Mastering Phase-Appropriate Characterization for Biologics Approval

Applying stage-appropriate scientific rigor is becoming increasingly essential for biotherapeutic characterization, according to Kelly Donovan, director, Characterization Services, KBI Biopharma, at the American Association of Pharmaceutical Scientists’s 2025 PharmSci 360 conference. In her talk, “Navigating the Biotherapeutic Commercialization Landscape,” she explains that successful biotherapeutic commercialization hinges on providing robust and progressive product characterization data. This analytical rigor is not merely a regulatory checkpoint, but a foundation for demonstrating consistency, understanding function, and ensuring patient safety (1).

Characterization forms a core part of the Common Technical Document (CTD) under the Elucidation of Structure section (3.2.S.3.1) (2), Donovan says. This comprehensive work, which includes liquid chromatography–mass spectrometry (LC–MS) and spectroscopic methods for primary and higher order structure, biological activity, and degradation pathway analysis, enables the definition of the quality target product profile, she adds. This, in turn, allows teams to determine the critical quality attributes necessary for establishing product and process controls under a quality-by-design framework, she explains.

Since the regulatory landscape for complex modalities and accelerated timelines demands increased data integrity, Donovan continues, one’s development strategy must recognize that characterization is a progressive process that "starts light and ends deep."

Why must analytical goals differ between IND and BLA filings?

Analytical goals and regulatory expectations must be clearly differentiated between the early and late phases of biotherapeutic development, Donovan states. This approach is necessary to maintain regulatory alignment and product quality. In the early phase, the focus is on safety and proof of concept, and the investigational new drug (IND) stage requires a fast, basic characterization package using platform methods to support first-in-human trials. Method qualification, however, is not required, she clarifies.

Conversely, the biologics licensing application (BLA) stage demands what Donovan terms the "complete package." This deep dive requires material representative of the final commercialization process and must use qualified, product-specific methods. Late-stage expectations significantly increase, demanding 100% amino acid sequence coverage and in-depth characterization of impurities (such as size and charge variants) down to the 0.1% level, she emphasizes. Biomanufacturers must therefore integrate this stringent level of control into their final process planning.

How can biopharma teams prevent costly regulatory delays?

Ultimately, regulatory success is fundamentally a mix of scientific rigor and strategic stage planning, Donovan states. Failure to align analytical strategies with regulatory filing milestones creates significant risk and inefficiency.

A crucial risk leading to project delays is the failure to qualify characterization methods, such as LC–MS and higher-order methods, as well as a lack of understanding of method performance, Donovan adds. Method qualification, she explains, while not required at the IND stage, should begin at the IND amendment stage—when methods are optimized for the product—and must be in place for the late-stage BLA package.

"If you delay characterization studies too long and wait until the BLA, there's a big chance that you might have some surprises that could delay your final product," Donovan noted. These surprises often stem from common pitfalls like incomplete characterization (e.g., assessing only size or charge, but not both).

For those managing timelines, ensuring that sufficient comparability data—using the correct methods and an adequate number of lots—is generated following process changes (such as scale-up or changes in raw materials) is essential for regulatory confidence and avoiding delays, she says.

Looking forward, the industry continues to explore how to increase efficiency, Donovan concludes. Meanwhile, advanced techniques, like achieving sub two-minute LC–MS methods, are already enabling rapid data delivery and supporting adaptive study designs. Furthermore, while artificial intelligence-enabled modeling may eventually replace manual characterization work, consultation with FDA is recommended when pursuing this new approach, Donovan says.

The AAPS PharmSci 360 2025 conference runs Nov. 9–12 in San Antonio, Texas. Click here for more conference coverage.

References

1. Donovan, K. Navigating the Biotherapeutic Commercialization Landscape. Presentation at 2025 AAPS PharmSci 360, San Antonio, Texas, Nov. 9–12, 2025.
2. FDA. Guidance for Industry, M4 Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use Guidance for Industry (CDER, CBER, October 2017).