This roundtable took place on Wednesday, 6 June 2018, in the BioProcess Theater at the BIO International Convention in Boston, MA. (Left to Right) Moderator: Dan Stanton, editor, BioProcess Insider. Panelists: Roger Lias (president and CEO, Avid Bioservices), Weichang Zhou (chief technology officer at WuXi Biologics), Jenifer Wheat (head of commercial development for mammalian manufacturing at Lonza Pharma and Biotech), and Jim Vogel (founder and director of The BioProcess Institute)

Moderator Dan Stanton, with Weichang Zhou, Jenifer Wheat, Roger Lias, and Jim Vogel

Single-use technologies (SUTs) are now prevalent within bioprocessing, but does this spell the end of industry’s historic reliance on stainless steel and fixed facilities? This roundtable was formed to discuss the wealth of investment in single-use (SU) equipment and flexible manufacturing solutions by contract development and manufacturing organizations (CDMOs) over the past few years, pitting that against what looks like a resurgence in fixed-cost stainless steel plants among some biomanufacturers.

In his introduction, Stanton noted that during the early part of this decade, mammalian cell culture contract manufacturing organizations (CMOs) were dominated by three companies: Lonza, Boehringer Ingelheim, and to a lesser extent Celltrion. According to reports from BioPlan Associates, those three companies held more than 76% of the outsourcing capacity, mainly in fixed, large stainless-steel tanks.

Today, the demand for third-party biomanufacturing has increased, and those three CMOs have increased their capacities further, joined by a growing number of others that have entered the commercial biologics space through adopting SU equipment and modular and flexible facility designs.

An Enabling Technology
Stanton asked Jim Vogel how SU equipment has enabled more companies to enter the biomanufacturing space as a service. Vogel explained that the key consideration is the lower initial investment for SU materials, which allows a company to get started faster. Scales also have gone down because of improved cell culture titers, so biomanufacturing platforms also benefit from the ability to produce drugs in smaller containers. But saving on the up-front investment is key relative to purchasing stainless steel equipment and maintaining (and validating) utilities and facilities space to support it.

Because WuXi has been expanding its operations using only SUT, Stanton asked Zhou how that environment allows the company to be such a large player.

Zhou pointed to issues of flexibility and the modest initial investment in SUTs but emphasized the advantage of speed in building a facility based on those technologies. That gives his company more time to develop a process for commercialization. A second significant advantage of SUT is in minimizing scale-up risk. WuXi’s SU “scale-out” strategy uses the same size of bioreactor for all product phases, including commercialization. That enables global expansion of the company’s capabilities using SUTs. He highlighted the importance of SUTs to effect process intensification now that a company can manufacture 5–15 g/L.

CDMO Perspectives: Stanton asked Jenifer Wheat to comment on the points about process intensification as a representative of a CDMO with large amounts of stainless steel capacity.

She replied that Lonza is not all stainless steel and that the company also appreciates the need to manufacture flexibly for smaller patient populations and multiple indications. It has everything from SU bioreactors and stainless steel at small, medium, and large scales. In some of its newer facilities, SU downstream combines with some stainless steel facilities at mid scale to handle much higher titers than previously possible. Lonza sees a great need for large-volume manufacturing of antibodies and other products, but it also tries to meet small-scale demands at earlier stages.

She elaborated on the importance of flexibility. “You can start with us at small scale and delay decisions and multiplexing until you hit a certain point. And then you can choose to go commercial with multiplexing of single use. Or you could choose to go midscale or large scale. Some clients may choose to move from SU multiplex to commercial, but they can delay that move until they achieve phase 3 success, reducing their cost of goods.

With a modular approach, a prebuilt shell can cut down a significant amount of the time required to build facilities. As Wheat said, “Every product, every business case needs something different, so the key is flexibility and reliability.”

Stanton asked how Lonza views the influx of CDMO competitors entering the space from a business perspective. Wheat answered that “it’s good to support the industry because there are still a large number of products that need smaller volumes and need to scale up quickly. And SU is a lower investment. If you’re going to build your own facility as an innovator, it makes a lot of sense. And there’s definitely a need for manufacturing capabilities across the CMO industry.”

Scale-Up As Horizontal Rather Than Vertical: Stanton asked Lias how Avid works with both stainless steel and single use. Lias explained that his company has a legacy stainless steel facility that goes up to a 1,000-L working volume, which is relatively small for stainless steel. That facility has been approved by the FDA and EMA for 15 years. He sees fewer opportunities for large-scale stainless steel facilities, although he noted that a large-volume therapy such as Humira might make sense to transition into large-scale stainless steel. Avid operates a new multiproduct facility with multiple 2,000-L SU tanks and views scale-up as a horizontal rather than vertical process.

In addition to improvements in specific productivity of the cell lines, the industry also is using higher culture densities. Lias reminded the audience that tremendous advances are happening on the downstream side as well, including technologies for filtration and chromatography. That is where he thinks the industry will see the biggest advances in the next five to 10 years. He believes that most current opportunities can be handled at the 2,000-L scale and agreed with Wheat’s comments that with higher productivities, different classes of products can be made in SU for smaller, niche markets. But ultimately, implementing disposable technologies lowers some of the high fixed costs for maintaining highly compliant environments.

Comparative Limitations
Stanton asked Zhou whether any customers have reported limitations with having only SU capabilities.

Zhou described WuXi as an enabler, helping its clients to meet set needs. Using multiple SU bioreactors in combination with larger columns could meet the needs of both cost and capacity. So far, even though some customers have asked for a dollar-pergram calculation, his company has found that SU meets the challenge.

Stanton asked Vogel to comment on whether SU presents limitations to process intensification. Vogel pointed to things that get overlooked when comparing the benefits of SU with conventional processes. “One example is filtration. Usually you need some pressure to perform filtration, and in some cases single-user may not withstand the pressures that people need. When your filtration isn’t as efficient as it might have been at lower cell densities, sometimes operators and/or process development chemists don’t understand how to manipulate single use through that challenge.”

He agrees with Lias that novel technologies are coming into play on the downstream side, and those developments are further supported by regulatory agencies urging development of continuous processing. Such demands and lessons learned from other industries using continuous operations may point to increased opportunities for hybrid approaches. He concluded that “single use does have some limitations, but with the proper design and considerations, a company usually can get around them.”

In response to Stanton’s question about limitations of stainless steel, Vogel drew on his experience with the ASME Bioprocess Equipment Standard to agree that even stainless steel does not last forever. He mentioned flexibility limitations in cleanability of gaskets and clean-inplace sterilization that can present a greater risk than with SU equipment. Lias and Wheat both agreed that many variables factor into the choice of manufacturing decisions. Legacy stainless steel processes involve dealing with rouging and cleaning concerns, but bags can suffer from cholesterol absorption onto plastics. Technical issues are encountered with both types of technologies. SUTs continue to advance — especially downstream — but Lias still sees a lot of complex products, even newer ones, that need handling in large-volume stainless steel over the long term.

Transfer and Standardization
Stanton asked whether SU that enables internal manufacturing might be a threat to outsourcing. The general opinion of the panelists was that SU manufacturing is more an enabler than a threat. It allows companies to do more work themselves at earlier stages, but they’re still likely to outsource a good portion of that work, perhaps at later stages. But one focus of discussion was the difficulty of technology transfer given the different types of bioreactors on the market, the need to store bags, and complexities of supply chains. So lack of bag standardization and other components such as connectors adds complexity overall. Lias agreed, noting that warehousing SU components might be complex for CMOs that have to store “cargo boxes everywhere full of disposable equipment” to handle customer projects.

Zhou said that his company manages well with different types of bioreactors, but that he discourages companies from implementing more and different types of bioreactors, if only to prevent inventory problems. Lias added, “It’s important to remember that these bioreactors are not all the same. They have built-in ports, and it’s not a one-size-fits-all issue. Transferring between one supplier’s SU bioreactor and another’s is not an insignificant challenge.”

Stanton brought back an earlier point about a trend of vendors buying CMOs — e.g., Thermo Fisher buying Patheon — and how that leads to a competitive advantage. Vogel responded that it might reduce flexibility if a client brought in a different system. “Almost every vendor has to buy components from the other ones, because if a process is validated on a certain filter, you’re probably not going to do a resubmission to change out that filter to the one that you’re using. And so brand X filter can be on brand Y assembly, and same thing goes for the connectors. If you’re starting from zero as a brand new company, you may want to choose one system, but that also may remove some flexibility if performance issues occur.” Changing to a different filter, for example, might provide a more competitive advantage.

Advantages of Vendor Consolidation on Standardization: Stanton asked whether vendor consolidation would make processes easier. Lias acknowledged that consolidation is happening, but that “some of those companies have been acquired by or merged with others with different operating systems, software, and control systems. So it’s then quite difficult to transition to running truly one operation at one company. A number of merged businesses still run as several separate entities. They’re not really very standardized yet. It’s a huge challenge.”

Zhou said, “I don’t think consolidation is the answer: I think it’s standardization. Undoubtedly there will be many products made by many companies, both technology providers and users. Standardizing to some extent would help the whole industry.” He sees that, over the years, technologies tend to become more standardized. But that it takes time.

Vogel suggested that the key might be alignment rather than standardization, such as agreeing to use one type of filter. But developing protocols for change management, such as those developed by BPSA and BPOG, might be a more practical way to help biotechnology companies try to normalize changes in vendors and equipment. Wheat agrees that although some standardization is happening as the industry matures, “standardization is going to be a challenge for some time. “

Market Considerations in the Postblockbuster Era
Stanton returned to the topic of capacity, speaking of investments by CDMOs such as Samsung Biologics. “They’ve suddenly jumped up from nowhere by investing in thousands of liters of stainless-steel capacity. At the same time Lonza and Boehringer Ingelheim also have increased their capacity through stainless steel.” He asked where demand for such huge capacity is coming from.

“People are getting smarter about how they perform their trials and what their applications are,” Wheat pointed out. “You see them choosing products with multiple indications or combinations.” Future blockbuster products, such as those to treat widespread diseases such as Alzheimer’s, still may be around the corner. She said it is a misconception that large companies are making only biosimilars. “A lot of other products need large volume, just as a lot of products need 2,000-L or 5,000-L processing. It’s not either/or.”

Capacity Management
Zhou noted that capacity management will be a critical issue going forward. He believes that building flexible facilities is critical for adapting to market forces. Vogel expects capacity needs to continue: “The work’s out there, and the demands are there. And I think it will just morph into other types of products. But he emphasized the importance of keeping an eye on scale as more personalized products enter the market. Lias directed attention to new markets opening around the world, with the biopharmaceutical industry still young and growing. The current customer base eventually will need manufacturing space. But scaling out with disposables can allow flexibility to balance future demand on a tactical level. Wheat agreed that the industry needs the capacity to serve different needs and said that the market corrects itself based on need like any other market in any other industry.

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This roundtable took place on Wednesday, 6 June 2018, in the BioProcess Theater at the BIO International Convention in Boston, MA. (Left to Right) Moderator: Tom Ransohoff, vice president and principal consultant, BioProcess Technology Consultants, Inc. Panelists: Chris Love (a professor at MIT), Jorg Thommes (head of CMC at the Bill and Melinda Gates Medical Research Institute), Geoffrey Hodge (chief technical officer at UNUM Therapeutics), and Rajesh Beri (technical director for biomanufacturing, research and technology, at Lonza Pharma and Biotech)

Moderator Tom Ransohoff, with Jorg Thommes, Chris Love, Rajesh Beri, and Geoffrey Hodge

For biopharmaceuticals to mature as a process industry, companies need to embrace the ability to adopt new technologies and bring new operational approaches to their biomanufacturing facilities. In this roundtable about adopting and implementing new technologies in the biologics industry, moderator Tom Ransohoff stressed the importance of understanding drivers for adopting new technologies and of developing enabling processes that factor in associated risks and challenges.

He offered the example of single-use (SU) bioreactors as a successful adoption of new technologies. “SU bioreactors have changed the way we sterilize the vessels, the way we connect to them, the way we sample them. So companies needed to develop new skills and develop new approaches for using the technology.”

Now, 20 years after introduction of the first SU bioreactor, that technology is a de facto standard for clinical and commercial manufacturing facilities at the ≤2,000-L scale. But SU bioreactors haven’t displaced conventional stainless steel equipment — which still dominates the landscape volumetrically for biologics production. And SU bioreactors are not envisioned to displace stainless steel completely any time soon, although technology continues to evolve and mature for the industry.

Forces driving adoption of SU bioreactors include speed and reduced capital — the need to bring manufacturing facilities on quickly and economically. Other needs include improving product quality and ensuring compliance with regulations that drive the need for new technologies. So cost often is not a major driver.

Ransohoff noted that highly regulated industries are conservative toward taking on risks inherent with adopting new technology — risks that can include significant penalties for delays and setbacks. The need to move programs forward quickly might seem to provide no good time to adopt new technology. But he argued that the biopharmaceutical industry puts relatively little investment into new technologies compared with other industries. As he invited the panelists to offer examples of successful technology adoption, he also asked them to consider whether their industry is spending at the right level for new technology development or is doing things about the way it should.

Successful Technology Adoption
Beri’s company has ongoing projects toward improving cell lines and expression systems while fortifying and simplifying its media feeds. It continues to invest in platform processes that incorporate new technologies, particularly sensors, and to realize the full potential of process analytical technologies (PAT) for real-time process monitoring and control. Lonza also has a strong interest in manufacturing execution systems (MES), working toward digitizing biomanufacturing eventually.

One good time to think about implementing new technologies is in the early stages of process development, perhaps when constructing a new facility. Adoption is more challenging in existing facilities and processes. Beri’s example of successful adoption involved converting conventional at-line UV spectrophotometers from traditional fixed-path, fixed wavelength units to variable-path wavelength spectrophotometers. As a contract development and manufacturing organization (CDMO), his company had multiple customer projects running in two manufacturing suites, so real-time adoption seemed impossible. Nevertheless, Lonza followed good risk-assessment strategies, made use of available protein standards, and showed good compatibility between the new and existing spectrophotometer results. Customer support helped the company to overcome many related challenges by recognizing the shared value of that adoption.

Incremental Advances: Hodge’s perspective was that advancements within the industry have not come from a few big inventions, but from the cumulative effect of many small innovations implemented over time. He asked how innovations get implemented in an industry that’s as conservative and risk-averse as biopharmaceuticals. From a biopharmaceutical innovator’s perspective, an incremental change to save perhaps 5% on cost of goods or shorten somebody’s timeline by 5% seems like solid justification. But from a consumer’s point of view, is such a small gain worth the very significant risk of an untried technology?

Hodge’s example of a successful adoption came from his work at Millennium Pharmaceuticals in a process development (PD) laboratory that was interested in SU technology. That group spliced together an entire antibody process at bench scale in SU components using SU sensors. It borrowed heavily from the medical industry’s use of many SU components as an early adopter of wave-motion bioreactor technology.

At that time Millennium was making a transition from drug-product manufacturer to service provider. It was building a manufacturing facility with an ambitious timeline for getting a product into the clinic, but none of the CMOs at the time could take on technology transfer and offer the needed capacity to meet that deadline.

So he described creation of a modular biomanufacturing process using SU components in a small cleanroom. And when Millennium moved out of biopharmaceuticals, its displaced biologics group gave birth to Xcellerex — which turned that modular technology into a product. The new company developed the first SU stirred-tank bioreactors that ultimately scaled to 2,000 L. Later, Xcellerex had one of its first big commercial successes when it installed multiple 2,000-L bioreactors instead of stainless steel at Shire’s Atlas facility, saving that company 18 months in bringing its facility on-line. None of these efforts were aimed at incremental improvements but, rather, toward meeting major unmet needs.

Hodge concluded that “as a product developer, you need to look for those places where you don’t just incrementally improve on a technology. You need to find a place where you can make a huge step change for one company, and then you can establish a baseline and some confidence in the product. Eventually it will be adopted by the industry.”

Three Drivers of Transformation
Love suggested that the panelists consider three key ingredients driving transformative solutions: need, disruptive technologies, and an ecosystem. In looking at the industry’s successful use of platform processes, he noted that in the 1980s, biomanufacturing of monoclonal antibodies (MAbs) with Chinese hamster ovary (CHO) cells came about through a combination of those three ingredients. The need was for medicines based on biologics. The disruptive technology was recombinant DNA. And the ecosystem comprised academics, industry, and government stakeholders who could think collectively think about how to enable it all as a platform. Incremental innovations happened since then, but those three ingredients at that time led to the production of many biopharmaceuticals.

