that PAT is also helpful for their quick release.

Finally, Brower offered an example involving ultraperformance liquid chromatography (UPLC) with automated sampling and dilution. Different detectors provide information on different attributes (e.g., product titer and concentration). Merck implemented UPLC into a continuous culture that ran it for 30 days with results comparable to offline methods. Brower concluded with the assertion that innovations such as PAT require some investment in development, but once implemented, they can pay for themselves through large cost reductions from real-time product release.

Panel DiscussIon
Ransohoff then asked about obstacles to implementing new technologies. Brower said that Merck has a clear long-term plan for getting to its goal of real-time release through incremental improvements. Beck pointed to her company’s collaborative relationships with suppliers to develop technologies jointly.

When asked about timelines in assessing and implementing technologies, Galliher said it depends on their maturity. If an innovative product is already proven to comply with good manufacturing practice (GMP) requirements, then a company can generate necessary data fairly quickly. But for very new technologies, biomanufacturers may need to spend time fine-tuning innovations with their vendors.

Beck lamented the fact that a commercial facility may be designed for flexibility, but that getting new technologies into it can be difficult over time. Large amounts of data must be shared across the groups involved, and here again she believes that suppliers can be invaluable. It’s very important for vendors to share their databases of information on raw materials, she said. “The more information we have, the easier it is to introduce a new technology.” Ransohoff added that information sharing can benefit everyone, particularly regarding leachables and extractables of single-use technologies.

Long “gestation” periods could hamper the development of new technologies. Frick pointed out that she and Galliher both had worked with start-up companies (Tarpan Biosystems and Xcellerex) that provided innovations to larger suppliers. But start-ups need funding from bigger companies to do so.

Galliher agreed. He pointed out the long life cycle of biotech drugs and compared that to the time it’s taken for single-use technology to reach its current level of saturation: The industry has adopted new technology, but that seems to work a decade at a time. Looking forward to the next 10 years, he described a trend toward smaller markets and smaller-scale products. Beck and Frick both agreed with that prediction.

Watch the full presentation in our BIO Theater 2015 Video Archive