A disciplined approach is needed to address complexity, limited knowledge, lack of platform processes and standard analytics, and regulatory uncertainty.
Key Takeaways
- Emerging modalities deliver new targeting and disease-pathway control but demand specialized infrastructure, cross-disciplinary integration, and advanced analytical frameworks because legacy stirred-tank scale-up and downstream workflows often misfit fragile products.
- Four recurring hurdles dominate industrialization: structural complexity with heterogeneity, lack of universal platform processes, difficulty sustaining productivity without quality erosion, and regulatory uncertainty that amplifies timeline and investment risk.
- Capital markets increasingly require phase 1 data plus credible phase 2 paths, commercial manufacturability, and sustainable COGS, shifting value inflection points and forcing earlier demonstration of scalable process readiness.
- Regulatory expectations evolve alongside innovation, making CMC, preclinical, and clinical requirements difficult to forecast; approval depends on validated identity, potency, mechanism-of-action linkage, process controls, and robust analytics.
- Early process development is hampered by undefined target product profiles and CQAs, limited process knowledge, and complex potency assays, increasing downstream remediation costs and incentivizing less novel targets to shorten timelines.
Emerging modalities encompass classes of therapeutics with greater molecular and manufacturing complexity than traditional biologics (ie, monoclonal antibodies [mAbs] and recombinant proteins). They include antibodies conjugated to various substances, multispecific antibodies and fusion proteins, viral vectors for in vitro and in vivo cell (regular and gene-modified) and gene therapies, gene-editing treatments, other DNA and RNA-based medicines, extracellular vesicles/exosomes, therapeutic peptides, and targeted protein degraders, many of which leverage novel delivery systems such as lipid nanoparticles and polymeric nanoparticles, leveraging new targeting technologies.
In addition to their greater molecular complexity, many of these molecules have underlying biology that is fundamentally different from that of mAbs and proteins and operate by novel mechanisms of action. That creates opportunities for addressing new targets and disease pathways and exerting better control.
While they are transforming how many diseases are treated, these emerging modalities often are highly sensitive to typical upstream and downstream process conditions. Consequently, they require specialized expertise, sophisticated development and manufacturing strategies, and advanced analytical frameworks.
What makes development of emerging therapies so challenging?
There are 4 common hurdles to development and manufacturing for emerging modalities, according to Sherry Gu, PhD, chief technology officer and executive vice president at WuXi Biologics. They include high structural and molecular complexity leading to more heterogeneity and harder quality control; lack of universal platform processes, which slows development and adds cost; difficulty achieving high productivity without compromising product quality; and regulatory uncertainty.
“These hurdles matter because they directly affect how fast we can develop therapies, their quality, manufacturability, and how predictable regulatory approval is—all key to getting these innovations to patients,” Gu states.
Most of these challenges ultimately stem from significant differences in the biological characteristics of emerging modalities and conventional biologics, according to Thomas Robert, PhD, senior innovation and product manager at Univercells Technologies (a Donaldson Life Sciences business). “Legacy batch bioprocessing techniques—stirred-tank scale-up strategies and downstream workflows originally designed for far more robust products—often don’t fit well with these novel therapies. This disconnect between biology and manufacturing technology is what makes the industrialization of emerging modalities uniquely complex,” he observes.
Subas Sakya, chief science officer for BioDuro, adds that emerging modalities “often require specialized design paradigms and synthetic routes, as well as analytical strategies.” Many incorporate bioconjugation, linker technologies, or macromolecular scaffolds, which introduce additional layers of variability and risk. Successful development of these modalities depends on deep expertise, special infrastructure, and close integration across chemistry, biology, drug metabolism and pharmacokinetics, and bioanalysis.
What about financial considerations?
From a broader operational and business perspective, Larry Pitcher, CEO, Kincell Bio, believes one of the most significant hurdles to emerging modality development is financial pressure tied to inflection points.
“While historically filing an investigational new drug application was a major value-creation inflection point, today’s funding environment often demands phase 1 clinical data and a well-charted path to phase 2 and beyond. Investors want to see not just compelling science but also evidence of clinical success, the assurance of commercial manufacturability, and confidence that the cost of goods is sustainable,” he explains.
How do regulatory uncertainties create development challenges?