Today, the needs are more diverse, but disruptive technologies enable learning biology directly from patients by reading out their genomes, from sequencing small bits of DNA, or from single cells from tissue samples. That gives developers great precision in thinking about an indication, defining it, and identifying a target. Pipelines are filling with ideas about where and how companies can innovate new solutions for drug products.

Challenging new modalities such as cell and gene therapies still need to be made amid constrained pipelines and limited resources.

Disruptive Biology: Love suggested that the disruptive technology today may not be another reactor or resin, but the biology itself, which in biomanufacturing is accessible now in ways that it has never been before through tools used in research and discovery. Transformative genetic engineering technologies now provide the ability to write information back into that biology, writing it into needed solutions that simply have not been possible before.

He asked, “What if you could fine-tune the medium based on what is actually needed when you need it? We’ve done some of that in the lab at MIT thinking about new media formulations for Pichia pastoris, a yeast organism, that are now fully defined based on transcriptomic information about what’s required in a fermentor during the cultivation. This one simple example shows how the lines are blurred between strain engineering and process engineering informed by the biology itself.”

His third example illustrated the ecosystem element. Today’s industry is robust in part because of leaders who were well trained in places in many different institutions. Those leaders worked closely with others in industry and the government to accelerate many ideas that are now appreciated today as standard processes. A robust ecosystem in which information is shared broadly is necessary to promote innovations — CHO cells are a very good example of what can develop from that. He concluded by saying that the industry’s goal should be to accelerate this learning. “Not only does it create the workforce and leadership necessary to be able to sustain new manufacturing strategies, but it also helps create a broader share of risk in establishing the right science and the right understanding of these technologies to bring them forward to regulators with confidence.”

When an Ecosystem Is Absent: Thommes agreed that given a need, disruptive technology, and ecosystem there always is a good time to implement new technology. But all three components are necessary. As an example, he said that IDEC Pharmaceuticals explored continuous chromatography back in 2001. The need was clear, and the innovative technology was developed. But the process was not implemented because the necessary ecosystem was absent. It would have been custom built, custom designed, and used by only that one group.

Thommes added that nothing is wrong with a custom-built system. But his group was trying to address its capacity and productivity problem with an engineering solution, whereas the resin manufacturer basically used chemistry to improve productivity.

By contrast, today there is an ecosystem to support continuous processing, with knowledge about how to make biologics continuously and cell culture for delivering a continuous stream for receipt in chromatography. There is a vendor infrastructure for support. What the IDEC group failed to do 15 years ago can happen today because all three drivers are present.

Still Stainless Steel?
An audience member asked why companies are still building large stainless steel facilities when the industry has so many single-use, flexible options. The panelists agreed that the industry still has demands that require both approaches. Some legacy processes are treating large patient populations with expression titers <5 g/L. For those existing businesses and successes in biosimilar approvals, the industry needs large expansions. But on the clinical side, SU systems can produce higher titers cost-effectively for lower patient populations. So for now, both stainless steel and SU implementations are increasing.

Thommes added that the industry continues to see increases in both stainless steel and SU infrastructure because of a multiplicity of needs and problems. The SU environment allows quick turnovers for small batches and efficient facility use. But for manufacturing huge-demand products, when combining the productivity and the cost of goods of a well-run, large stainless-steel infrastructure, the SU infrastructure might never compete cost-wise for continually operating facilities. Therefore, companies with such products invest in large infrastructure, and companies with very mixed portfolios invest in single use. Large companies that are committed to a multiplicity of modalities will not find one solution to address all needs.

Hodge pointed out that smaller markets requiring frequent turnover between batches and products favor the SU model. But that “there’s some cut-off point where, if you’re making the same drug at a very large scale, stainless steel is just going to be more cost effective.” Although single-use has been advancing the scope of its applications, he wondered how continuous biomanufacturing will change the equation. One big advantage of single use is the ability to change over equipment quickly and reduce cleaning and steaming costs. Continuous manufacturing would appear to reduce some of that benefit.

Love pointed to the value of looking outside the biopharmaceutical industry for examples of why things happen. Using parts manufacturing as an example, he cited 3D printers as a disruptive additive manufacturing technology that creates the opportunity to make unique, specialized one-off solutions with specific capabilities. It allows a company to prototype and move ideas forward faster. The industry still needs products that it can manufacture at low cost at very large volumes. Drawing from other industries for guidance about how to approach manufacturing innovations can be a valuable guide toward developing fast, agile solutions. He offered an example of work at the Massachusetts Institute of Technology toward solutions for intensifying processes. Such approaches eventually could reduce the need for large facilities.

Reducing Supply Costs for Developing Industries
An audience member asked for an update on efforts through the Bill and Melinda Gates Foundation to bring the costs of manufacturing supplies down for developing countries.

Thommes answered that the foundation has been active in thinking about alternative hosts and about decentralized, perhaps localized microfacilities. Love added that a broader program with the foundation is addressing ultra-low–cost vaccine production, with a goal (metrics) of 15 cents per dose in a vial at 40 million doses per year. With a glass vial for a single dose currently costing six cents, economies of scale cannot be used as an argument to reach that target point. His company is working with the University of College London and the University of Kansas on a platform for recombinant solutions to this, and another group is working toward inactivated viruses or attenuated virus solutions for a polio vaccine in particular. Through cross modeling, they know that the key drivers will be small, modular, highly intense processes. Downstream processes would look very different if products from alternative hosts could have 80–90% purity directly out of a reactor.

Collaborative Ecosystems
Ransohoff returned to the importance of an ecosystem for supporting manufacturing innovations, focusing on the value of collaboration both within industry and between it, academia, and government. He mentioned the work of the BioPhorum Operations Group (BPOG) toward developing a technology roadmap and the Biotechnology Innovation Group (BIO), where industry veterans are advising companies about requirements for new technologies. Other initiatives including the Defense Advanced Research Projects Agency (DARPA) and the National Institute for Innovation in Manufacturing (NIIMBLE). He asked, “What role do these types of efforts play in this process, and how can or should we expand our efforts to improve such collaborations?”

Beri spoke about BPOG, which began as an on-line collaboration community. Participants realized that the Internet (a key enabling technology) enabled manufacturing groups to collaborate effectively on-line, networking across multiple time zones. In addition to biomanufacturing work streams, the group began looking at technology solutions to address future needs, examining cost, quality, and technology drivers. The resulting industry roadmap, three-years in the making, focuses on traditional recombinant protein manufacturing. He noted that since publication of that roadmap, member companies have launched nearly a dozen critical projects.

Hodge added that collaborations accelerate innovation by bringing people together who have similar interests, needs, and technologies, increasing their opportunities for finding and addressing unmet needs. He said that “industry representatives working together with government and academia can help push technology to the point that companies and investors are willing to put some time and money into it.”

Thommes highlighted NIIMBLE, part of the Manufacturing USA network, as a public–private partnership that addresses large-scale problems better than people can individually, within their company niches. He noted that sharing initiatives helps lessen the risk in introducing technology innovations.

An important quality of a sustainable ecosystem is long-term commitment from all stakeholders, whether that entails time, intellectual input, or money. NIIMBLE provides one avenue for exploring advanced technologies for manufacturing. Other groups, such as the US Food and Drug Administration’s Emerging Technology team and its equivalent in the European Medicines Agency, provide an avenue to start conversations early among researchers, academics, and regulators. Love added that “from an ecosystem standpoint, finding the right way to seed and establish long-term sustainability as an industry is going to be really critical as we look at advancing new technologies and the people necessary to bring them forward into the next generation.”

Future Directions
Ransohoff posed a final topic for the panel: “In what areas do you see the greatest need for new technologies, and what excites you the most? What area in particular do you see as a big driver moving new technologies forward?”

Love pointed to the opportunity to rethink how medicines are delivered to patients. Currently an entire supply-chain cycle takes 18–24 months. He asked, “what if, instead, a pharmacy could make the drugs a patient needs on demand, release them in real time, and have them ready within days? Technologies exist to do this now.” He broadened that to addressing the ~8,000 rare diseases for which medicines and specialty products are in high demand, asking, “What if you could make those materials when and where you needed them? What would it mean for global access, to be able to bring medicines to patients anywhere when they needed them? It is possible to do this today. It’s possible to move to an agile supply chain. And there are substantial benefits to thinking about a more uniform supply chain of raw materials and a short time of holding finished product.”

Thommes added that his interest is in development of an alternative host expression system to lessen the time from gene to IND to three to four months (from 12). That could bring more potential candidates into the clinic and “democratize access to clinical candidates, at which point maybe an academic lab could run clinical studies.”

Hodge pointed to the cell therapy world, where some of the above processes already are being realized. Autologous cell therapies involve taking blood from a patient, making a product for that patient, and then giving it back. Current challenges have to do with reducing that cycle time from a month or several weeks to a number of days as well as making hundreds or thousands of batches in parallel instead of scaling up. Challenges remaining for regenerative medicines include different approaches to analytics that involve running hundreds or thousands of product quality tests in parallel. “Probably the biggest need for innovation in the cell therapy space is analytics: both new techniques and ways to automate them to turn around lots of batches in parallel very quickly.”

Beri expressed his excitement in the increase of truly curative therapies for oncology. The ability to better understand each person’s disease and lifestyle and maybe make even antibodies more personalized would require huge investments, not only in biology, but also multiplexed manufacturing. “My goal,” he concluded, “is a cure for every disease.”

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The 2018 BPI Theater at BIO

David J. Kenyon, senior director of global scientific and technical affairs, Patheon (Thermo Fisher Scientific)

Kenyon has over 25 years of experience in the pharmaceutical/biotechnology and vaccine industries. He began his career with Johnson and Johnson, where he managed the production of the first monoclonal antibody (MAb) approved for human therapy. He joined Patheon in 2014. Kenyon received his PhD from the Rutgers School of Medicine and Dentistry of New Jersey.

Patheon is now part of Thermo Fisher Scientific. Thermo Fisher provides 400,000 customers worldwide with life sciences solutions, laboratory products, analytical instruments, and specialty diagnostics. Patheon is part of its pharma services group. The company provides process development services, clinical trial manufacturing, support, and logistics; and commercial manufacturing.

Data from the US Food and Drug Administration (FDA) show that the volume and approval pace of biologic therapies is accelerating. For instance, seven of 17 breakthrough therapies (41%) in 2017 were biologics. Although small molecules still account for 58% of the market, biologic therapies grew at 18% compared with a growth rate of 2% for small molecules over a two-year time period (2016–2018).

Client companies of all sizes are saying that they need to complete clinical trials quickly, they need complete datasets, they need sufficient drug product for all required testing, and they need to screen drug candidates fast. Small companies that are venture funded need to get their drugs into clinical trials as fast as possible. Large pharmaceutical companies that traditionally might have been able to do everything in-house now find themselves with multiple possible candidates and need outside help to screen all of them rapidly for further development.

Among critical topics to consider are the difference between investigation new drug (IND) filing and approval, the amount of stability data will be sufficient to suppose those, process development and the tradeoff between speed and process robustness, a company’s short and long-term objectives for each asset, and the quantity of material needed for all trials and studies.

Patheon is proud to offer its Quick to Clinic program for biologic drugs for first-in-human clinical trials. Patheon will provide what is necessary for “F3” – fast, flexible, and full – genes to produce IgG1 and IgG4 MAbs in 14 months or less and F3 clones in 12 months or less to begin first-in-human trials. It also will provide all the necessary data and testing to enable rapid IND submissions. For F3 genes, you bring your own genetic sequence, and Patheon will conduct your cell-line development. For the F3 clones, you already will have a cell-line developer and its accompanying media and feed. In both cases, you will end up with one kilogram of drug substance. In an additional two months, Patheon can fill your drug product up to 200-L scale. All the vial sizes have been prequalified, and your product can start immediately in the filling suite. Fisher Clinical services can assist you with preparation for clinical trials by providing primary and secondary labeling and packaging as well as specimen kits.

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The 2018 BPI Theater at BIO

Igor Fisch, chief executive officer, Selexis, SA

Fisch first posed this question: “How can we accelerate the number of drugs going into the clinics?” Speed matters because the faster a drug can get into clinical testing, the faster it can make it to market. He discussed both Selexis and KBI Biopharma and their collaboration, which started in 2012 when KBI developed a heterodimer purification process. JSR acquired both companies with an interest in entering the life sciences business.

Selexis has best-in-class cell-line development and manufacturing. It has been a part of more than 100 clinical programs, three commercial products, 154 patents, and nine key technology launches. KBI has 101 product development programs, 101 manufacturing batches, over 12 investigational new drugs (INDs) per year, and more than 240 analytical services projects. It has collaborated on 10 Selexis cell lines.

Using the SUREtechnology platform, the companies work together for speed and high-performance research cell banks. This platform includes advanced gene transfection technology and procedures with proprietary vectors; the solid foundation of a proprietary CHO-K1 cell line, media, and feed strategies; and now whole-genome sequencing of the Chinese hamster ovary (CHO) cell line with full annotation of its genes. That has led to understanding the complexities of the CHO-K1 cell line and an ability to certify and authenticate recombinant cell lines, provide complete regulatory packages, and barcode recombinant cell lines in the future.

Fisch described the workflow from transfection to a pool of possibilities to the top four clones to testing. He described KBI’s abilities in analytical services and innovation using new equipment and technologies. For example, KBI was the first CDMO to implement 2,000-L single-use CGMP operations. Because of KBI’s analytical know-how, the company can work on an upstream process for a product that still is at the pool stage. Titers have been measured for monoclonal antibodies (MAbs) at 9.5 g/L and for bispecifics and Fc-fusions at 6.4 g/L. MAb and non-MAb process platforms provide titers of 2–10 g/L.

From DNA transfection through developing a research cell bank to producing a drug substance with all necessary process and analytical development, timelines of nine months are achieved. Analysis includes considerations of clonality, purity, transgene integrity, site of integration, and gene surveys that identify mutations and adventitious agents.

The next challenge is to speed up that process even more and deliver in six to eight months. One improvement is to deliver a clonal research cell bank in nine weeks. A second strategy is to improve the original host cell line by creating virus-free CHO cells and developing a platform process, both upstream and downstream, to go with it for which fewer purification steps will be needed.

“It takes a village to make a MAb.” Drug discovery programs can range from three to five years, then a company must overcome challenges such as the cost of manufacturing, safety, and markets for the drug. Finally, the cell clone must be produced. Then the decision is made whether to proceed. Good partners such as Selexis and KBI can help to make these steps and decisions easier.

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This roundtable took place on Tuesday, 5 June 2018, in the BioProcess Theater at the BIO International Convention in Boston, MA. (Left to Right) Moderator: Patricia Seymour, senior consultant at BioProcess Technology Consultants, Inc. Panelists: Jennifer Michaelson (vice president of preclinical research and early development at Cullinan Oncology), Weichang Zhou (senior vice president and chief technical officer at WuXi Biologics), Michael Kaufman, senior vice president, CMC, at Mersana Therapeutics), and John Lee (senior vice president of pharmaceutical development at Decibel Therapeutics)

Moderator Patricia Seymour, with John Lee, Michael Kaufman, Jennifer Michaelson, and Weichang Zhou

Following introductions of the panelists and their companies’ technologies, moderator Patricia Seymour began the discussion about challenges related to choosing different modalities and addressing related manufacturing concerns.

Targeting Modalities
Michaelson began by describing how Cullinan Oncology selects its targets and modalities, how it approaches those early phase decisions, and what its primary driver is to get into the clinic as quickly as possible.

She talked about challenges in oncology, particularly immune-oncology, which is a highly competitive and fast-moving area for several of Cullinan’s projects. Michaelson highlighted the goal of accelerating the timeline for chemistry, manufacturing, and controls (CMC) development, hoping to reduce that to 15 months. Cullinan wants to accelerate progression of multiple candidates in parallel at the early phases of CMC development. In such early stages, additional developability data coming in from orthogonal assays on various molecules can speed the process of narrowing down candidate selection.

Another challenge is to find a contract manufacturing organization (CMO) that provides a “one-stop shop” experience, offering broad coverage of all aspects of CMC development, from DNA to the drug product. Cullinan also is managing many contract research organizations (CROs) for preclinical development. So a goal is to bundle as many activities together as possible under a single CRO. A successful CMC campaign rests on finding a high-quality contract development and manufacturing organization (CDMO) with a proven track record. Such a partner must be flexible and interactive, providing good service and partnership toward molecular development.

Speed, Product Development, and Complex Supply Chains: Seymour agreed on the importance of evaluating different variants early to save time in cell-line development. Speed is a challenge in such a competitive space, especially if a company’s exit strategy is to out-license as well.

