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Speed-to-market, capacity, technology development, and increased investment top the list.
The development of biologic drugs continues to increase at a rapid pace. Growing numbers of conventional recombinant proteins and monoclonal antibodies, as well as next-generation molecules such as multispecifics, antibody-drug conjugates, and cell and gene therapies, are advancing through the clinic. Many of the biopharma companies behind these drugs are seeking assistance with bioprocess development from outsourcing partners with platform solutions and specialized knowledge, expertise, and technologies.
The increased level of bioprocess development outsourcing can be attributed to several macro- and micro-level drivers.
On the macro level, there is significant growth in the biologics development and manufacturing pipeline worldwide due to increased treatment successes, according to Judy Chou, CEO and president of AltruBio. She highlights the development of advanced cell and gene therapies and gene editing as being particularly important.
Growth of COVID-19 related projects, biosimilars, and the burgeoning Chinese market is further increasing demand, adds Jeetendra Vaghjiani, senior director of clinical development and strategic marketing at Lonza. “With most of the drug development pipeline being held by emerging and small biotechs, the support of contract development and manufacturing organizations (CDMOs) is gaining even more importance,” Vaghjiani says.
Creative approaches recognized by regulatory agencies to address unmet medical needs are another factor noted by both Chou and Vaghjiani. “New challenges have brought accelerated approval pathways such as FastTrack and Priority Review,” Vaghjiani says. That opportunity places increased pressure on biopharmaceutical companies to deliver therapies quickly for patients with commercially ready products, which puts pressure on process development.
Changes in the industry ecosystem have also favored increased investment in biotech and biopharmaceuticals, according to Chou. This trend is attributed by Vaghjiani to the COVID-19 pandemic, which has generated greater interest and awareness in the biotech sector.
All of this growth, however, has also resulted in a general trend of biopharmaceutical capacity shortage, Vaghjiani observes. He does note, though, that many companies are announcing expansions to ensure flexibility with respect to project needs.
CDMOs like Lonza, for instance, have responded by investing heavily in shortening development timelines. This achievement has come through the introduction of new expression technologies, use of parallel workflows for activities not on a critical path, and implementation of high-throughput, scale-down modeling systems. “These improvements have resulted in a significant reduction in process development timelines and therefore are having a positive impact on upstream capacity,” comments Vaghjiani.
The micro trends driving bioprocess development outsourcing are also related to technology development. Identifying technologies that improve stability and distribution as a way to improve access to medicines and to manage cold-chain limitations while reducing costs, is one example noted by John Koleng, vice-president of product development and manufacturing at TFF Pharmaceuticals, which develops dry-powder formulations of biologics using proprietary Thin-Film-Freezing technology.
Biologics developers are also, according to Koleng, looking for technologies that allow biologics to be administered through alternative routes to injection and platform technologies that can be applicable to a variety of biologic products to facilitate rapid scale-up and rollout.
The COVID-19 pandemic is impacting the outsourcing of bioprocess development activities and often magnifying previously existing trends. “The rapid development of COVID-19 vaccines has put a spotlight on biologics and has shed light on limitations that have historically not been appreciated, as technologies were not available to address them,” states Koleng.
The COVID-19 vaccines from Pfizer and Moderna are a case in point, according to Koleng. They remain dependent on extreme cold-chain storage-distribution and injectable administration, both of which limit access to broad patient populations.
“These problems existed prior to the COVID-19 pandemic, but were limited to much smaller scales. The COVID-19 pandemic has emphasized a need for technologies that allow for biologics to be provided as stable compositions that do not require extreme cold-chain storage-distribution; to be administered by noninvasive routes of administration, such as inhalation; and to be scaled up rapidly to support global rollout of essential medicines,” Koleng asserts.
The COVID-19 pandemic has also focused emphasis on speed to market, says Vaghjiani. Additionally, he observes, it is leading to increased demand for single-use equipment used for biologics manufacturing.
Awareness of the healthcare system and the lack of investment resources funneled to the sector has also been raised during the COVID-19 pandemic, according to Chou. “Recent investment in novel therapies and technologies in biotech has created opportunities not only to respond to the needs of the COVID-19 pandemic, but also to introduce more molecules into development that can be applied to other diseases,” she explains. This increased investment and development of biologics has elevated the outsourcing needs in bioprocess development.