Although regulatory guidance exists to some degree for most emerging modalities, there is significant uncertainty as regulations evolve, new science is learned, and manufacturing technologies are developed.
“Sponsors often find that written regulations don’t fully address the questions they encounter as they advance a program. Much depends on dialogue with regulatory authorities and on individual reviewers’ interpretations of the program at hand,” comments Bruce Thompson, president and chief technology officer at Kincell Bio. That uncertainty, he adds, directly impacts timelines, investment decisions, and development risk.
Joseph Jeong, executive vice president and head of research and development (R&D), Samsung Biologics, notes that regulatory guidelines for emerging modalities are being developed in parallel with drug development. Consequently, the specific regulatory requirements for chemistry, manufacturing, and controls, as well as preclinical and clinical studies, remain unclear. “This uncertainty leads to challenges in accurately forecasting project timelines and estimating R&D costs,” he says.
When regulatory expectations lag innovation, therapeutic performance can be logically deduced and clear from a scientific perspective. Still, the path forward can be clouded due to the propensity of regulators to be conservative in thinking with risk in mind, adds Jeffrey Mocny, vice president of regulatory strategy with Abzena.
These hurdles are noteworthy, therefore, because they dictate whether a therapeutic is business viable, and regulators will not approve new therapeutics based on positive clinical results alone, remarks Horst Ruppach, executive director, scientific and portfolio global biologics, Charles River Labs. Developers also need to establish a mechanism of action via therapeutic identity and potency, appropriate process, analytical methods, and controls to gain commercial approval.
As a consequence, despite the transformative effects of new modalities, the time it takes to get programs through clinical development has lengthened, according to Christian Cobaugh, CEO, Alloy Genetic Medicines. “To reduce time to market, developers tend to go after similar targets rather than push the boundaries of these modalities,” he says.
Cobaugh believes that to bring innovation to more patients, regulatory agencies have the power to create even more standardization within the industry by discounting fees or directly rewarding companies to develop and share best-in-class technologies. “Rules and standards on both sides of emerging modality clinical development can be exploited to speed up cures, reduce costs, improve capital efficiency, and encourage even more transformative innovation,” he contends.
What are the biggest process development challenges?
For emerging modalities, 2 of the biggest hurdles that must be overcome during early development are lack of process knowledge and platform processes. “Many emerging therapy companies begin with compelling biology but lack a defined target product profile, yield expectations, dosing strategy, or clarity around critical quality attributes,” Thompson says. “Without that foundation, it’s challenging to design scalable processes or robust analytics.”
Due to a lack of standardized, repeatable manufacturing approaches, developers often start from scratch, which makes development timelines longer and increases risk when moving from early stage to clinical and commercial scales, comments John Maslowski, president and CEO of Forge Biologics. The need for specialized equipment, facility designs, and production technologies that are not widely available or fully optimized also creates bottlenecks when demand increases and can significantly impact the cost of goods and speed to market, he adds.
Lack of product and process knowledge can also lead to underestimation of the developability of these often highly complex molecules, according to Rob Holgate, vice president of research and innovation for Abzena. “Without a systematic approach early in development to design and select molecules with a derisked profile, issues might arise in manufacturing or clinical studies that are significantly more expensive to fix,” he says.
Analytical challenges can be significant as well. Novel therapies often have more complex critical quality attributes, requiring specialized assays and advanced analytical methods. Such hurdles, according to Maslowski, “are noteworthy because without robust characterization, it becomes difficult to ensure consistency, potency, and patient safety.”
For example, Matt Hewitt, vice president and chief technology officer of the manufacturing business division at Charles River Labs, notes that the ability to design, qualify, and validate potency matrices for products is crucial for establishing a consistent mechanism of action, which is strongly encouraged by the regulators for approval.
Selecting the right technologies that balance innovation with reliability and regulatory acceptability and bridging the gap between research and development early are essential to avoid costly delays, according to Thompson. In addition, Pitcher emphasizes the importance of finding the right contract development and manufacturing organization partners that can support both early clinical supply and long-term commercial readiness and consider long-term cost of goods, supply chain robustness, and regional manufacturing strategy (particularly for autologous therapies) to address pressures surrounding the cost and efficiency of process development.