Lee talked about the approach that preclinical-stage Decibel takes toward product development. “In addition to the multiple therapeutic modalities that we’re looking at, we have to develop multiple routes of administration,” whether through traditional oral dosages or local injections. He mentioned the importance of building a baseline understanding of how different modalities intersect with different routes of administration.

Because fewer CMOs work in audiology, Decibel invests in specific companies to build those capabilities and enable smooth transition from preclinical discovery into clinical testing. Decibel also tries to leverage therapeutic adjacencies that may be applicable to the products it is developing and to find CMOs and CDMOs with applicable expertise. Examples are products developed for local administration to mucosal surfaces and small-volume ocular products.

Complexities in Antibody–Drug Conjugate Development: Kaufman spoke about the complex manufacturing and the supply chains for antibody–drug conjugates (ADCs), as well as the unusual regulatory environment. Not only are the drug substance and the drug product subject to investigational new drug (IND) application sections and regulations, but the antibody is making INDs “enormously complex.” Manufacturing work has to be staged so that the drug, linker, and antibody all come together to be further processed downstream. Kaufman said that finding available bioreactor capacity is a concern, even though more facilities are being built, but that companies must plan at least a year out for scheduling antibody manufacturing.

For his company, the hardest task is to find external CDMOs with skill sets to supply the linkers. But all three components have to be on manufacturing schedules that run parallel. The ultimate step is to convert all three elements into one ADC, which for his company is outsourced. He noted that “it is a little nerve-wracking when you bring these millions of dollars of components together in the hope that one reaction works really well.”

Zhou added that another difficulty in ADC development and manufacture is that one company might make the antibody and another the toxin and a third the linker. So managing the timing of those shipments can be critical.

Seymour agreed that the risks are high. Partnering with good CDMOs is critical because if any one component goes significantly off schedule, that throws everything else off, and regaining a spot in the manufacturing queue could delay a project by months.

She asked Zhou to comment on how WuXi deals with such complex time lines and technical issues that call for multiple elements to come together amid high technical and regulatory compliance risks. Zhou emphasized the importance of building in capabilities and capacities. In addition to speed is the issue of process robustness. On the antibody side, his company starts by building a good platform cell line and works toward shortening cell-line development timing before using a platform manufacturing process. WuXi’s goal is to reduce the R&D timeline to below 15 months by performing multiple parallel developability studies for multiple candidates at the beginning for developing that initial cell line.

Facilities of the Future
Seymour asked the panelists to offer perspectives about future facilities. What kind of scales will be in demand? What is that going to mean for access to capacity?

Michaelson said that the challenge is knowing what capacity will be needed so that a company doesn’t have to wait to take its molecule into development. But she also noted that in oncology development, the biggest challenge is not CMC. “Right now it’s how all the molecules in development will find their right use for the right patient in the right combinations because there are so many molecules currently in development and so many combinations being tested. It’s probably going to take time in the clinic and some carefully planned translational work to find the appropriate molecules for the appropriate patients and indications.” She thinks that CMC becomes secondary to trying to predict scale, but she warns against underestimating how successful some immunotherapy products might be — and how quickly those could be developed and moved into commercialization.

Personalized Medicines and Capacity: Seymour asked about the impact of personalized medicine on manufacturing. “The scales could become quite small, and they could become quite mobile, depending on what technologies or modalities you’re talking about. That’s quite challenging, particularly from a CMC perspective. Can you actually set up a mobile facility close to a patient population?”

Lee agreed that the shift from very large manufacturing to more personalized cell- and gene-therapy medicines will necessitate manufacturing flexibility. “Capacity is not going to be the driver; it will be the quality of the material. Lots will be smaller and based purely on drug need.” He said that beyond assessing quality aspects when selecting a CDMO is the importance of understanding that company’s philosophy. Does its business model intersect with a client’s needs?

Kaufman returned to CMC challenges in the oncology space, where developers typically toward the “maximum tolerated dose.” That might not be known until late in a program. Oncology drugs also are tested for different tumor types and cancer indications. So it also can be late in the game before a company knows whether it will need 200,000 or 10,000 doses per year. Finally, if a company gets good results, many breakthrough-therapy and other accelerated-approval schemes become available. All those elements make it challenging to know what the manufacturing scale and timelines will be. One advantage for ADCs is their potency, which can help reduce their supply-chain complexity.

Zhou described WuXi’s approach to scaling out rather than up. The company bases its manufacturing on single-use bioreactors that scale from 200 L to 4,000 L. Because product quality is key, he suggests staying at one scale (2,000 L, for example) in phases 1 and 2. Then by adding more bioreactors instead of scaling up to 20,000 L, a company can lessen risks economically without compromising product quality comparability. Essentially that keeps cell culture at the same scale but satisfies product demand. A company doesn’t have to commit to investment in a large facility early on, and with single-use bioreactors, can build a facility in as little as two years from green field to operation. That allows time for defining a CMC process as well as determining product demand.

With such a strategy, WuXi can build a facility where a product will be needed. That provides supply-chain robustness and mitigates the risk of facility-to-facility validation because the scale does not change while a manufacturer meets product demand in a different geographic location.

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BioProcess Insider brings the news as it breaks. At the BPI Theater @BIO, editor Dan Stanton conducted a series of interviews live on stage to report on the latest movements in the biomanufacturing industry to start each busy day of dealmaking in Boston. Below we summarize his DAY ONE conversations with a number of biopharmaceutical executives on Tuesday 5 June 2018. You can watch the full interviews online at www.bioprocessintl.com/BIO-Theater-2018.

Andy Topping, Chief Scientific Officer, Fujifilm Diosynth Biotechnologies

Gene therapies show great promise, and future demand is growing. Current manufacturing capabilities are not adequate to keep up with current demand. Contract manufacturing organizations (CMOs) such as FDB are running to keep up with new products. New companies are looking for early phase services. Early phase manufacturing isn’t really manufacturing per se; it entails laboratory processes performed in a different environment. The laboratory environment is challenging for making enough of these products even for early clinical development.

FBD started looking into gene therapies in 2014 when it acquired Kalon Biotherapeutics, a viral vaccine company. Although FBD still supports viral vaccines for pathogens, it is increasingly using those facilities to produce gene therapy vectors because the technology is very similar.

One of the real challenges for gene therapy manufacturing is how to make enough product. If you’re using adherent cell culture technology, for example with HYPERStack cell culture vessels, and attempting to scale out, it quickly becomes very difficult if you want to treat more than a few hundred patients. For instance, FDB runs some processes that use 50 HYPERStack units per batch. But procuring enough HYPERStack hardware is a current issue for the industry, which speaks to the explosion of early phase manufacturing and illustrates how cumbersome these laboratory processes are compared with real manufacturing processes. Using HYPERStack systems requires complicated manual handling. If the company could switch to a suspension cell culture, it could get five times more product from about a 2-L suspension culture cell line. Eventually, after switching to a suspension culture, you could use a 2,000-L bioreactor, an option that will be available in FDB’s new Texas facility.

Dave Kenyon, Senior Director of Global Scientific and Technical Affairs, Patheon Biologics

Throughout our network, we are seeing an increase in capacity needs for biologic products, both in the United States and overseas, and single-use technology is the key to supplying a range of products to the market. Many customers are developing novel therapies for unmet needs, and having single-use capability allows them to switch over very quickly, scale up and down as the market changes, and ensure a low risk of cross contamination. Patheon is investing $50 million in facility upgrades and expansion that will be doubling its manufacturing capacity and will continue to expand as the need arises. We are building a smart factory that allows us to gather data throughout the process and produces data very quickly and efficiently.

ThermoFisher Scientific provides support for the market across the biotechnology industry, so whether for analytical complexities or diagnostics or pharma services, it has a strong infrastructure. This gives the newly acquired Patheon a substantial reservoir of resources in technology, subject matter experts, ability to meeting market demands, and general support. ThermoFisher will remain our suppliers, and Patheon will use ThermoFisher bioreactors. Customers with later stage projects that have been using different equipment have no need to worry about transferring technologies halfway through. We have been successful in moving clients from glass reactors to singleuse reactors and across different systems.

Both from a statistical point of view and from the field, clients say that there is a strong need to increase the pace and accelerate manufacturing products for first-in-human trials. Patheon has devised a program that streamlines the supply chain and produces clinical material as part of its “quick to clinic” strategy.

ThermoFisher is looking into new therapies and new ways to treat unmet needs. In time, we will be providing additional support for different types of modalities.

Kevin Noonan, Partner, McDonnell Boehnen Hulbert & Berghoff LLP

In discussing how litigation has restricted the approvals of biosimilars, we find that it has not. Congress intentionally didn’t set up biosimilar litigation schedules like it did for the Hatch–Waxman Act (1984) for small-molecule generics. Biologics have a much longer time of exclusivity. A small-molecule drug has five years of exclusivity. In addition to the life of a patent, coverage is extended by a portion of the time a drug is under regulatory review by the FDA.

For biopharmaceuticals, patent exclusivity is 12 years from the time of biologics license application (BLA) filing. With four years for approval, you get eight more years. Congress says that in those eight years the parties can litigate to determine the first wave of patents that could prevent biosimilar drugs from coming onto the market at the 12-year mark. But most biosimilar applications are for drugs that have been on the market for a long time and have been approved much more quickly than anticipated. That is because the FDA decided to accept European testing data, so the drugs made it to market much quicker.

Instead of what Congress anticipated, companies have ended up doing a “patent dance.” One side presents the patents it expects to be infringed, and the other side presents why those patents won’t be infringed, and they negotiate until they get down to one or two patents to litigate. However, Sandoz has found “a clever legal technique” to forestall that, and the US Supreme Court agreed in a 2017 decision that it could bring treatments to market immediately upon FDA approval — without waiting an additional six months.

Also in 2017, Amgen reached a settlement with AbbVie to delay the US launch of the biosimilar competitor for AbbVie’s blockbuster rheumatoid arthritis drug (Humira) until 31 January 2023. In this case, an innovator had invested a great deal of money into its drug and into the market. For it to be challenged by a generic of any kind meant that a lot of money could be made and a lot of money could be lost. If a biosimilar manufacturer loses such a lawsuit, then its product will be off the market until the patents expire, which in this case would be much later than 2023. On the other hand, an innovator might be willing to trade exclusivity for the certainty of knowing when a biosimilar is coming to market.

European countries do not run into the same patent litigation concerns because their governments are more closely involved in these endeavors. European governments prioritize biosimilars and an end to innovators’ market exclusivity as a way to get drug prices down.

Rory Mullen, Vice President of New Business, IDA Ireland

Irish companies have manufactured small molecules for a long time and retain a reputation for high-quality products. A large part of Ireland’s economic development strategy is to attract new and exciting companies to the country, with the biotechnology industry recognized as a key target. We have been successful in the technology space and life sciences in particular. Many large companies have facilities at multiple sites, so when the biopharmaceutical industry as a whole increased its investment, Ireland specifically set out to attract some of that by ensuring that we had the infrastructure and necessary skills available.

The Industrial Development Authority (IDA) of Ireland divides the life-science industry into three main areas: small-molecule manufacturing, large-molecule manufacturing, and biotechnical services. The latter is growing the most quickly. We have seen huge growth in biologics manufacturing for both drug substances and drug products. Although some classical pharmaceutical facilities closed their doors a few years ago, we have maintained many of those sites and repurposed them for biologics.

The Irish government supports training and upscaling in this industry by supporting multiple programs that people can enter to learn new techniques and technologies for working with large molecules. IDA Ireland works with institutes and colleges across Ireland to ensure that the pipeline of skilled people will be filled.

The United Kingdom is our closest ally and partner in the European Union, and we are sorry to see it leave through “Brexit.” We would prefer that it reconsider that decision. There might be some opportunities in which we seek to compete with our UK neighbors, but we hope for them the softest Brexit possible. Our challenge will be to remain close allies with the United Kingdom while remaining an integral part of Europe.

Ireland has a competitive tax rate because, regardless of what happens at the Organization for Economic Cooperation and Development (OECD) level, we need to have a competitive tax rate with the United States. Combined with an excellent operating environment and the availability of skilled people, that forms a large part of our value proposition. Tax rates are only a part of that. The business-friendly environment, availability of skilled workers, and active and forward-thinking managers are what encourage businesses to come to Ireland.

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The goals of process intensification are to enhance production while shortening timelines, lessening contamination and environmental risks to products and operators, and reducing operating footprints. Previous publications from Sartorius Stedim Biotech (SSB) have highlighted key elements of such activities. In this report, the authors extend the scope of this discussion to tools and technologies that enable intensification of viral vector manufacturing processes.

The first article summarizes presentations from a 2018 seminar for viral vaccine manufacturers. Three guest presentations highlighted the need to
intensify viral vector production: a labor-intensive process for which the high titers and vector quantities needed demand careful process
optimization. Building on its platform of single-use technologies, Sartorius offers tools and technologies to reduce capital costs and decrease the consumption of energy and water during vaccine production.

Vaccines, however, are too diverse a product category for a single platform approach to address all of the challenges. In the next article on predefined platform technologies, Amélie Boulais describes how predefined technologies can be integrated with one another to enable development and manufacturing of vaccines. She offers examples of upstream and downstream processing technologies that viral vector manufacturers can use within their processes.

Even established multinational pharmaceutical companies often do not have the capabilities and/or expertise to manufacture viral vectors that are large (>0.2 μm) or replicating or both, especially at industrial-scale batch sizes. A significant endorsement of SSB’s platform for viral vector processing and single-use design, the ABL facility described in the third article offers capacity designed to help in the manufacture of viral vectors for a wide range of applications such as oncolytic, vaccines, and gene therapy products.

None of this work can ignore continuing needs for both safety and processing flexibility. The fourth article explores risk factors in viral vector production with single-use  components. The authors discuss preventing bag ruptures and filter blockages, along with ways to ensure robustness of processing equipment against long-term working pressures and temperatures. Operator safety should be a significant concern in selection of a single-use technology for vaccine manufacturing. The authors conclude with the importance of challenging single-use bioreactor vendors on their approaches to biosafety risk mitigation to allow a company to make well-founded decisions regarding its future bioreactor platform.

Contents

Viral Vector Development, Manufacturing, and Process Intensification
Miriam Monge, Amélie Boulais, and Gerben Zijlstra

Single-Use Platforms Accelerate Viral Vaccine Development and Manufacturing
Amélie Boulais

GMP Manufacturing Facility for Viral Vector Production at ABL Europe
Amélie Boulais and Nick Hutchinson

Biosafety Considerations for Single-Use Bioreactors
Davy De Wilde, Joerg Weyand, Ute Husemann, Bernward Husemann, and Gerhard Greller

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Fast and cheap: These criteria are becoming ever more urgent drivers for manufacturers of biologics, faced with increased scrutiny on the costs of developing novel drugs, the lengthy timelines for delivering these drugs to patients, and the tightening competition to capitalize on new targets. The challenge for manufacturers is further heightened by the expectations to deliver on quality as well.

Although development and production of molecules such as monoclonal antibodies (MAbs) have greatly benefited from the “platformization” of core technologies and processes, the transition from research and development (R&D) to a manufacturing organization (internal or external) often is uneven at best, resulting in delays to overall timelines. That such delays often occur may seem curious at first glance, because even early phases of discovery research require production of pure molecules to support cellular and in vivo efficacy models. Manufacturing platforms increasingly find their way into R&D organizations to facilitate eventual transfer to the next production group. However, such transfers may suffer from an imperfect fit of the platform processes practiced in the respective organizations, or worse, from a misalignment of strategic goals of the R&D and manufacturing functions within one organization. Lack of communication between the two functions of one organization creates an even more difficult environment for facilitating transfers, both in the short term (projects) and long term (technology development and implementation).

For many R&D organizations, a critical path activity for filing an investigational new drug application (IND) includes the pivotal GLPtoxicology study to ensure that a proposed new drug candidate has an acceptable safety profile at the dosages anticipated for human trials. As IND filing deadlines approach, other activities often appear on the critical path – for NBEs (novel biological entities), those may include creation of the production cell line (and master cell bank) and development of formulation and analytical methods for specification and release. Upstream and downstream processes, even if they are platform, must be verified and locked before production of the first GMP batch. The quality function must ensure that such activities are appropriate and conform to the highest acceptable standards, both internally and in compliance with regulatory expectations. What is often unclear, or even unaddressed, is where these functional responsibilities reside and how best to use the strengths of participating organizations within the company. Often missing as well is a central, overarching strategy to move promising candidates through the pipeline efficiently from research into development, including a clear understanding of decision-makers and decision stage-gates as the product candidate progresses.

