By John Koleng, Ph.D., R.Ph.; Donald E. Owens III, Ph.D.; and Kayla Hannon; TFF Pharmaceuticals, Inc.
The COVID-19 pandemic led to an unprecedented level of biotechnology innovation but also made weaknesses in pharmaceutical production and distribution much more apparent. As demand for therapeutics increased, it surpassed existing capacity for manufacturing and, paired with added stress to the supply chain, drug shortages ensued. The FDA allowed for several Emergency Use Authorizations (EUAs) to meet product demand for vaccines, which led to a rapid rollout through a non-traditional route to initial market. Outside of pandemic-related issues, shortages typically begin as manufacturing problems.1 In order to meet the growing demand for vaccines, pharmaceutical companies were forced to lean on outsourcing partners more than ever before, which led to a massive push to establish contract development and manufacturing organization (CDMO) partnerships in the industry.2
The need for streamlined manufacturing is especially challenging given the increased development and uptake of novel and complex biological therapeutics, including vaccines. Modalities like mRNA-LNP (lipid nanoparticles) based vaccines are highly complex and expensive to process, scale, store, and ship, which throughout the pandemic has resulted in numerous delays in global distribution and, ultimately, access. The acceleration of new technology has been somewhat stymied due to specialty products that require custom manufacturing capabilities and equipment, short shelf lives, sterile facilities, and ultra-low temperature (-80˚C) cold chain storage. Engineered products such as those designed for targeted delivery (e.g., inhalation) can be even more challenging to manufacture.
The manufacturing lag in developing innovative drug therapeutics has created a bottleneck in the industry, with backups in supply chains also contributing to and ultimately extending drug and clinical development timelines. As these ever more complex APIs (active pharmaceutical ingredients) become the norm in the biotech and pharma industry, there is a crucial need for more rapid development of advanced manufacturing and drug formulation technologies to keep pace with the rollout of these new modalities and ensure future supply chain shortages and disruptions are minimized.
Strategic Partnerships Can Improve Uptake Of Biologics
Biological APIs are much more sensitive to environmental stresses when compared to more traditional small molecule drugs. Biologic products have a much higher tendency to degrade, oxidize, agglomerate, and become therapeutically inactive in response to temperature, shear, and/or interfacial (air-water) stresses, limiting how these materials can be processed, stored, and even administered.
The mRNA-LNP based COVID-19 vaccines epitomized today’s main challenges in biologic manufacturing and drug development. While traditional vaccines are more commonly stored at typical refrigerated temperatures (i.e., 2-8˚C), mRNA-LNP based vaccines require ultra-low (-80˚C) temperatures to preserve activity. This creates particular challenges in stockpiling and transporting medicines globally as well as storage in countries without access to cold chain technology. Early on in the pandemic, crucial supplies of vaccine material had to be discarded due to short shelf life once the drug was reconstituted or, even worse, due to short lapses in temperature control during shipping and handling. The success and efficacy of the recent mRNA-based COVID vaccines has also created an opportunity to further evolve mRNA-based therapies for other indications, but in order for mRNA and other biologic materials to have this game-changing impact, there remains a significant need to optimize their formulation, product manufacturing, and shelf stability.
Establishing more strategic manufacturing partnerships could help solve some of the current and future challenges in biologics drug development, especially for smaller companies whose in-house technological capabilities and capacities are limited. These partnerships allow pharmaceutical companies to reduce production and manufacturing costs, as well as speed up development to meet deadlines and demand, rather than performing those activities in-house and investing in expensive equipment and infrastructure, which may not always be practical. In today’s challenging market where there is a need to be mindful of the allocation of funds, CDMOs can provide an opportunity to help companies progress their programs in a more cost-efficient and strategic way. Many CDMO partners also offer the extra benefit of having in-house technical experts with specialized skills and experience that can complement those found in other drug development companies. These experts can offer valuable insight into scale-up and manufacturing challenges that drug development companies may encounter as they move beyond the lab scale, reducing delays in milestones and timelines and recommending new technologies and approaches to solve drug formulation and development issues.