In addition, Chou believes the continuation of remote working will make it harder for start-up companies to build up their internal bioprocess development capacity quickly, thus increasing their need to establish CDMO partnerships too.
Combined, these trends will likely result in more entities offering bioprocess development services, Chou says. It could also, she remarks, lead to continued innovation in optimizing and improving supply chains in case of future external disruptions.
With many of the biopharmaceutical pipeline candidates being developed by emerging and small biotechs, often with next-generation biologics, the need for outsourcing early on in the drug development cycle has become clear.
“Small and emerging biotech companies typically rely on the development and manufacturing capacity, expertise, and flexibility of CDMOs to bring their candidates to the clinic, and thus services for bringing potential drug candidates from gene to investigative new drug (IND) [are] gaining importance,” Vaghjiani explains.
The shift to next-generation biologics also leads to the need for deeper understanding of the biological mode of action early on, according to Vaghjiani. “This understanding is strengthened by advances in science and access to data and sequencing capabilities, and will increase demand for bespoke and flexible development strategies and new technologies to handle unique product features,” he says.
In addition to good manufacturing practice capacity for product launches, early development for IND enabling studies is one of the most in-demand outsourcing services today, Chou agrees. “New advances in science will continue to drive the increasing bioprocess/biologics development needs,” she states. She elaborates that the need to develop and produce novel COVID vaccines/therapeutics has created a capacity crunch in biologics development that must be addressed in the upcoming years, given that further increases in demand for biologics development services are expected.
Regardless of the shift to new modalities, the overall goals for bioprocess development across the development lifecycle, including process and product development, remain the same. “Drug companies want help finding solutions that improve the stability of biologics, provide alternative routes of administration, improve therapeutic outcomes, and manage manufacturing costs,” Koleng comments, “Historically,” he adds, “biologics have been extremely expensive to develop, so pricing has an important role to play—the priority will be to reduce costs while also increasing therapeutic outcomes and access.”
As demand for bioprocess development services expands and the specialized nature of those services increases, the need for CDMOs to invest in additional capacity, both equipment and capabilities, is growing.
“The goal is to help new medicines reach patients faster and give customers the flexibility to manage supply, addressing drug development uncertainty and market demand changes,” Vaghjiani says.
Indeed, a CDMO has to keep up with advancing technology to best serve customers and ultimately patients, stresses Casey Franklin, vice-president of business development at Alcami. To do so requires upgrades over time. “An example would be the shift from traditional restricted access barrier systems (RABS) to isolator technology for increased sterility assurance during the fill/finish of biopharmaceutical products,” she observes.
When presented with an unexpected project, Lonza performs an assessment to determine what changes are needed in the process or facility to accommodate the project. Usually processes can be adapted to fit its current facilities, which according to Vaghjiani, highlights the advantage of operating a plug-and-play concept, such as Lonza’s Ibex. If capital investments are deemed necessary, the strategy is scenario-specific.
When a CDMO takes on a specialized project, such as one involving an innovative product with special and sometimes complex requirements that creates a need for investment in additional equipment or capabilities, the investment can be fully funded by the CDMO or the customer, or a shared investment.
“There are many considerations here, including the footprint of the equipment or facility modification, the capacity required for the customer, the market demand or potential to serve other customers, the necessary expertise and staffing implications, and the stage of the program and expected long-term requirements,” says Franklin.
Whichever party is responsible for the equipment depends on what is right at any given point in time for the arrangement, adds Koleng. “In general, the investment equation typically varies and depends on the volume of work and stage of development. At TFF, we’ve found CDMOs to be particularly receptive to customizing their facilities and maintaining a variety of arrangements,” he remarks.
Chou agrees that there are different business models that can be established to address the mutual interests of CDMOs and the sponsors. “We have found that most CDMOs try to fit development projects into their existing equipment and systems, but it is not unusual for a CDMO to customize a bit to meet the need if the modifications are minor. If substantial revisions are required in the facility, usually a cost-sharing model is built,” she observes.
CDMOs always aim to maximize utilization of their facilities and equipment to stay profitable and grow, but this optimization becomes even more crucial with capacity shortages across the industry, according to Franklin. Some facilities may be able to increase capacity by implementing an extra shift or purchasing additional equipment, she notes.