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Health authorities are requesting substantial details from sponsors regarding practices used to generate production cell lines for recombinant DNA–(rDNA) derived biopharmaceuticals. Authorities also are asking for information about the clonality of master cell banks (MCBs) and control strategies to minimize genetic heterogeneity. Such requests are prompted by recent reports indicating “nonclonality” for certain production cell lines. To address these and related issues, the CASSS CMC Strategy Forum on “Production Cell Line Development and Control of Product Consistency During Cell Cultivation: Myths, Risks and Best Practices,” was held 23 January 2017 in Washington, DC. The overarching objective of this forum was to define myths about and risks to cell line development and product quality associated with cell cultivation. Forum participants identified current best practices to ensure that sponsors meet regulatory expectations when assessing and assuring the appropriateness of cell lines for biopharmaceutical production during development and commercialization.

This report summarizes considerations for development of production cell lines including

• The choice of expression system
• Strategies to minimize genetic heterogeneity of production cells
• The characterization of cell population genetic heterogeneity and potential approaches to improve cell line performance through host engineering
• Assurance of consistent production of desired product
• Approaches to ensuring appropriate control of product quality throughout a cell culture process, including advancements in analytical control strategies
• Strategies for accelerating early product development though the use of pool clones
• Lifecycle management of production cells.

The forum offered introductory presentations by representatives of regulatory agencies including the FDA and the EMA and by industry representatives. Their presentations were followed by panel discussions of selected topics of interest.

Presentations: Clonality and Host-Cell Engineering
The meeting began with Anthony Lubiniecki (Janssen R&D, LLC, Malvern, PA USA) presenting on an “Industry View on the Relative Importance of ‘Clonality’ of BiopharmaceuticalProducing Cell Lines.” He noted recent feedback from some regulators saying that without adequate proof that a cell bank is derived from a single cell, additional studies/controls of the cell line and product may be required to ensure a product’s purity. Although Lubiniecki stated that developers can provide reasonable certainty that a cell bank is derived from a single cell, they cannot conclude that all resulting cells are genetically identical. Indeed, mutations are an inherent property of DNA replication and will accumulate during expansion of a cell culture. Single-cell cloning cannot prevent genetic heterogeneity after cloning. Thus, assurance of product quality depends on developing an integrated control strategy that includes, but is not limited to control of starting materials (including a demonstration that end-ofproduction cells yield a product consistent with the desired product), raw materials, process conditions, and product testing, as appropriate. Lubiniecki finished by stating that emphasis should be placed on ensuring product quality of all materials administered to patients.

Lianchun Fan (Bristol-Myers Squibb Company) presented on “Evolving Biological Product Expression Systems with Host Cell Engineering.” Several successful case studies demonstrated the power of host-cell engineering technology to drive development of new host cells with improvements on cell-line productivity, product quality, and/or cell-line development efficiency. Fan described improvements in host cell lines that include engineering cell lines by expressing an enzyme to increase afucosylation, enhancing ADCC activity, and switching to newer platforms. Of note was the use of targeted gene integration to develop more homogeneous cell populations, shorten selection processes, and enhance cell-line stability.

Luhong He from Eli Lilly and Company then presented the industry viewpoint for “Characterization of Production Cell Lines.” He emphasized that production cell lines are clonally derived populations of cells exhibiting various levels of genetic heterogeneity, including aberrant splicing and sequence variants. Risks associated with genetic and phenotypic heterogeneity can be mitigated through extensive characterization of an expression construct’s stability as well as product expressed  by end-of-production cells. This characterization includes assessment of transgene integrity (by RT-PCR and Southern blots), copy number (by qPCR), and population drift (assessed by qPCR of single cell clones). Cell lines showing transgene heterogeneity are rejected. Such a characterization strategy enables identification of production cell lines that express appropriate and consistent product quality — even though the absolute genetic and phenotypic homogeneity of clonally derived Chinese-hamster ovary (CHO) production cell lines are not achievable due to low-frequency changes in the genetic composition of a cell (an inherent property of DNA replication). The promising potential for applications using targeted integration also was discussed.

Rachel Novak’s (FDA CDER) presentation highlighted current “Regulatory Expectations Regarding Characterization of Cell Substrates.” Assurance of clonality is expected to minimize genetic heterogeneity within a company’s MCB because every change to an upstream process for a nonclonal cell bank presents a potential risk to select for a product variant that might alter a final drug product. Such assurance involves both a calculation of the probability of single-cell cloning and additional “supporting data,” presumably on cell-bank growth parameters and homogeneity.

High probability that the MCB is derived from a single cell is a critical component of an integrated control strategy. It can be achieved through two rounds of limiting dilutions or appropriate FACS or clonal analysis. Imaging techniques can supplement the choice of cloning strategy. During an initial IND application, the cloning process should be described along with stage-appropriate cell-bank characterization.

Cells should be adapted to serum-free conditions before final cloning. A high probability of single-cell cloning would not require a heightened control strategy. Although a lower probability of clonality can be acceptable, either additional data supporting assurance of clonality or augmentation of an integrated control strategy to reduce the risk associated with cell line heterogeneity would need to be submitted. Enhancement of a control strategy could entail shortening the limit of in vitro cell age, adding additional critical process parameters, or adding specifications for minor amino acid variants or various glycoforms, even if a glycoform is not important for the mechanism of action. A more robust comparability analysis for qualification of a new working cell bank (WCB) also is expected when assurance of clonality is low.

Panel Discussion: Cell-Lines and Expression Systems
The first set of questions to the panel explored the nature of cell lines and expression systems currently leveraged for biopharmaceutical production along with their impact on bioprocess development. Attendees generally agreed that certain CHO lines have been used extensively and are well understood, but that introduction of other cell lines should include as much information as possible on the origins and processes for generating them. Cell lines of human origin were noted to pose a greater risk to viral safety, requiring more characterization work than is typical for common CHO lines. The host cell line can dictate a product’s critical quality attributes (CQAs) and must be considered carefully. The potential impact of expression systems on bioprocesses had been described by Lianchun Fan (see above), but during discussions it also was noted that when a product has been found to be toxic to production cells, inducible expression systems have been used successfully by some manufacturers.

What types of information support the assurance of clonality? The FDA indicates that information required would be determined case by case but could include application of NGS, FISH, or subclone analysis, as appropriate. Stephan Gross from the Paul-Ehrlich-Institut indicted that clonality is not a big issue in Europe but that full genetic characterization of the expression construct is expected for marketing applications. That has generally included analysis by reverse transcription-polymerase chain reaction (RT-PCR, Southern blotting, and assessment of copy numbers. Full analytical characterization of a final product from end-of-production (EoP) cells also is expected. Most participants agreed that consistent quality of a final product is the primary concern when considering cell line stability; if a commercial process is in a demonstrated state of control, then extra controls are not needed. However, if changes to a process could select differentially for a product variant, then a comprehensive analytical comparability exercise should be performed. That exercise would evaluate lot-to-lot consistency of the product following a change in the cell production process, including a new WCB. The question was posed whether characterization of production cells would be different for implementation of a continuous culture process. The audience felt that there would be no special concern as long as data supported cell line stability and as long as attributes were well controlled.

If unexpected genetic heterogeneity is observed during genetic characterization of a production cell line, what additional work might be necessary? One company with this issue resorted to subclone analysis, demonstrating that although a couple of product variants were observed, all the subclones had the same genetic structure. That information was accepted by regulators for demonstrating consistency of the expression construct because the production cells were stable. In other cases, subclone analysis can show more genetic heterogeneity than desired and sometimes correlate with variable productively, but even singly derived clonal lines can show such variability. A decrease in copy number might be common, but what really matters is the quality of the final product. However, in one case, a significant loss of copy number (e.g., 25%) without an impact to product quality also raised a concern about the control of a process and a potential increased risk of an undesirable selection process. That resulted in a regulator’s request to tighten the population doubling limit (PDL).

In all cases, control of CQAs should be demonstrated. In some cases, additional process controls could be warranted particularly if heterogeneity potentially introduces undesired product-related variants. Although recloning can yield a more homogenous cell population, the potential risk to product quality can be high — a factor to consider when planning to reclone an MCB.

What should a company do for cell lines for legacy products that typically are not up to today’s expectations and may show some genetic heterogeneity? If clinical or biological characterization data support that a variant has no impact on safety and efficacy, then such justification should be acceptable. If an undesired variant is present, developers should monitor that variant whenever a process change might compromise the stability of production cells. Developers need to include additional routine testing to control that attribute. A variant sequence can be associated with a metabolic issue rather than genomic heterogeneity, so developers should think about the origin of variants and potential consequences to their control strategies. Forum participants agreed that the main concern is how it affects the quality of product that is administered to patients. Therefore, regardless of origin, the root cause must be understood and controlled.

Several participants noted that the use of cell-line pools for early clinical development can help accelerate product development and obtain information on proof of principle. Nonclonal lines have been used successfully for toxicology lots with a transition from “pool” to clonally derived production cell line. A thorough comparability study to assess the switch to a clonal cell line would be needed. However, the FDA does not recommend pooling for phase 1 studies. The use of transient mammalian expression systems was not viewed as a realistic approach to proof of concept for early clinical studies.

Regarding use of new analytical methods to assess clonality/stability of a cell line, participants saw no barrier to using new tools that provide value. New analytics for cell-line characterization are becoming powerful, but developers must balance understanding what a technique delivers and the utility of that information. For example, next-generation DNA sequencing can provide a great deal of information, much of which may not be relevant to a final product. Participants generally agreed that the higher the resolution of an analytical method, the greater are the chances that low-level events can be revealed that are unlikely to be meaningful. So developers must guard against overinterpreting risks to product quality.

Presentations: Screening, Characterization, and Product Consistency
The afternoon session started with a talk by Christopher Sellick (MedImmune Limited, Cambridge, UK) on “Screening Approaches for Product Quality to Enable Attribute-Driven Cell Line Development with an Eye Toward Commercialization.” The development of non-MAb entities has raised new challenges to cell-line development and requires upfront loading of a desired target product profile and titer together with distinguishing between cell-line– dependent and process-dependent attributes. Sellick described an analytical toolbox for monitoring product attributes (e.g., glycosylation, truncation, aggregation, and terminal clips) that permitted high throughput, required low sample volumes, was applicable to crude supernatants, and had a fast turnaround to enable timely decisions. The tools were successfully applied to the qualification of a new cell line during phase 2, the development of a highly glycosylated Fc-fusion protein, and a large multimeric Fc-fusion protein.

Jason Rouse (Pfizer, Inc., Andover, MA USA) then presented on “Advances in Product Characterization During Cell Cultivation.” A best practice identified in characterization of cell production systems was through application of various ultrahigh-resolution MS-based methods at the clone selection stage and during cell culture process development. That was shown to yield vital product-quality information at the molecular level for C-terminal lysine, trisulfides, N-glycosylation patterns, aglycosylation, signal peptides, genetic sequence variants, and misincorporations. Such activities greatly enhanced assurance that the desired product quality was obtained and that the product was manufacturable.

Steffen Gross (Paul-Ehrlich-Institut, Germany) presented on “Product Consistency During Cell Cultivation: Regulatory Expectations” and started out discussing risks to product quality and the potential controls to ensure consistency of a production cell line and resulting product. He added that appropriate controls can be placed at different steps in a process depending on the issue at hand. For example, several MAb products showed a significant decrease in copy number over time and led to a tightening of the proposed limit of in vitro cell age. That was particularly critical if the levels of heavy and light chains were different. Genetic drift during cell-bank establishment is a recent observation, but apparently it is a widespread phenomenon possibly associated with implementation of more sensitive analytical methods that can detect low levels of variants. Observed variants are evaluated to assess the impact to safety or efficacy, and depending on the criticality, where controlled by establishing an in-process action limit or specification on the variant and/or reducing the limit of in vitro cell age. Emphasis was placed on the concern that posttranslational modifications such as glycosylation are sensitive to changes in a production system and can influence ADCC/CDC activity, antigenicity, and PK. Changes in the production system also can influence the HCP profile as shown by coelution of phospholipase-B–like activity that caused degradation of polysorbate 80 over time and would have restricted the shelf life of the product if the impurity were not eliminated. Gross described a case in which a 24-amino acid insertion in a production cell line affected up to 10% of the product. It was not detected by SDS-PAGE, SEC, or IEF but was detected by RP-HPLC with MS. His presentation concluded that the final purified protein (and final product) must be rigorously evaluated to ensure consistent quality of a DNA-derived product.

Juhong Liu (FDA CDER) presented “Regulatory Expectations and Case Studies for Product Cell Line Development.” He stated that cell production systems are fundamental building blocks in production because multiple critical attributes are sensitive to both clonal selection and cell culture conditions. He discussed a phaseappropriate approach for development of a production cell line that allows for modifications to production cells during product development. The approach relies on a defined target product profile, prior knowledge of a product and process, well-qualified methods, and a robust comparability study. Under circumstances in which differences in CQAs are identified, additional clinical data also may be needed.

One case study Liu described involved a proposed new production cell line at the end of phase 2 that was evaluated by a strong analytical comparability package showing minor changes in critical glycans. A nonclinical PK study was requested and showed comparability sufficient to go into phase 3. Another case study showed that three WCBs derived from the same MCB yielded a comparable product but different productivity, illustrating that clonal variations can occur during expansion of a WCB. MCB changes along with changes in culture conditions have resulted in both noncomparable and comparable products, illustrating the risks associated with changes in cell-line production systems.

Panel Discussion: Sequence Variants and Regulatory Expectations 
What are the expectations in terms of understanding and controlling sequence variants through a cell culture process? There was general agreement that understanding whether the root cause of a sequence variant is genetic or caused by a misincorporation event is important because that knowledge is needed to implement an effective control strategy. For example, if a variant is associated with a misincorporation with depletion of an amino acid during cell cultivation, then supplementation of the media with the appropriate amino acid is an easy fix. Genetic variants may need to be controlled by limiting population doublings, by monitoring the variant, or if early in the development process, selecting a new clone. It was noted that clones with different levels of sequence variants can be generated using the same expression system, so developers should screen for and select the most appropriate clone. In general, it was felt that the ideal situation is to eliminate all sources above a certain level for nucleotide variants even to the point at which one manufacturer stated that it will try to select a better clone if a silent nucleotide change occurs. Some regulators also worried about the potential impact of a nucleotide variant on protein translation, so developers must carefully consider the risk to product quality.

What is an appropriate limit of detection for sequence variants? Although no set LoD was identified, several participants mentioned that they have used methods with an LoD of 0.5% and that no regulator has questioned the adequacy of that detection limit. A robust discussion was held on what level of a variant would be a concern, particularly because some MS methods can quantitate sequence variants below 0.1%. There was some agreement that the level of a variant could in part depend on its biological significance, but participants generally agreed that if the observed level of a variant is linked to clinical data, then there should be few safety or efficacy concerns if the control strategy maintains that level. However, if a new variant is observed that was not present in material used in clinical trials, immunogenicity concerns could be raised that might warrant new immunogenicity studies. The level of a new sequence variety that would trigger an immunogenicity study would depend on the potential risks to product quality as it relates to safety.

What methods should be used to evaluate sequence variants? Two methods were discussed extensively aside from traditional methods: LC-MS/MS-based and NGS-based methods. Sequence variants can be reliably detected, identified, and quantitated by LC-MS/MS (with bioinformatics) down to very low levels and provide information about the primary structure of a product administered to patients. That is thus viewed as a powerful tool for characterizing sequence variants. However, some companies are moving to NGS at least as part of initial screening activities because it has a good sensitivity (0.4–0.5 %) and is relatively fast and cheaper than MS-based methods. Generally, there is good agreement between these two methods. Use of NGS during product development as a screening tool and MS during full characterization was viewed as a best practice.

What are regulatory expectations regarding use of these new technologies and applications? Regulators were cautious about providing detailed recommendations because they have limited experience with the newer technologies. Each situation may require different approaches, but in general, it is important to understand the limitations of such methods and obtain data supporting them to provide meaningful results.

Regarding changes to cell production processes, introduction of a new WCB generally does not require submission of a supplement or a variation if a company is following an approved protocol. Protocol changes require a submission for review and approval. Regulators in the United States and European Union noted that scale-up of a cell culture process has not been a significant issue unless the process changes the way cells interact with their environment (e.g., media changes, addition of wave-motion bags, and extension of the limit of cell culture age). For changes in a cultivation process, a comprehensive comparability study is warranted that might include in-process testing. Differences in CQAs must be justified.