Finding the right partner can be very challenging, especially for more complicated biologic-based medicines. Some CDMO partners will be able handle an entire project from scale-up all the way to commercial production, while others may only focus or specialize on one aspect of a product’s life cycle. Additionally, in many cases, outsourcing for these types of products requires booking a minimum of one year in advance, so identifying potential CDMO partners early on and factoring in lead time is critical in the drug development process to help alleviate capacity shortages and reduce timelines. Typically, the greatest demand for services is usually in the early stages of the development life cycle, especially for sterile or specialty manufacturing. In these early phases, identifying a CDMO experienced in a range of formulation technologies could improve optimization and troubleshooting. A good CDMO partner should have the foresight to anticipate possible issues early in the development process that could be much more expensive to fix or scale up later in the development cycle and ensure that the companies they are working with are thinking about the commercial manufacturing facility (utilities, electrical, environmental class, etc.) and equipment requirements.
Allow your CDMO to be seen as a true collaborator rather than a source of one-off contract services. We believe in the importance of identifying suitable manufacturing partners that share a similar vision that complements the company’s business model and can provide adaptability for a more successful long-term partnership.
Platform Technologies Can Help Streamline Drug Delivery
When selecting a CDMO partner, there is also a need to identify platforms that are robust and can be used for more than one product to alleviate the need to create new processes for each product. The uptake of innovative platform technologies could help optimize development and logistical distribution of novel therapeutics, such as biologics, ultimately reducing logistical challenges and the timeframe to get medicines to patients in need.
Platform technologies that improve modality stability and distribution can accelerate development and scale-up. Extensive research has shown that formulating biologics as a dry powder can improve thermostability compared to liquid formulations and can minimize the reliance on cold-chain technology, allowing for more convenient storage and broader accessibility to patient populations around the globe.3 Alternative formulation technologies can also facilitate rapid rollout and accessibility, although this may require specialty manufacturing technology and expertise from CDMO partners.
One thing to keep in mind is that many traditional cryogenic and freeze-drying techniques to develop dry powder formulations of biologics may also impart thermal and physical stress in the formulation process, conditions that can be especially damaging to the API. One technology that our company, TFF Pharmaceuticals, has developed to overcome some of these challenges is known as thin film freezing (TFF), which is a rapid freezing technique that can process both biologics and traditional small molecule APIs into a dry powder capable of being delivered directly as a dry powder for inhalation or as a sterile powder for reconstitution and injection. Compared to many other particle engineering techniques, TFF has proven to be a more robust and gentle processing technology for the formulation of biologics resulting in better drug stability and retention of bioactivity.4,5,6,7 Vaccine powders produced using TFF technology can be stored at higher temperatures than liquid-based formulations, which reduces the need for ultra-low temperature cold chain logistics.8
While injectable routes of administration are more common for vaccines and biologics, exploring non-invasive vaccine therapies could also circumvent the need for ultra-cold chain refrigeration and reduce logistics and administration costs. Further development and proliferation of commercial freeze-drying capacity is needed to help reduce cold chain limitations and production costs, especially for biologics and other complex and sensitive APIs.
At TFF Pharmaceuticals, our experience has offered important perspective on how strategically crafted CDMO partnerships can facilitate more efficient manufacturing and scale-up of complex modalities such as biologics. Ultimately, the goal for the biotech industry is to bring innovative medicines to more patients faster. The current market is not able to meet demand, especially for bioprocessing and biologic development, with delays across the board from bench to bedside. These challenges are further heightened when there is a need for developing, manufacturing, and treating in real time, such as during a pandemic. In order to be prepared for the next global crisis and to deploy more life-saving therapies to large populations, biotech and pharma companies should identify CDMO partners early in the development process that use innovative technologies that improve stability and speed of distribution.