Biopharma companies need to take action as well. “One way to help alleviate the capacity shortage is for sponsors to be more proactive in scheduling, and some are beginning to identify key players much earlier. Consolidating work with fewer CDMOs so that a sponsor can be a more substantial customer or client, and garner greater resources for their projects is another strategy,” Koleng explains.
CDMOs already near full utilization have to focus on effective project management and transparent communication with customers to ensure manufacturing readiness and minimize dead time due to project delays, Franklin says.
“With the supply-chain challenges and the general element of unpredictability that has come with the COVID-19 pandemic, it also helps for the CDMO and the customer to be as flexible as possible. CDMOs must keep in constant communication with customers around these challenges and work creatively to find alternate solutions when needed to keep project timelines on track,” Franklin asserts.
To address capacity shortages for development projects in particular, Chou notes that on the technical front, companies are improving bioprocess development efficiency by introducing advanced platform technologies. Development is also being accelerated through the application of automation, modularization, and digitalization solutions. On the business front, she points to improvements in the partnership model to ensure that business processes do not get in the way of development.
Strong partnerships are, in fact, the key to successful provision of services across the entire development cycle. To accelerate the progress of development, the “one-stop-shop” or “end-to-end” CDMO model would be more attractive, in general, according to Chou, and she believes most CDMOs are moving in this direction.
“The technical challenges in bioprocess development, however, often require specific expertise, and therefore in some cases, a development-driven company is needed to address these challenging issues,” Chou states. Both types of CDMOs are needed as a result.
In fact, the sheer volume of work in outsourcing right now is being appreciated by all CDMOs, whether they are a one-stop shop or handling only one piece of the process, Koleng observes. He also believes that true one-stop shops are rare, since usually there is at least some project component that requires a third party or subcontractor to meet the demand for capacity or production.
It is, adds Franklin, actually difficult to find “end-to-end” CDMOs that truly function as a single provider, since so many of these organizations are born from mergers and acquisitions. “We find that many biopharma companies are more interested in forming a lasting partnership and prefer the customer focus that you more often find at smaller, more specialized firms,” she notes.
Franklin also points out that small and mid-sized CDMOs can offer the advantages of a “one-stop-shop” by teaming up with synergistic organizations. For instance, as a fill/finish provider, Alcami focuses on drug product and analytical services, forming strong relationships with its customers and supporting them long-term in those areas. “But we also work with biologics drug substance manufacturers to understand complementary operations and processes and offer customers an efficient, streamlined approach that saves time and gets products to patients faster,” she comments.
“Ultimately,” stresses Vaghjiani, “to address increasing cost pressures, it is critical for pharma and biotech companies to partner with CDMOs that have the right manufacturing scale at the right time in the lifecycle of their products in order to optimize the cost of goods and meet market demand. He believes that end-to-end CDMOs like Lonza, which operates across nine global sites, three continents, and a spectrum of scales in single-use and stainless-steel bioreactors, help address demand uncertainty and fluctuations.
The COVID-19 pandemic has emphasized the need for innovative drug products and technologies, according to Koleng. TFF Pharmaceuticals is striving to develop such impactful solutions. “With the support of our CDMO partners, we continue to prioritize improving therapeutic outcomes and access, reducing cost of goods and enabling faster rollout of breakthrough medications,” Koleng states.
Chou adds that although the bioprocess development of proteins and antibodies is becoming a commodity, there is still work to do to bring it to the next phase: Industry 4.0 and leveraging big data and the Internet of Things. “Bioprocess developers should push boundaries to ultimately benefit patients with cost-effective medicines,” Chou asserts.
The alternative regulatory approaches established to enable the introduction of COVID-19 vaccines should also continue to be applied going forward to accelerate novel drug development, according to Chou. “Adjustment of the bioprocess development mindset may be needed to fully realize the value of innovative treatment,” she concludes.
Cynthia A. Challener, PhD, is a contributing editor to BioPharm International.
Vol. 34, No. 10
When referring to this article, please cite it as C. Challener, “Trends in Outsourcing of Bioprocess Development" BioPharm International 34 (10) 2021.