It was noted that changing a culture conditions to increase the yield of a production cell line without changing the cell bank can adversely affect product quality because depletion of amino acid pools or a lack of ability to synthesize various glycoforms has resulted in unacceptable changes in product quality. Changing a cell bank in the middle of a phase 3 study was not recommended.

What considerations are appropriate for characterizing cells at the limit for in vitro cell age? As discussed above, full genetic characterization in alignment with ICH Q5C is expected to assess the genetic heterogeneity of EoP cells. This could include the use of more advanced techniques such as subcloning, NGS, and MS analysis. Characterization of the EoP cell for consistency of a desired product should include evaluation of CQAs for the product, including posttranslational modifications such as glycosylation and the HCP profile. The HCP assay should be qualified for use in evaluating EoP cells to ensure that they are suitable for their intended purpose. Characterization of a drug substance synthesized at the end of production was viewed as a best practice. Thus, isolation of EoP cells and evaluation of newly synthesized products were preferred rather than characterizing the accumulation of product over several days incubation, which looks at the average product produced and not specifically at newly synthesized protein.

Corresponding author Barry Cherney is executive director of quality at Amgen Inc. (bcherney@amgen.com). Dieter Schmalzing is a senior principal technical advisor at Genentech (a Member of the Roche Group). Steffen Gross is head of the monoclonal and polyclonal antibodies section at the Paul-Ehrlich-Institut. Juhong Liu is a biologist with the FDA’s Center for Drug Evaluation and Research. And Christopher Frye is a research advisor for Eli Lilly and Company.

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New technologies bring new regulatory challenges. The biopharmaceutical industry must be cautious in its implementation of new scientific ideas and technology platforms — no matter how promising those might be. Regulators will look skeptically on any claim that isn’t backed up by good data, and with no solid history of successful use to build on, a company must have all the answers itself. How do compliance professionals anticipate what kinds of questions reviewers will ask when the time comes — and how can those in development laboratories and manufacturing suites best be prepared to respond to them? With all that in mind, this eBook addresses a number of new approaches to the regulation-defined areas of chemistry, manufacturing, and controls (CMC) for protein biologics.

Many new product modalities are challenging the old ways of thinking and doing things, and new bioprocess and analytical technologies can offer solutions to the problems they introduce. Meanwhile, those new technologies also suggest new methodologies for established and familiar product types. Changing legacy processes may not be feasible in most cases (because of associated regulatory hurdles), but the overall paradigm will shift over time as advanced platforms are applied to new projects going forward.

Ultimately all work performed under current good manufacturing practice (CGMP) must follow proper standard operating procedures (SOPs), including required documentation for eventual inclusion in regulatory filings such as biological license applications (BLAs). In this eBook, I have arranged sections on chemistry (product characterization, formulation, and cell-line development), manufacturing (platforms, single-use technologies, and continuous processing), and controls (modeling, process control, and data management) not to exactly reflect the regulations, but rather to follow a logical framework for discussion. From a regulatory standpoint, “CMC” sections are those parts of a filing that do not address preclinical and clinical product testing results.

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Cell-based therapies are used to treat diseases that require the replacement of diseased, dysfunctional, and injured cells (1). To produce these therapies, a wide range of reagents and materials such as antibodies, growth factors, and enzymes are used in their manufacturing processes. Such necessary materials are administered through a cell culture medium. Active pharmaceutical ingredients (APIs) are the main ingredients that make products therapeutic. Ancillary materials (AMs) and raw materials (RMs) are essential components used during production but are not supposed to be present in final products. Some advances in cell-based therapies have revealed inconsistencies and lack of regulation in classifying materials that are used to produce these products as RMs, AMs, and APIs. Clear guidelines and regulations are needed regarding RMs and AMs in cell-based therapies.

In cell therapy products, cells are cultivated in a cell culture medium, which contains all materials that are essential for cell growth and proliferation, including growth factors, hormones, and other necessary factors (2). Cell culture has many uses in the development of cell-based therapies. For example, it can be used to grow more effective and efficient influenza vaccines (3, 4). Cell culture medium is involved in cell-therapy manufacturing through the transfer of starting materials (tissue or cells) to a cell culture that contains growth factors and serum, followed by cell selection and the development of a cell therapy product (5). So cell culture medium is an essential product that allows the development of cell-based therapies.

An API is the main component of a pharmaceutical drug and the active ingredient of a drug product (6). This active ingredient creates the intended effects of a drug. An API starting material is a raw material, intermediate, or an API that is involved in the production of an API and is part of the essential “fragments” that make an API (6). APIs are essential for making pharmaceutical products and generally have welldefined guidelines for use.

Other than APIs, cell-based therapies are manufactured using raw materials (RMs) and ancillary materials (AMs). A raw material is a general term that refers to “starting materials, reagents, solvents, process aids, intermediates, APIs, and packaging and labeling materials” (6). AMs are materials or products that come into contact with pharmaceutical products during manufacturing but are not supposed to be in final products (7, 8). AMs and RMs are used to produce final APIs. AMs can be reagents such as enzymes, anticoagulants, buffer solutions, and culture media as well as containers or transfer devices such as bags, pipettes, needles, and culture flasks (8).

Although the industry refers to cell culture media as neither APIs nor significant structural fragments of APIs, determinations about whether cell culture media should be considered RMs or AMs have been inconsistent. That inconsistency stems from a tendency for regulatory agencies to disregard the difference between RMs and AMs and the lack of a consistent definition for AMs. The industry also suffers from inconsistencies in RMs for manufacturing cell and gene therapies (9).

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While the growth in biopharmaceutical manufacturing capacity in developed, major market countries is continuing its slow and steady climb, developing regions often are seeing double that growth rate. Over the past eight years, as detailed in the “About the Data” box, our company’s index of the top 1,000 biomanufacturing facilities (1) has tracked and ranked bioprocessing facilities worldwide in terms of

• known or estimated bioprocessing capacity (cumulative onsite bioreactor volume)
• number of biological products manufactured at clinical scale
• commercial scale
• bioprocessing-related employment.

Significant strategic implications come with those changes in growth rates, especially in developing regions. As production of biologics becomes more globalized, we are regularly seeing active pharmaceutical ingredients (APIs) produced in one region, fill–finish activities performed in another, and marketing and sales done in yet another. As more opportunities develop outside the US/EU markets, both biologics innovators and their suppliers are considering how these shifts in growth require predictive plans.

Our database now tracks over 16.5 million liters of active production capacity at more than 1,500 facilities worldwide. That includes 6 million liters (37%) in the United States and Canada, 5.5 million liters in Western Europe (33%), and 4.7 million liters (25%) in the Asia–Pacific region, with 870,000 liters in China and 941,000 liters in India. Those capacity figures are higher than some reported capacity data, partly because we include all global active capacity, including facilities making human and veterinary vaccines, vaccines, and “biogenerics” capacity — noncompliant with good manufacturing practices (GMPs) — used for therapeutics in lesser regulated markets.

Although non-GMP facilities currently do not sell biologics on regulated Western markets, they are part of global capacity. Such emerging global facilities need their own biomanufacturing tools, technologies, and services. As their importance to their own local/regional drug markets increases, many of these facilities eventually (in the not-so-distant future) could be producing APIs, biosimilars, or even finished innovative biologics for global markets. So it is important strategically for the industry to track such regional growth. Much current biomanufacturing capacity being added in developing countries is targeting those biomanufacturers’ domestic markets, but that is likely to change as such facilities achieve their production quality goals and increasingly reach for developed-market export opportunities.

Advances in bringing biomanufacturing capacity online have been notable particularly in China and India (2, 3). Biopharmaceutical contract manufacturing organization (CMO) capacity is growing in China, especially as its regulations are changing to allow third parties to manufacture clinical and commercial biopharmaceutical products. The country is building capacity and adopting newer technologies faster than India and thus will pull ahead of it in biomanufacturing and related services. That has translated to a significant influx of investment. China recently bested India in its number of biopharmaceutical facilities — now with >50% more facilities, although its average facility size is significantly smaller than India’s. Much of India’s well-established biomanufacturing expertise and capacity is in vaccines production, whereas China intends to expand in a broader range of product platforms.

Capacity is growing faster in developing countries than in the major Western markets. But note that members of the former group, especially China, recently have begun from relatively low baselines, so that growth rate is not likely to continue over the long term. Such developing countries are unlikely to represent an immediate threat to US and European dominance in the biopharmaceutical industry, especially for the most profitable activities of innovative product development and GMP manufacturing.

Demand for Bioprocess Equipment and Supplies
Many companies outside the West are establishing commercial-scale biomanufacturing and CMO facilities to serve both domestic and regional needs. According to our studies of China and India, many such companies are targeting eventual CGMP-compliant manufacturing to supply Western markets (2, 3). Doing so will require technologies that meet both GMP and industry standards. We already see markets for bioprocessing supplies and services increasing significantly in those developing countries. Some major bioprocessing suppliers report double-digit sales growth in the Asian markets. At present, very little such equipment and supplies are manufactured in developing countries. Nearly all companies in China, India, Brazil, and elsewhere targeting eventual sales in highly regulated countries are buying US- and EU-sourced “GMP-ready” bioprocessing supplies. Thus, the demand in developing regions for such tools and services is continuing to grow, so Western technology and suppliers will continue to expand in the developing world as domestic revenues increase.

One strategic consideration is the current relatively high cost of Western materials, equipment, and supplies. Such expenses are creating demand potential for domestic/regional suppliers outside the West that can develop acceptable alternatives at lower cost. And as such domestic suppliers emerge, they will create competition for Western suppliers — not just locally, but also possibly in their home markets. Single-use devices, bags, tubing, and filters are a few examples. Chinese suppliers already are developing alternatives to Western equipment and bioprocess materials. And although most may not meet industry standards today, these competitive suppliers are likely to promote their devices (with GMP quality) to Western markets in the future.

Table 1: Worldwide capacity and facilities summary data

Global Facility Capacity Distribution
Biopharmaceutical manufacturing itself represents the great majority of the world’s biomanufacturing-related capacity, supplies, and services — with research and development (R&D) facilities representing just a small portion of that. We estimate from aggregated data that total worldwide bioprocessing capacity is now about 16.5 million liters. Table 1 lists top-level capacity and facilities data.

Our free online database indexes the global top 1,000 biopharmaceutical facilities and contains records for facilities with ≥500-L capacity, accounting for 99.5% of the total worldwide capacity (1). Facilities with ≥1,000-L capacity generally are involved in commercial-products manufacturing, with 98.7% of worldwide capacity. An estimated 68% of the ≥15 million liters of culture/fermentation-based capacity (excluding capacity for blood/plasma products) is based on mammalian cells (~10.2 million liters), the great majority for MAb manufacture and nearly all using Chinese hamster ovary (CHO) host cells. Nearly all the rest — just under five million liters — is microbial (most of which is using Escherichia coli host cells).

Our database does include a growing number of cellular and gene therapy facilities, but so far only a few of these fit the criteria to make the Top1000bio.com list. Among these facilities, most current capacity is used for manufacturing viral vectors used with gene therapy, including some facilities having scaled up to bioreactors of 1,000-L to 2,000-L scale (4). By contrast, capacity used for cellular therapies generally remains at much lower scales, with many sites manufacturing just a single patient’s cellular therapy for each process line. Besides, few of those products yet are manufactured at the commercial level.

Global Bioprocessing Hotspots: The United States and Western Europe continue to lead in biopharmaceutical R&D based on the number of companies involved, their manufacturing activities, and revenues. That is reflected in facilities and capacity data: North America is the leading region in terms of manufacturing capacity (~6.0 million liters, with ~5.6 million of that in the United States) and very closely followed by Europe (~5.5 million liters).

Table 2: Regional bioprocessing concentrations based on facility index ranking

The ratio of a country’s or a region’s total capacity to its number of facilities (“average capacity per facility” in Table 2) is related to its average facility size (capacity). Western Europe has facilities with larger average capacity than those in Canada and the United States. The latter has proportionately more R&D and smaller facilities (based on single-use technologies). Asia is home to about 85% of the number of facilities that Western Europe has, with significantly less total capacity.

By far, the United States boasts the largest number of biopharmaceutical manufacturing facilities (592). But China, which ranks second, has 209 facilities, with about half the US average capacity/facility. With a very large domestic market primarily for biogenerics and vaccines, China now ranks fifth worldwide in total capacity. Its many facilities have low average capacity.

Whether China and other developing countries will adopt now classic bioprocessing (e.g., ≥10,000-L stainless steel bioreactors for commercial MAb manufacturing) or adopt scaling-out with multiple 1,000-L to 2,000-L disposable-based biomanufacturing schemes remains to be seen. However, most facilities in China and other developing countries typically are not large, and large-scale MAb production could use either approach. Among the top countries (those with ≥250,000 L), China is the only one whose manufacturing generally does not meet the GMP standards of highly developed countries.

Only three countries boast a total capacity near a million liters or more: the United States, India, and Ireland. Indian facilities provide much of the world’s biogenerics, and Ireland is home to many of the very largest bioprocessing facilities for leading MAb products. A second tier of just six countries sits in the range of 500,000–1,000,000 L, the next group of nine countries have capacity in the range of 250,000–500,000 L, and six more are home to 100,000– 250,000 L, with all other countries having <100,000 L total capacity.

In average capacity, the 10 counties with the largest average facility capacity are Ireland, Singapore, Austria, (South) Korea, Belgium, Brazil, Switzerland, Japan, Italy, and Iceland (with >15,000 L each). These countries generally have much more commercial manufacturing than R&D activity and facilities. Much like Ireland, Singapore is home to many of the largest international company facilities that supply regional Asian markets.

Table 3: Biomanufacturing-related market estimates for 2018

A total of 522 facilities are indexed as offering CMO services, holding ~3.5 million liters of capacity (19.8% of that worldwide) at an average of 6,715 L/facility. That number may be an overestimate, however, because some biologics developers also use their manufacturing facilities to offer CMO services, and some CMO-allocated capacity may not be open for contract operations. Thus, the actual dedicated capacity for CMO services would be lower. A total of 193 facilities are indexed as involved in biosimilars/biogenerics manufacturing, with a total of ~2.3 million liters in capacity (13% of that worldwide) at an average of ~11,900 L/facility. Some of those facilities also manufacture mainstream products, and most (117) are located in Asia.

Figure 1: Global bioprocessing operations concentration (by facility index)

Regional Concentration of Bioprocessing: Capacity is just one measure of a region’s bioprocessing presence. To assess a region’s capability more accurately, we established a facility-ranking system. By summing a region’s overall ranking factors, we can compare bioprocessing competence and strength. These rankings are based on four factors: capacity, bioprocessing staff, number of commercial biologics made, and number of clinical-scale biologics produced. Those data create a ranking number for each facility. The resulting index is used to define a region’s overall bioprocessing concentration. Our index numbers can be used to compare and predict where robust capacity and bioprocessing employment are based. Table 2 shows the regional distribution of facilities and capacity worldwide.

Figure 2: Distribution of worldwide facilities by capacity size range

Global Capacity Distribution
The largest number of facilities are in the range of 100–500 L. That includes many involved in process development and making early clinical supplies. Among facilities in this range, 84% are located in the United States or Europe, which reflects those countries’ strength in R&D. We expect the smaller cluster encompassing the range of 2,001–5,000 L to grow, including many single-use facilities coming online in this size range.

Companies and Products Distribution: Table 4 lists a few total capacity estimates for major capacity-holding companies. All have multiple facilities, generally on different continents to supply regional markets and/or serve as backups. Nearly all companies with the largest capacities are making major MAb products, with some of them manufacturing vaccines. Sanofi (including its Genzyme subsidiary) has the most estimated capacity, much of that vaccine-related, followed by a number of other companies with blockbuster (≥$1 billion/year sales) MAbs and other products. Among leading capacity holders, nearly all are based (headquarters) in the United States or Western Europe. And of the largest facilities, the only ones outside those regions are Bio-Manguinhos in Brazil, Biocon in India, and Samsung and Celltrion in South Korea. Despite the vast size of its own domestic market, China does not yet have facilities or companies with >100,000-L capacity. Its largest facility is reported to have 77,000 L.

Table 4: Leading biopharmaceutical company capacity

Supplies and Services Markets: Based on our analyses over the past 28 years, the market for bioprocessing tools, materials, and services continues to grow at 12–14% annually (5, 6). The current worldwide market for biomanufacturing-related goods and services (the direct costs of such manufacturing) is ≥US$22.0 billion — ~8.0% of the total current biopharmaceutical revenues. That includes bioprocessing equipment, supplies, and services — e.g., CMOs, contract research organizations (CROs), and others.