- Socal, M. P., Sharfstein, J. M., & Greene, J. A. (2021). The Pandemic and the Supply Chain: Gaps in Pharmaceutical Production and Distribution. American journal of public health, 111(4), 635–639. https://doi.org/10.2105/AJPH.2020.306138
- Mordor Intelligence. (2021). Global Pharmaceutical Contract Development and Manufacturing Organization (CDMO) Market Research Report 2022 - Market Size, Current. https://www.mordorintelligence.com/industry-reports/pharmaceutical-contract-development-and-manufacturing-organization-cdmo-market
- Zhang, Y., Davis, D. A., AboulFotouh, K., Wang, J., Williams, D., Bhambhani, A., Zakrewsky, M., Maniruzzaman, M., Cui, Z., & Williams, R. O., 3rd (2021). Novel formulations and drug delivery systems to administer biological solids. Advanced drug delivery reviews, 172, 183–210. https://doi.org/10.1016/j.addr.2021.02.011
- H. M. Dao, S. Sahakijpijarn, R. R. Christowski, C. Moon, F Mangolini, Z. Cui, and R. O. Williams III, Aggregation of Lactoferrin Caused by Droplet Atomization Process Via Two-fluid Nozzle: The Detrimental Effect of Air-water Interfaces, BioRxiv online, DOI: 10.1101/2021.12.06.471411 (Dec. 7, 2021).
- Watts, A. B., Wang, Y. B., Johnston, K. P., and Williams, R. O., 3rd (2013). Respirable low-density microparticles formed in situ from aerosolized brittle matrices. Pharmaceutical research, 30(3), 813–825. https://doi.org/10.1007/s11095-012-0922-2
- AboulFotouh, K., Zhang, Y., Maniruzzaman, M., Williams, R. O., 3rd, and Cui, Z. (2020). Amorphous solid dispersion dry powder for pulmonary drug delivery: Advantages and challenges. International Journal of Pharmaceutics, 587, 119711. https://doi.org/10.1016/j.ijpharm.2020.119711
- Hufnagel, S., & Sahakijpijarn, S., Moon, C., Cui, Z. and Williams, R. (2022). The Development of Thin-Film Freezing and Its Application to Improve Delivery of Biologics as Dry Powder Aerosols. KONA Powder and Particle Journal, 39, 176-192. https://doi.org/10.14356/kona.2022010
- Thakkar, S. G., Warnken, Z. N., Alzhrani, R. F., Valdes, S. A., Aldayel, A. M., Xu, H., Williams, R. O., 3rd, and Cui, Z. (2018). Intranasal immunization with aluminum salt-adjuvanted dry powder vaccine. Journal of Controlled Release, 292, 111–118. https://doi.org/10.1016/j.jconrel.2018.10.020
About The Authors:
John J. Koleng, Ph.D., R.Ph., serves as vice president of product development and manufacturing at TFF Pharmaceuticals. He co-founded AlphaVektor, LLC and Axxis Innovations, Inc., life sciences development and industrialization consultancies focused on product development, manufacturing, scale-up, commercialization, and supply chain management. Koleng has 20+ years’ experience in the pharma industry, including 10+ years as a consultant. He has a B.S. degree in pharmacy and a Ph.D. in pharmaceutics, both from University of Texas at Austin, and he is a registered pharmacist.
Donald E. Owens III, Ph.D., is director of product development at TFF Pharmaceuticals. He has nearly 20 years of experience in pharmaceuticals, polymers, and personal care industries. Before joining TFF, Owens held senior leadership roles within Saudi Basic Industries Corporation looking after the scale-up and commercialization of polymer products. He holds a B.S. honors degree in chemical engineering from Purdue University and a Ph.D. in chemical engineering from the University of Texas at Austin.
Kayla Hannon is manager of process engineering at TFF Pharmaceuticals and works with the internal process development team and CDMOs. She has years of experience in sterile pharmaceutical manufacturing as a process, validation, and facilities engineer. Previously, Hannon was a consultant concentrating in commissioning, qualification, and validation activities. She was also previously at Moderna assisting production scale-up and working with CMOs to optimize worldwide production of the COVID-19 vaccine. She holds a B.S honors degree in chemical engineering from Drexel University.