Avoiding regulatory setbacks in OSD development: Why early formulation decisions matter

The hidden cost of getting to FIH fast: Bioavailability, stability, and scale-up risks

For example, a formulation with borderline solubility might pass preclinical pharmacokinetic studies but later show bioavailability or efficacy issues, stability failures, or require reformulation. In many cases, these challenges stem not only from solubility itself but from minimal or suboptimal formulation work in the rush to FIH, with problems surfacing during scale-up. These detours slow progress and consume critical resources at pivotal moments.

According to an analysis of more than 1,000 IND applications received by the FDA’s Center for Drug Evaluation and Research between 2016 and 2021, more than 350 INDs were placed on clinical hold due to quality-related safety issues. Many of these holds were linked to CMC deficiencies—such as inadequate stability data, poorly characterized APIs, inadequate CMC documentation, or unfit manufacturing processes—underscoring how early-phase formulation choices can reverberate downstream. These findings highlight the value of strategic formulation planning in setting a strong CMC foundation.
 

Formulation strategy for regulatory readiness and scalability

Achieving CMC readiness for regulatory milestones and scale-up begins with strategic formulation decisions. These early choices influence everything from stability data to manufacturing feasibility, making them critical to long-term success—even if they aren’t directly reviewed by regulators at Phase I or not required for IND submission.
 

How CDMO partnerships reduce formulation and regulatory setbacks

Because most early-stage biotechs lack in-house CMC and regulatory depth, selecting the right development partner is critical to program success.

To avoid common formulation and regulatory setbacks, an experienced CDMO can help minimize risk factors during early development by:

• Selecting excipients that are widely accepted across global markets to avoid unnecessary reformulation and streamline development
• Evaluating enhancement strategies for low-solubility APIs—from salt formation to amorphous solid dispersions or lipid formulations—based on API characteristics, scalability, and program goals
• Stress-testing formulation scalability
• Flagging mismatches between process design and long-term commercial goals
• Performing predictive stability studies and helping to ensure a smooth scale up process

Along with the necessary technical capabilities, a strong partner helps shape the strategy early by bringing regulatory insight, lifecycle planning, and formulation expertise to reduce risk and support better decisions throughout development.
 

A vision-led approach to risk mitigation and time savings

While early development choices may not be directly reviewed by regulators at Phase I, they lay the groundwork for CMC readiness, scalability, and global alignment—factors that become critical as programs advance. But it does require clarity about how formulation choices will hold up over time. That clarity comes from combining the right tools with scientific and regulatory insight, including:

• Predictive modeling to assess solubility, stability, and performance risks
• Regulatory considerations that align formulation choices with global expectations
• Deep understanding of the API to identify constraints and guide optimal delivery

In practice, capabilities such as in silico modeling, accelerated stability testing, and platform formulations help reduce guesswork and create a more predictable path forward.
 

Start smart: Questions to ask before formulation

Clarity in early development starts by engaging with your CDMO partner early and asking key questions to help surface risks, clarify strategy, and prevent costly pivots later on. Consider asking:

• Is this formulation scalable, or will it require redesign later?
• Are there regulatory concerns tied to any excipients or processes or any regional restrictions?
• How can predictive modeling help identify stability risks?
• What formulation options exist for low-solubility APIs?
•  What technology is the optimal for my selected formulation?

Getting the answers to these questions early lays the groundwork for more informed, forward-looking decisions throughout development and helps ensure alignment between early decisions and long-term goals.
 

Build for what comes next

Early formulation missteps in OSD development often show up as bioavailability issues, stability concerns, or regulatory documentation gaps. Addressing these risks with scalable strategies and quality-focused partnerships helps programs progress smoothly from IND to NDA.

Speed matters but getting it right matters more. Precision today prevents costly rework tomorrow.