So bioprocessing supplies represent a healthy, consistently growing market that tracks related biotherapeutic product revenue. Facilities performing late-stage — and particularly commercial — biomanufacturing account for ~90% of such consumption and revenue. (For example, the protein A resins used for initial MAb purification from a large-scale bioreactor run can cost millions of US dollars.) This includes the >600 facilities worldwide, each with ≥1,000 L in capacity known to be manufacturing commercial biologics.

Our company’s annual survey data show that the biopharmaceutical industry’s use of outsourcing is becoming more strategic and long term (5). Even “big-pharma” companies that formerly eliminated some in-house capabilities to cut staff and maximize outsourced operations now are taking a more sophisticated approach. Companies now evaluate and weigh their manufacturing options carefully, including assessing options from longer-term perspectives.

A Bright Future
Biopharmaceutical manufacturing capacity continues to expand around the world. This is driving growth of the related supplies-and-services market that closely parallels biopharmaceutical revenues, generally in the range of 12–14% per year. Expansions seen in emerging markets and for developing new technologies such as cell therapies indicate that this market growth is likely to continue. We believe that there is every reason to assume that future growth in biopharmaceutical sales will continue in kind, and along with it growth in markets for supplies and services. Measuring regional capacity and using concentration indexes over time are important ways to gauge the strategic relevance of regional segments.

References
1 Rader RA, Langer ES. Top 1000 Biopharmaceutical Facilities Index. BioPlan Associates: Rockville, MD, 2018; www.top1000bio.com.

2 Xia V, Yang LC, Langer ES. Directory of Top 60 Biopharmaceutical Manufacturers in China. BioPlan Associates: Rockville, MD, February 2017.

3 Langer ES, et al. Directory of Top 60 Biopharmaceutical Facilities in India. BioPlan Associates: Rockville, MD, September 2008.

4 Rader RA. Cell and Gene Therapies: Industry Faces Potential Capacity Shortages. Gen. Eng. Biotechnol. News 37(20) 2017.

5 Langer ES, et al. Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, 15th Edition. BioPlan Associates: Rockville, MD, April 2018.

6 Rader RA, Langer ES. Thirty Years of Upstream Bioprocessing Improvements. BioProcess Int. 14(2) 2015: 10–14.

7 Rader RA. Biosimilars/Biobetters Pipeline Directory. BioPlan Associates: Rockville, MD, 2018; www.biosimilarspipeline.com.

Ronald A. Rader is senior director of technical research, and corresponding author Eric S. Langer is president and managing partner of BioPlan Associates, Inc., a biotechnology and life sciences marketing research and publishing firm in Rockville, MD; 1-301-921-5979; elanger@bioplanassociates.com; 1-301-921-5979. www.bioplanassociates.com.

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From the global shift in demographics to increased efficiencies in chromatography media, change is constant within the bioprocessing industry and a major reason delegates flock to the annual BPI Conference and Exhibition. As a place to get an overview of the hot topics affecting this industry, the meeting brings together key aspects of bioprocessing — therapeutic modalities, cells, expression systems, upstream production, downstream processing, development, and manufacturing — with digital integration and the increasing importance of analytics.

Add in macrobusiness and political developments, and the conference becomes “a really good place to get an overview of some of the trends in this industry; a sort of one-stop–shopping experience,” Günter Jagschies, strategic customer relations leader at GE Healthcare and author of the book Biopharmaceutical Processing: Development, Design, and Implementation of Manufacturing, said at the opening session of the conference in Boston, MA.

“But our world is about to change,” he warned. “If you can’t be part of the change, then you better move out the way because other people are coming to take your place.”

The change he spoke about referred not to politics, but rather to demographic transitions. “The face of this planet will change mainly because the population living on it is aging,” he explained. “Over the next 80 years or so, predictions are that there will be 2.3 billion more people my age or older in Asia and Africa.” (Although Jagschies did not divulge his own age, his LinkedIn profile shows that he began his university studies in 1974). Healthcare markets will change dramatically along with that population shift. “Even while they are going up the wealth ladder, these people are not going to be able to afford price levels that we have in the western world today for most of these therapies that we develop here in this industry.”

Thus, as the biopharmaceutical industry begins to target those 2.3 billion customers, the places where its business is conducted will change — and the conditions, price levels, and entire financial situation will need to adapt.

“We don’t really know cancer yet,” continued Jagschies. “We know almost nothing about Alzheimer’s. And these people are going to be in desperate need for better medicines — or medicines at all in the first place.” Many African and Asian countries will need to create their own healthcare systems, he added. “They have a double burden: They have so many people who are in need and so little infrastructure.”

Therefore, major investments will be necessary, but those will need to be balanced against the realization that many of those countries have only just managed to pull themselves out of poverty. “Noncommunicable diseases could break the bank of many nations,” he pointed out, which is something the industry must help prevent.

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The production of biologics will always have the risk of viral contamination. Manufacturers have developed a multitiered approach — tailored to individual processes — to prevent adventitious viruses from entering production processes, detect contamination in raw materials and process intermediates, and remove viruses in downstream purification. This article provides an overview of the global regulatory framework to ensure the viral safety of biologics.

Past Contamination Events
Past contamination events have resulted in corrective and preventative actions to reduce the risk of viral contamination in biologics. A number of viral contamination events have been reported in different production processes.

Many of those events involved Chinese hamster ovary (CHO) cells, a commonly used cell line for monoclonal antibody (MAb) production, and in some cases, bovine serum was identified as the likely source of contamination. The most frequently reported viral contamination of CHO cells has been with minute virus of mice (MVM), and the most likely sources were media components such as glucose. Porcine trypsin was the likely source of porcine circovirus contamination of rotavirus vaccines.

Unfortunately, not all adventitious virus contaminations are easily detected. For instance, most insect viruses silently infect insect cells. Nodavirus or rhabdovirus infections of insect cells are common, and although scientists generally believe that such viruses are not of concern to humans, nodavirus can produce morbidity after injection into suckling mice.

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Figure 1: Seven steps proposed by BioVesel for procuring CMO services

Three major concerns predominate biotechnology executive management in organizations of all sizes and above all other risks: finance (or its absence at critical moments), technological performance, and failures in coordination. Some business functions, such as human resources (HR), are effectively siloed horizontally and therein are more likely to be susceptible to only one of those risks (1). Few functions are subject to this trinity of risks simultaneously; all functions may be exposed to failures in internal coordination, and a smaller subset can be prey to challenges of both internal and external coordination. But manufacturing can be exposed to all three concerns (2).

Biotechnology companies are vertically integrated by nature – and particularly companies pursuing contemporary novel biological therapeutic platforms such as cell, gene, and viral therapies (3). They operate within a predominantly virtual business model by outsourcing key functions to domain experts such as contract manufacturing organizations (CMOs) and contract development and manufacturing organizations (CDMOs). Outsourced tasks otherwise would necessitate high operational and capital expenditure but, relative to an overall business, would register low-use levels if brought in-house (4).

Start-up biotechnology companies are likely to spend 50% of their first two years of operating budgets on CMO services, seeking to move academic manufacturing processes to manufacturing levels suitable for producing good manufacturing practice (GMP) material for phase 1b–2a clinical studies. When translated into crude numbers, that cost usually is between US$2.5 and $6 million (5). By comparison, contract research organization (CRO) services to conduct preclinical good laboratory practice (GLP) studies and to prepare materials for investigational new drug (IND) submissions are likely to cost somewhere between US$750,000 and $1.5 million, with the randomized control trial (RCT) costing US$1 to $5 million alone (6).

The sobering reality is that most start-up biotechnology companies will spend nearly half of their hard-raised capital on CMOs to produce material critical to filing IND applications and conducting preclinical studies (7). Considering the significance of the figures involved, the current vacuum (rather than corpus) of harmonized processes and standards to support evaluation and appointment of such critical vendors seems to be an oversight with potential for significant repercussions. This is the central issue that creation of biopharmaceutical vendor evaluation and selection minimum standards (BioVesel) will seek to resolve.

How the Current Landscape Emerged
The lack of harmonization and standards in CMO tendering processes results from both evolution and inertia, the exact origins of which are unfortunately impossible to pinpoint. However, we see the following factors as contributing to the current status quo.

Specialization of Biopharmaceutical Procurement: Historically, pharmaceutical procurement departments focused on procurement of nonspecialized (and often high-volume) services. The focus was on price rather than technical performance or differentiation (8). Therefore, deep, lasting relationships were forged on a now-flawed and outdated basis between procurement departments of biopharmaceutical companies and key vendors, including CMOs. Conversely, procurement of biopharmaceutical CMO services requires a structured approach centered on ensuring that each technology is treated as de novo given the significant technological diversity of product pipelines and the multiplicity of experience, equipment, and capacity among available CMOs.

Limited Public Sector Participation: Most comparable sectors in terms of procurement value and complexity of service have significant public sector involvement (e.g., aerospace and defense industries) (9). Their procurement processes are consequently subject to public-sector procurement processes and standards. With the exception of early stage public-health applications, the biopharmaceutical industry remains largely independent of public-sector activities.

Dominance of Preexisting Relationships and Contractual Structures: Companies that have negotiated a master service agreement (MSA) or the (dreaded) first statement of work (SoW, also known as SoW 1) with a major vendor (10) often have been surprised by the months taken to finalize the SoW — and the sometimes substantial accompanying legal bills. Such companies will understand the convenience of remaining with an existing vendor for pipeline programs, independent of that vendor’s expertise (or lack thereof) or track record with other specialist technologies (11).

Opacity of CMO Attributes: An initial major challenge in CMO procurement can be simply identifying CMOs at a primary level, then understanding their respective expertise and capacities at a secondary level (12). Awareness of potential CROs for inclusion is based mostly on word-of-mouth, personal experience, conference presentations, and general awareness of larger “blue-chip” CMOs with significant experience in legacy technologies such as small molecules, fine chemicals, and dyes (13). A single compendium of CRO capacities and expertise does not exist. Therein lies an inclusion bias in CRO selection to tender processes.

Agency Relationships: Biopharmaceutical vendor contracting is subject to an inherent linearity and interconnectivity whereby selected tools and technology manufacturers in turn make introductions to selected CMOs, which then recommend their own preferred CROs (14). This informal network has some merits in (for example) leveraging industry experience. However, it also suffers from a reporting bias due to individual agency relationships and the lack of a compendial reporting resource for all suppliers (15).

Technological Inertia: Most large-scale request-for-proposal (RFP) processes have reverted to centralized tendering software platforms that require vendor and purchaser
registration and prequalification. Such platforms confer some transparency to the tendering processes, but coordinating the requirements of multiple vendors and products would be challenging (16).

Limitations in Vendor Incentives for Progress: Ultimately, established vendors are disincentivized to invest in cross-industry platforms — which would of course include those of competitors — to support tendering activities (17). Service purchasers would benefit from investment in such platforms, but companies with a limited number of assets would have a corresponding limited need to use such platforms frequently, curbing the return on investment (ROI).

Human Capital Constraints Among RFP Specialists: In other industries, entire subsectors have emerged with companies offering RFP support services or project-managing RfP processes. This is now slowly emerging in biotechnology (18) but remains limited in adoption across company sizes and platform technologies for active pharmaceutical ingredients (APIs).

Biopharmaceutical Vendor Evaluation and Selection Minimum Standards (BioVesel)
Standardization of procurement processes leads to resource optimization and best practice. This stands in contrast to ad hoc processes that, as indicated by our collective experience above, may eventually yield outcomes but through an approach that is cumbersome and rarely yields optimal results.

BioVesel intends to develop a standard form of procurement of services through a common industry framework. It will enable new entrants to benefit from a procurement procedure that already is in place. It therefore proposes to achieve this without recourse to developing new processes and will prevent clients from incurring the inefficacies incumbent in nonstandard purchasing and outsourcing. Existing organizations will benefit from contributing to a common marketplace and optimizing procurement services over time.

We suggest the following seven steps to establish a basis for procurement of CMO services (Figure 1).

Contracting Framework Opt-In: A not-for-profit organization and/or independent multiple-stakeholder advisory group with membership drawn from the community will be responsible for maintaining BioVesel standard(s) and developing procurement procedures. New entrants will register with this organization and gain access to process and standard commercial templates and legal contracts. Those documents can be modified and extended by member organizations to fit individual circumstances, but they will be sourced from standard agreements maintained by the framework organization.

Gathering of Presubmission Requirements: Requirements for services will be gathered against a standard pre-RFP submission checklist, taking into account factors that influence analysis, design, and initiation of services. Common issues and pitfalls incumbent to requirement gathering will be structured against a standard risks–actions–issues–decisions framework. Detailed interview questions for key stakeholders will allow for the critical capture of data required for development of an RFP.

Release of Requirement: A pre-RFP notification will be sent to all framework members to indicate an associated need. This will allow for preparation of resources necessary for a response. During this stage, the sourcing organization will complete a templated RFP that will be validated by the BioVesel not-for-profit for best fit.

Request for Proposals: An RFP will be released.

Vendor Selection: Vendor selection will be completed against preselected criteria.

Contracting: Following vendor selection, standard framework templates will form the baseline for the commercial offer, subject to any project-specific requirements.

Continuous Feedback: Users of all guidelines and templates will compete a short evaluation questionnaire after use, which will be collated and used by the not-for-profit organization and/or independent multiple-stakeholder advisory group to propose and implement updates.

Next Steps
We will develop a preliminary research and engagement proposal as a basis for stakeholder engagement and discussion. Once that proposal is acceptable to the community following discussion and peer review, we will convene an advisory board to develop the envisaged not-for-profit organization to develop, maintain, and enhance the BioVesel framework and associated standards. This also will include participation from standards implementation organizations including the National Institute of Science and Technology (NIST) and notified bodies such as the British Standards Institution (BSI).

Procurement process for CMO services at first may appear to be a mundane and perhaps “dry” area for multiple-stakeholder engagement and academic research. However, the adage that “someone has to do it” perhaps best encapsulates our motivation to address this industry-wide need.

It is challenging to be emotive about a potential standard. But in purely commercial terms (notwithstanding the prospect of greater transparency, improved corporate governance, and opportunity to minimize coordination risks), if the standard reduces the lead time to CMO contracting by a single month for an organization, that saves one month of burn and accelerates critical time to market by a month. The benefits will be exponential for a number of stakeholders: for CMOs, that can better plan capacity and resources; for potential CMO clients, that will be able to save time and money and operate in a more transparent environment; and also, ultimately, for patients.

We propose that all interested stakeholders now work together to ensure that substandard procurement practices become a thing of the past. They are not a valid reason to protract unmet patient needs. Now is the time to bring this too-long-neglected horse to predefined selection of a suitably standardized watering hole – where it can thrive in a healthy and sustainable environment.

References
1 Baldi S, Vannoni D. The Impact of Centralization on Pharmaceutical Procurement Prices: The Role of Institutional Quality and Corruption. Regional Studies 51(3) 2017: 426–438.

2 Glass HE, Beaudry DP. Key Factors in CRO Selection. Appl. Clin. Trials 17(4) 2008: 52.

3 Gbadegeshin SA. Stating Best Commercialization Method: An Unanswered Question from Scholars and Practitioners. International Journal of Social, Behavioural, Educational, Economic, Business and Industrial Engineering 11(5) 2017: 1088–1094.

4 Dillen L, Verhaeghe T. Outsourcing Bioanalytical Services at Janssen Research and Development: The Sequel Anno 2017. Bioanalysis 9(15) 2017: 1195–1201.

5 Lowes S. Outsourcing in Bioanalysis: A CRO Perspective. Bioanalysis 9(15) 2017: 1161–1164; doi:10.4155/bio-2017-4994.

6 Hayes R. Bioanalytical Outsourcing: Transitioning from Pharma to CRO. Bioanalysis 9(15) 2017: 1149–1152; https://doi.org/10.4155/bio-2017-4996.

7 Welink J, et al. White Paper on Recent Issues in Bioanalysis: Aren’t BMV Guidance/Guidelines ‘Scientific’? Part 1 – LCMS: Small Molecules, Peptides and Small Molecule Biomarkers). Bioanalysis 9(22) 2017: 1807–1825; doi:10.4155/bio-2017-4975.

8 Sanderson J, et al. Towards a Framework for Enhancing Procurement and Supply Chain Management Practice in the NHS: Lessons for Managers and Clinicians from a Synthesis of the Theoretical and Empirical Literature. Health Serv. Deliv. Res. 3(18) 2015.

9 Decoin M, Boisleux Charlet C. A Portrait of the Ideal CRO. Phytoma La Defense des Vegetaux 1997; www.phytoma-ldv.com/article-22651-Phytoma_La_Defense_des_ vegetaux_et_l_8217_evolution_de_la_ protection_des_cultures.

10 Ferrario A, et al. Challenges and Opportunities in Improving Access to Medicines Through Efficient Public Procurement in WHO European Region. WHO Regional Office for Europe (Copenhagen, Denmark, 2016); www.euro.who.int/en/publications/abstracts/challenges-and-opportunities-in-improving-access-to-medicines-through-efficient-public-procurement-in-the-who-european-region-2016.

11 Spooner N, Cape S, Summerfield S. Outsourcing Strategies in Bioanalysis. Bioanalysis 9(15) 2017: 1125–1126; https://doi.org/10.4155/bio-2017-4986.

12 Cohen B, Neubert M. Price-Setting Strategies for Product Innovations in the Medtech Industry. In EuroMed Research Institute’s 10th Annual Conference of the EuroMed Academy of Business, Rome, Italy, 13–15 September 2017.

13 Handfield R. Patient-focused Network Integration in Biopharma: Strategic Imperatives for the Years Ahead. CRC Press: Boca Raton, FL, 2016.

14 Danzon PM, Mulcahy AW, Towse AK. Pharmaceutical Pricing in Emerging Markets: Effects of Income, Competition, and Procurement. Health Economics 24(2) 2015: 238–252.

15 Abberley L. Outsourcing of Bioanalysis at GSK: A Hybrid Approach with a Robust Support Model. Bioanalysis 9(15) 2017: 1139–1144; https://doi.org/10.4155/bio-2017-0062.

16 Craddock A, Nadarajah S. Future Trends in Outsourcing: A Summary of the Bioanalysis Zone Survey. Bioanalysis 9(15) 2017: 1127–1129; doi:10.4155/bio-2017-4985.

17 Slack D. eProposals: An Interactive Approach to eProcurement. Appl. Clin. Trials. 6, 2009; www.appliedclinicaltrialsonline.com/eproposals-interactive-approach-eprocurement.

18 Grohn K, et al. Lean Start-Up: A Case Study in the Establishment of Affordable Laboratory Infrastructure and Emerging Biotechnology Business Models. J. Commercial Biotechnol. 21(2) 2015.

Alison R. Carter is a research fellow, Edward Meinert is a Sir David Cooksey research fellow, and David A. Brindley is a senior research fellow in Healthcare Translation and Group Lead at the University of Oxford, Healthcare Translation Research Group, Department of Paediatrics, Oxford, UK; corresponding authors: david.brindley@paediatrics.ox.ac.uk and alison.carter@paediatrics.ox.ac.uk.

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Triton X-100 detergent makes an interesting case study in bioprocess sustainability strategy. Also known as octylphenol ethoxylate (OPE), this nonionic surfactant has many uses in biopharmaceutical research and development. Among other laboratory applications, it is used to lyse cells and DNA in research, to solubilize membrane proteins and decellularize animal-derived tissues, to reduce the surface tension of aqueous solutions during immunostaining, and to remove sodium dodecyl sulfate (SDS) from polyacrylamide gel electrophoresis (PAGE) gels for analysis. It also serves as a vaccine excipient and most notably a virus-inactivation agent in downstream processing. Despite a long history of industrial use and an established safety profile, OPE has been listed in Europe as a “substance of very high concern” because it recently has been shown to degrade in the environment to yield an endocrine disruptor. Consequently, many users are looking for alternatives — especially for high-volume uses such as viral inactivation of large-scale product streams.

In this exclusive eBook, BPI’s senior technical editor reviews the problem and potential solutions in the works, including discussion with scientists at Bayer and Biogen.

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Biopharmaceuticals are a particularly complex expression of medicine — and immunotherapies perhaps even more so. As treatments, these products themselves often also need “partners” of a kind: e.g., radiation/radiotherapies, traditional MAbs, and chemotherapies. Just as this field of endeavor requires the input and expertise of many different disciplines — from medical researchers to process engineers, clinicians to business leaders, and market experts to policy makers — this discussion of the topic of partnerships in immunotherapy brings together different experts in the field. BPI’s senior technical editor introduces contributions by Angela Miklus of Datamonitor Healthcare (an Informa company), Stephen T. Isaacs of Aduro Biotech, Raymond Tesi of INmune Bio, Michael Har-Noy of Immunovative, and Patricia Reilly of Pharma Intelligence (an Informa business).

Introduction
Immunotherapy seeks to harness the power of our human immune system to fight disease. In this rapidly evolving field, collaboration among different stakeholders is essential to bringing new treatments to market. Patient advocacy groups, researchers, hospitals, manufacturers, and government entities all are working together to translate promising new research into life-saving products. Types of immunotherapy include monoclonal antibodies (MAbs) and antibody derivatives, checkpoint inhibitors (immune-modulating proteins), cancer vaccines, T-cell therapies, and cytokines — so the approach involves a range of product modalities: proteins, gene therapies, and cell therapies. Thus, their manufacturing issues run the gamut of bioprocessing. Product development involves specialized clinical trials and efficacy test methods, however.

With the complex nature of human immune systems and cancer biology, novel collaborations are needed to turn exciting research into viable treatments. For example, private research institutions collaborate with public entities to gain funding and resources that facilitate their advancement of new therapies. As clinical advancements are made and new treatments or potential cures are developed, the inevitable question of affordability arises. New services and technologies are needed to provide a wide range of patients with improved access to immunotherapies. Novel pricing models may be necessary.

Immunotherapies aren’t only for cancer treatment (also, e.g., allergies, infectious disease), but that is so far the largest area of their development. The US government’s “Cancer Moonshot” program has helped to accelerate such endeavors. A number of partnerships have been initiated (Table 1, and see Partnerships and Licensing), many involving Moonshot money, among large and small pharmaceutical companies, research institutions, contract service providers, and disease-focused patient advocacy groups. Each organization has something unique to offer and seeks out particular capabilities in potential partners.

Just fill out the form below to download and read the complete eBook now.

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Expect the expected. But plan for the unexpected. If your Biosafety Development takes a nose dive, Eurofins Lancaster Laboratories’ team of regulatory experts and experienced scientists will help you land safely on two feet. Download The Complete e-Book of Biosafety Testing to learn more about our expertise in biologics raw materials, cell bank preparation, adventitious virus testing, viral clearance studies, next-generation sequencing, genetic stability testing, and more.

This e-Book contains the following chapters:

• Mitigating Risk and Reducing Regulatory Scrutiny of Biologics Raw Materials — Andrew D. Schaefer and Terry Schuck
• The Importance of Proper Cryopreservation of Cells for Cell Bank Preparation — Svetlana Mogilyanskiy
• Need to Test Viral Products for Adventitious Viruses? — Katherine Marotte
• Viral Clearance Studies — Doug Rea
• Next-Generation Sequencing Revolutionizes Adventitious Virus Detection — Jeri Ann Boose and Thomas Brefort
• Compendial Quality and Function Testing of Fetal Bovine Serum — Heather Beyer and Andrew D. Schaefer
• Genetic Stability Testing Ensures Product Integrity — Weihong Wang

Just fill out this form to download The Complete eBook of Biosafety Testing now.

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Veterans of the US military still struggle to access healthcare despite the 2014 congressional passing of the Veteran’s Choice Program (VCP), a US$10 billion-dollar “fix” that allows qualifying veterans to see community physicians who have contracted with the Department of Veterans Affairs (VA) to provide care. Veterans who enrolled in VCP to avoid long wait times at department medical facilities still have faced month-long delays before seeing a doctor, according to a 2018 GAO report. Investigators have found that the VA protocol for scheduling VCP appointments caused veterans to wait up to 81 days for treatment and an average 51 days to receive care, despite the VA’s own standard to administer care within 30 days of a patient’s request.

One key factor in the failed implementation of VCP could be the excessive delay in physician reimbursement that ultimately is driving away community provider participation in the program. Hospitals, clinics, and doctors across the country have complained about not getting paid, and many healthcare centers have stopped participating in VCP altogether. A lack of trust in VCP reimbursement also may discourage the use of physician-administered drugs for veterans. Under VCP, physicians are expected to purchase high-cost specialty drugs through their normal office protocol and submit for reimbursement from one of two VA contracted program administers.

Veterans who receive community care also are required to fill prescriptions at a VA pharmacy or use the VA mail-order system. Only urgent medications can be accessed through a retail channel at veterans’ own expense (and with 14-day quantity limits) until they are able to successfully navigate a complex and lengthy reimbursement process through the VA.

The MISSION Act
A new era of healthcare may be in store thanks to the VA Maintaining Systems and Strengthening Integrated Outside Networks (MISSION) Act, the most comprehensive healthcare reform bill passed by Congress in over 25 years. It will provide for a new, streamlined community care expansion program that replaces the VCP and consolidates multiple community care programs into one program. Changes will include

• Expanding the VA’s comprehensive caregiver support program, opening the program to eligible pre-9/11 veterans
• Allowing veterans and their doctors to determine the best option for where a veteran should receive care (inside VA or in the community)
• Increasing telehealth programs
• Establishing walk-in healthcare services with local community providers.

A Closer Look at the Legislation
The MISSION Act is the first real step toward incentivizing a growing number of community providers to treat VA patients. Physicians will be paid Medicare rates within 30 days of claim submission rather than having to wait up to a year for reimbursement. The act will provide $5.2 billion for VCP expansion, consolidate community care programs, and remove the 40-mile, 30-day rule previously required for VCP enrollment.

Some healthcare experts have suggested that the VA should contemplate adopting a system similar to the Department of Defense (DoD) healthcare model. This hybrid system provides two channels of care: integrated healthcare facilities that specialize in the treatment of military-related trauma and illnesses, as well as an open community network option called Tricare. Currently, two-thirds of all DoD beneficiary care is provided by community physicians. Physicians participating in the new VA community care program will be required to adhere to the VA National Formulary when prescribing medications.

However, unlike what Tricare allows, all VA prescriptions must continue to be filled through local VA pharmacies or through the VA’s mail-order program rather than through a nearby retail pharmacy. Although the MISSION act contains provisions related to improving the safety of opioid prescribing practices (to include associated data integrity), it does little to protect physicians with regard to reimbursement assurance for office-administered products and veterans’ access to medications through a means that complements the community care practice (retail channels).

Implications for Drug Manufacturers
Although the new legislation is meaningful progress, more is needed — and soon. The VA healthcare system needs reform well beyond that provided by the MISSION Act. The common suggestion for total privatization of the VA is problematic because many ailments applicable to this population (e.g., service-related disease states) benefit from specialty medical centers

Adopting the DoD’s dual-channel model of care to include adequate and accessible prescription drug coverage, however, would be a crucial step toward a standard of care that US veterans deserve. The MISSION Act brings them a step closer to this, but to a much lesser scope. Although it opens a new chapter in care options for veterans, whether the VA can implement a viable community access to care program remains to be seen. Pharmaceutical companies should begin thinking about how this access-to-care expansion might affect current market access strategies for the federal segment.

Better Formulary Positioning: If a prescription does not follow the VA National Formulary (VANF), a VA pharmacist will follow up with the prescribing provider to determine whether that prescription can be rewritten for one that is available on the VANF — or whether certain criteria are met to qualify for access under medical necessity.

Nonformulary drugs are reviewed case by case. Few other health systems — e.g., DoD, Medicare, and Medicaid — have formularies as restrictive as the VA’s formulary. However, manufacturers can pull multiple levers to improve their VA formulary preference. Overall, the increased community physician spillover created by the MISSION Act may incentivize drug manufacturers to improve their products’ positioning on the VANF, especially because formulary controls and adherence under this expanded system remain to be tested.

Greater Exposure to Providers: The MISSION Act provides funding dedicated to better administration of the Choice Act program, which is expected to result in better physician reimbursement, and therefore improved rates of physician participation. Community providers are required to adhere to the VANF, which includes working directly with the VA to adjudicate nonformulary medical exceptions. This may lead to improved exposure for manufacturers with community physicians for therapies that are preferred on the VANF, especially in regions with a high concentration of veterans.

Potential for Improved Retail Access: The time and effort involved in coordinating prescriptions and adjudicating reimbursement under the current model may prove too cumbersome for the VA’s already overburdened system, prompting the VA to allow a more meaningful retail access option in the future.

More Influence: If the VA patient set is significantly different from the civilian population seen by a physician or at a community hospital/clinic, drug manufacturers with treatments for related conditions might have a larger amount of overall exposure and influence.

Better Data Exchange and Insights: The MISSION Act will improve health data exchanged for veterans seeking care through the community care program. The VA has long been reluctant to share patient data. The Act mandates the VA share health economics research (HER) data with non-VA providers to include medication prescription information, with the intention of improving prescription drug monitoring. This could provide insights related to the VA Choice population volume and other relevant data, which has been difficult to obtain with the DoD Tricare model.

Continuing a push for better access to care and vital medications for the nation’s veterans will be important going forward. They face a range of personal, societal, and logistical barriers in accessing care. Every stakeholder across the healthcare continuum should recognize the importance of removing barriers to care and improving quality of life for those who have sacrificed their well-being for the good of their nation.

Cheryl Nagowski is senior director of Federal Markets at D2 Consulting; 1-650-296-9216; cheryl.nagowski@d2rx.com.

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On Thursday 6 September 2018 at the annual BioProcess International Conference in Boston, the first “Technology Round Robin Featuring Six Innovative Bioprocess Technologies” was presented in an interactive session with attendees as active participants, asking questions and engaging in conversation with the six featured entrepreneurs. Detailed below, this session was a culmination of several steps in an overall strategy for some of the companies participating. To fully appreciate the launch of new technologies into the bioprocess arena, you first must understand the challenges faced by such early stage suppliers and what we can do to support technology development and innovation in support of the biopharmaceutical industry.

Figure 1: The “valley of death” in biopharmaceutical drug development

Drug development has an identified “valley of death” that comes when the gulf widens between finding a promising new therapy and moving to the necessary clinical trials that can demonstrate its safety and efficacy in humans (Figure 1). Funding does not always keep up with the needs of early drug development, which is characterized by inevitable delays in preclinical data generation or safety results, in early process development, and/or in accessing manufacturing capability. One manifestation of this gap is a lack of growth in new drug approvals despite an over 10-fold increase in inflation-adjusted spending by the pharmaceutical and biotechnology industries over the past 40 years (1, 2). Translational research, the term often used for that bridge from drug candidate to human testing, is considered widely to be underfunded and suboptimal (3). That represents a complex factor in the drug development valley of death that impedes the progress of bringing promising new therapeutics to market.

Development Parallels
Herein I refer to “technology development” as that for the bioprocess tools market: companies offering the equipment, supplies (reagents, consumables), software, and emerging new technologies needed by biopharmaceutical companies to increase efficiency and innovate in drug development and biomanufacturing. The dynamic of advancing products to commercialization in this market parallels drug development in one important way: Because of the significant upfront funding required, it is nearly impossible for a company to move a project forward using existing resources. However, early development funding mechanisms such as government-sponsored grants and programs, angel funding, and top-tier venture capital (VC) funding are not nearly as available to early stage technology and “biotool” companies as they are to drug developers. That is somewhat understandable given that VC firms have seen no active initial public offering (IPO) environment for such tools companies over the past several years. Historically, it has been challenging for technology suppliers to achieve exit multiples upon acquisition that reach the typical VC thresholds more commonly seen in sales of biotherapeutics companies. For biotools companies, merger and acquisition (M&A) exits often take longer than anticipated because of slow market traction resulting from the challenges of integrating new technologies into highly regulated good manufacturing practice (GMP) environments.

According to life-sciences and diagnostics investment banker David Wood, “Top-tier VC investing in early stage tools companies has been relatively weak in the past several years compared with biotechnology investment. Outside a few select areas, such as new sequencing technologies that have attracted considerable VC investment at the development stage, many VCs that invest in tools have focused more on growth-equity deals with companies wanting to expand existing commercial footprints and sales. The market has improved somewhat in 2018, driven by exciting developments in areas such as new single-cell analysis tools and an intense focus on technologies that will facilitate the manufacture of next-generation biotechnology drugs (e.g., cell and gene therapies), as well as more strategic investing by prominent players in the space. Despite that improvement, until the IPO market strengthens for tools companies, I still expect the level of top-tier VC investment in their early stage development to remain well behind that of biotechnology.”

That is somewhat understandable given the models followed in the venture world regarding multiples and returns. In the life cycle of technology development, the earliest technology pilot stage, when first proof-of-principle data are collected, usually precedes the development of a commercial prototype, so no customer testing or verification has happened yet. Therein lies the problem: How do you build a working prototype, engage with customers, and test the utility of a technology before you have secured adequate funding? The answer is to focus on activities that will quickly derisk a technology using the least possible time and money to do so.

Why Invest in New Technology?
Howard Levine (president and chief executive officer of BioProcess Technology Consultants) gave a presentation at the AGC Biologics 2018 Global CMO Consultant Summit in Seattle, WA, this past September. “We should fine-tune our approach to manufacturing,” he explained, “to implement new technologies wherever and whenever possible that allow for operational excellence. And we must encourage the development of new technologies to develop a varied and expanding manufacturing toolbox.” When well implemented, such varied and expanding toolboxes can improve manufacturing efficiencies, lower costs, and shorten development timelines. Therefore, Levine argued, the industry should innovate.

As part of Harvard Business School’s Forum for Growth and Innovation, Professor Clayton Christensen is Kim B. Clark professor of business administration. He explains that companies failing to approach new challenges with new business models will not be able to innovate for the future (5). In many cases, a separate work environment, group, or site provides the best way to segregate business objectives, creating a new business model that will be free from the constraints of the existing business.

Technology innovation and adoption in the drug industry can be difficult, however, because of the inherent and understandable bias toward “tried and true” conservative, low-risk approaches. Given the criticality of product-development timelines to the stated mission of a biopharmaceutical company, it is expected that the timeline to an investigational new drug (IND) application dominates senior management’s thoughts and thus determines how teams must spend their time. Looking to other industries, however, we realize that our unique and highly regulated drug development and manufacturing creates a fundamental truth of the drug industry: It is averse to change, and relative to other industries, it is slow to adopt and implement technology improvements.

Figure 2: Dual valleys of death in development of bioprocess technologies (SOURCE: BIOGUIDES LLC)

Suppliers’ Dual Valleys of Death
Over the years, I have faced the technology valley of death when launching new products into critical-path functions in which adoption of even well-engineered products is painstakingly slow. And I have come to realize that the bioprocess technology adoption cycle actually has two valleys of death (Figure 2). The first is perhaps the most obvious: when promising technologies often developed in universities or by entrepreneurs who file a patent or acquire a license on specific intellectual property fundamental to the technology, come to the point at which a lack of funding, market understanding, or clear business strategy causes a slowdown in progress. The initial euphoria of “Hey, this is going to work!” quickly passes as the reality sinks in of the investment needed to complete a product prototype, get it into testing, and refine the product. Without a working technology, it is difficult to collect data, go out to raise more funding, or seek customers — and it is difficult to make a case to the industry that a given technology or tool will have a benefit.

Once that first valley is in your rearview mirror, and the industrial design, full commercial software (if any), and robustness of the new technology have been proven in the hands of at least a few important and influential customers, then it’s time to introduce your new technology to the industry at large. Just when you think you’ve made it, however, the second valley of death in technology adoption looms: commercial product launch. Often it feels like the hard part should be over: Your product works, it had been debugged, the data look good, maybe the industrial design has won an award, and you have a few happy customers. But in fact, the adoption risk is largest to the industry as a whole, and many a sales professional has been blamed for the resulting inability to sell new technology effectively. Perhaps the technology should have been derisked significantly much earlier in the development process (even before the first valley of death)? Strategies for doing that effectively identify the adoption risk before full development of a technology and thus decrease the length of time spent in the dreaded “sales stall.” That should shorten the product adoption time and bring revenue generation as soon as possible.

Strategies to Improve Technology Adoption Success
To decrease the adoption risk of a new technology, suppliers can take a number of steps very early in their development processes. In the early days of biotechnology, the drug candidate you had was one you moved forward. Over time, drug developers began to focus on specific early data that could predict roadblocks in future development and commercialization — e.g., toxicology data, degradation pathways, and manufacturability — to increase the chance that a drug candidate at least would not be stalled by such concerns. Similarly, a series of processes can be applied to bioprocess technology development for increasing its chances of future product success. By focusing early on three related yet distinctive strategies for derisking new technologies, the dual valleys of death can be decreased and sometimes even eliminated.

Strategy 1 — The Fractional Business Development Model: Engage with senior product development, business development, and strategy teams early on.

Early stage technology companies require diligent exploration of different market opportunities, assessment of a potential technology’s fit to market, and a clear business strategy from the beginning. Balancing the demands of product development, hiring, fundraising, and early experimentation with customer outreach is challenging for entrepreneurs and young technology companies. To establish a good plan, an early stage company needs immediate industry contacts; market information; identification of the most accessible application areas; and assessments of market fit, competitive landscape, and timing.

My organization, BioGuides, uses a fractional business development model to accelerate exploration and establishment of sound business strategies often before a technology or product is developed fully. This concept is based on an existing and oft-used strategy for early stage biopharmaceutical companies: fractional chief financial officers. New biotechnology companies pursuing funding need senior leaders who have “been there” before, who know the norms of the industry and can devote a fraction of their time to financial planning and making the necessary connections to approach the investment community. An early stage company cannot afford to hire a professional with such experience full time — nor is it necessary — so a fractional approach of 10–15 hours per week works best.

The same is true for accessing senior business development and product development professionals. You want a team of people who have “been there” before, experiencing successes and failures, and who are dedicated to establishing a long-term relationship with your company as it grows. An emerging company can choose to hire a junior business development or sales person or a consulting firm, which only might have experience in technology adoption. However, a fractional business-development team can save money and get faster results than a single professional could. Accessing part-time senior people with relevant experience can help young companies avoid or get past the dual valleys of death.

Strategy 2 — “Customer-Centric” Development: Young companies should go to customers early for iterative product development, testing, and refinement. One methodology that is much more formalized in the world of large bioprocess technology suppliers is a “survey of needs” or “voice of customer” study to help in setting the direction of technology development and develop return on investment (RoI) calculations for new technologies. Emerging companies need to go to customers even before new products or ideas are fully defined. Steve Blank describes this kind of engagement in his book, The Four Steps to the Epiphany (6). The premise is to undergo a methodical evaluation of what Blank calls “customer development” in parallel with product development. Both activities are integrated, so you do not end up with a “build it and they will come” product-development strategy. If the process is followed effectively, customers will be waiting when you are ready to sell your technology. “You cannot create a market of customer demand where this is no customer problem or interest” (6).

The most notable lesson of a customer-centric strategy is to engage with customers early in product development to gain understanding and refine the messages that will resonate with various customer groups, their problems, and market niches. It is probably better for a small company to seek to “own” a niche with a new technology or service and expand from a point of domination. That has proven to be an effective strategy for launching new products in many cases.

For example, when Tarpon Biosystems was an early stage startup company seeking projects in the area of continuous chromatography, several potential collaborators could have benefited from a stainless, clean-in-place (CIP) version of its BioSMB technology — an asset Tarpon sold to Pall in 2015 — such as insulin and large-scale industrial enzyme applications. But the company decided that first it must own the “single-use” niche of continuous chromatography, given its patent protection and high growth of the market for single-use technologies. What seems obvious now was a difficult decision at the time: to pass on potential funding.

A lesson I have learned is that veering off the intended product development pathway to satisfy a few important customers can be dangerous to the overall strategy of seeking to “own” a niche. Trying to address too many needs in too many markets often leads to delays and overspending on early products for many technology startups. There is a fine balance between exploring all the options available to apply a new technology and the need to pick a path and stay the course.

Strategy 3 — The BioInnovation Group: A consortium of senior industry professionals offers counsel on your new technology.

The BioInnovation Group is an organization of industry professionals who volunteer their time and represent themselves — not their companies — united in the goal of forwarding technology for broad industry use. The mission of this group is to help technology advance by providing industry insights to aid in market application and development. This group was established as a “for-public-benefit entity” with a portion of proceeds returned to its executive members, who donate to causes that are important to the biopharmaceutical industry and for public benefit. Participation is by invitation only, and technology companies pay a fee to come before the group.

The voices of this consortium are powerful, representing years of experience at many different companies: e.g., industry giants such as AbbVie, Amgen, Biogen, Genentech (Roche), Medimmune, Moderna, Pfizer, Shire; major organizations such as the Bill and Melinda Gates Foundation; cell and gene therapy companies such as Bluebird Bio and Unum; and emerging companies such as Cobalt Biosciences, Compass Therapeutics, Evelo, and Visterra. If the collective agrees that one application area seems more viable or one strategic direction may speed adoption of a technology, then given the many and varied experiences within the group, that is likely to be correct.

The consortium identifies applications and areas where a technology should have the most impact and — perhaps most important — where adoption should be easiest. Members are committed to benefiting the industry by offering guidance and consultation to technology companies and educating technology providers on biopharmaceutical customers’ requirements. Technology adoption derisking can shorten the customer-input phase (or customer development) and streamline codevelopment and universal proof-of-concept studies in which technology providers maintain their own intellectual property (IP) independence while members of the consortium work together to establish a viable test plan for the associated technology. This is one of many services offered through the BioInnovation Group.

The above strategies all can help shorten the time it takes for a young company or entrepreneur to bring a new bioprocess technology through the customer development process. As more people focus on this as a complement to product development, technology adoption should become easier, faster, and less costly than ever before.

BPI Technology Round-Robin Session
This year’s BioProcess International Conference and Exhibition introduced a new session format in which six new companies participated in a technology round robin. The session began with a panel discussion on the importance of supporting technology innovation. I moderated the session, and the panelists were Thomas Seewoester (executive director and plant manager at Amgen Rhode Island) and BioInnovation Group members Michael Laska (vice president at Cobalt BioMedicine), Derek Adams (chief technology and manufacturing officer at Bluebird Bio), Neal Gordan (chief development officer of Cobalt Biomedicine), and Jorg Thommes (head of chemistry, manufacturing, and controls at the Bill and Melinda Gates Foundation). They talked about ways that the biopharmaceutical industry can help forward technology. All agreed that new technologies outside the industry should be evaluated and that hearing about new technologies early in their development is helpful to determining their most useful applications. Thommes introduced the BioInnovation Group’s mission and explained that he thought it was a valuable way to encourage innovation in the bioprocess industry.

The round robin of emerging technology companies was conceived during a BioInnovation Group meeting, where participants decided that several companies that had been through the consortium process could benefit from industry exposure. The aim was not to “sell” their technology, but rather to provide a forum of engagement with attendees at the conference. Engaging in this direct discussion was very helpful to several of the attending companies.

Each table at this session was staffed by an entrepreneur and a BioInnovation Group member who served as moderator to keep discussion on track. The audience members rotated from table to table every 12 minutes, which added energy to the room. Each entrepreneur had about three minutes to offer an “elevator pitch” or “shark-tank” style description of the company’s technology to the table audience — for a total of six repetitions. Audience members could ask questions directly of those entrepreneurs, all of whom were either the technology inventors or senior technical people at their respective companies.

Cheryl Huie (cofounder of the BioInnovation Group) later said, “The round robin provided a great forum for BPI attendees and innovation companies to exchange information and investigate the merits and value proposition of emerging technologies. Gaining insight on the possible impact these companies could have on scientific improvements, speed to market, or reductions in cost of goods is like getting a glimpse of what could be.”

The technology company participants were Ran Biotechnologies of Beverly, MA, at Table 1; Covaris of Woburn, MA, at Table 2; Nirrin Analytics of Billerica, MA, at Table 3; TeraPore Technologies of South San Francisco, CA, at Table 4; Elektrofi of Boston, MA, at Table 5; and 4th Dimension Bioprocess of Cambridge, MA, at Table 6.

At Table 1, Roger Nassar (founder and chief executive officer of Ran Biotechnologies) introduced a nanomaterial-based “point of use,” universal, rapid microbe-detection technology with a handheld device. He was joined by BioInnovation Group Member David Fritsch (senior director of strategic programs for the project management office and operational excellence at Sanofi). “The forum was an excellent way to gain attention for our newest product,” said Nassar. “In short, it provides a rapid yes-or-no screening test for live microbes. I was able to provide a quick elevator pitch and obtain immediate feedback from the group, and as a result, my pitch changed over time — and hopefully improved. This interaction already has led to further discussions with a high-profile organization and several potential collaborations.”

At Table 2, Carl Beckett (vice president of Covaris) sat with BioInnovation Group member Michael Laska (vice president of Cobalt Biomedicine). Although Covaris has a thriving business in its Adaptive Focused Acoustics technology for sample preparation and DNA shearing, Beckett was exploring potential new applications of the technology in this forum. “It was a great opportunity to gain exposure of our technology to many industry experts,” he said. “They immediately understood it and identified a number of potential applications where it could be of use in biological processing environments.” At

Table 3, John Ho and Bryan Hassell (principal scientists at Nirrin Analytics) sat with BioInnovation Group member Natraj Ram (associate director of purification at AbbVie). Nirrin has a novel near-infrared (NIR) monitoring solution for biomanufacturing that delivers noninvasive, nondestructive, real-time monitoring of aqueous solutions. “As a customer discovery exercise,” Ho said, “both the roundtable session and the BioInnnovation Group were very effective in introducing us to industry veterans and in exposing the challenges we are facing in commercialization of our technology. Both were invaluable.”

At Table 4, Rachel Dorin (founder and chief executive officer of TeraPore Technologies) and Mary Siwak (TeraPore’s chief commercial officer) sat with Bioinnovation Group member Neal Gordon (chief development officer at Cobalt Biomedicine). Dorin and Siwak showcased a novel, cutting-edge membrane technology for high-resolution nanofiltration using a proprietary and scalable block copolymer self-assembly technology that creates highly uniform precise pores for high permeability.

At Table 5, Chase Coffman (cofounder of Elektrofi) sat with BioInnovation Group cofounder Cheryl Huie (business consultant with Axiom Collaborative). The Boston-based startup seeks to redefine the delivery of biologics by enabling very high-concentration subcutaneous injections using its novel Elecktrojet particle technology. Elektrofi also presented to the BioInnovation Group and learned much from the interaction.

At Table 6, I represented 4th Dimension Bioprocess, a next-generation intensified-bioprocess contract development and manufacturing organization (CDMO) working to democratize access to advanced biomanufacturing platforms. With an emphasis on automation, data analytics, and artificial intelligence (AI) technology, open-source software, and a quality system built to accommodate continuous platforms, the company plans to offer development and manufacturing for biologics. Bioinnovation Group member Tom Ransohoff (vice president and principal consultant at BioProcess Technology Consultants) joined me. “The round-robin setup was a great way to test various business models and do a quick market survey,” he said.

Putting Strategies to Work for Entrepreneurs
Reducing innovation risk by sifting through different technology applications can be challenging if your industry experience is not extensive. The above strategies help identify areas in research, development, and biomanufacturing where particular technologies could offer significant improvements, thus helping to identify target customers. Gaining consultative advice from industry experts who can recommend the steps required to advance your technology in life sciences — and getting assistance with “proof-of-concept” studies — are important in reducing the dual valleys of death and shortening time to market. Early industry exposure and immediate feedback help entrepreneurs set the direction of not only product development, but also customer development.

We all benefit as an industry if technology innovation can be easy, fast, and productive, with as little risk as possible. The next time an early stage technology entrepreneur asks you to take a moment to give feedback in evaluating his or her technology, please remember that you are helping an entrepreneur reduce innovation risk, shorten time to market acceptance, and perhaps increase industry acceptance. You just might help someone get past a valley of death.

References
1 Austin DH, et al. Research and Development in the Pharmaceutical Industry. US Congressional Budget Office: Washington, DC, October 2006; www.cbo.gov/publication/18176.

2 Wood AJ. A Proposal for Radical Changes in the Drug-Approval Process. N. Eng. J. Med. 355(25) 2006: 618–623; doi:10.1056/NEJMsb055203.

3 Manjili MH. Opinion: Translational Research in Crisis The Scientist 10 September 2013.

4 Levine H. Implementing New Technologies in Bioprocessing. 2018 Global CMO Consultant Summit. AGC Biologics: Seattle, WA, 10–13 September 2018.

5 The Forum for Growth and Innovation. Harvard Business School: Cambridge, MA; www.hbs.edu/forum-for-growth-and-innovation/Pages/default.aspx.

6 Blank S. The Four Steps to the Epiphany: Successful Strategies for Products that Win, fifth edition. K&S Ranch: Palo Alto, CA, 2 October 2013.

Lynne Frick (lynnefrick@bioguidesllc.com, 1-978-979-4222) is founder of BioGuides LLC, a Massachusetts-based company focused on accelerating product and technology adoption, and cofounder of The Bioinnovation Group, Inc., a group of industry professionals assessing technology for the greater good.

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