Flexible Formulation Strategies Boost Early-Phase Clinical Success

Formulations are created and refined throughout the product life cycle, beginning with simple compositions that gradually become more complex. The challenge for early clinical development is the manufacture of a good manufacturing practice-compliant drug product formulation that aligns with the clinical trial design.¹ First-in-human studies are challenging due to limited knowledge about the dose, safety profile, and pharmacological effects in humans.² Clinical pharmacologists and medical experts define the dose range and select the preferred route of administration based on the drug substance characteristics. The chemistry, manufacturing, and controls team is then tasked with translating the clinical requirements into a suitable drug product formulation.

Criteria for Early Phase Drug Product Formulations

To ensure successful formulation development in early phase trials, several key criteria must be considered:

• Dose adaptability
• Tolerability/palatability
• Matching placebo
• Development effort

With these criteria in mind, the formulation strategy must accommodate the unique demands of first-in-human (FIH) studies, particularly regarding dose flexibility.³

The Importance of Dose Flexibility in FIH Trials

In early clinical trials, drug product formulations are designed to enable administration of the drug substance to clinical trial participants. FIH trials require drug products that support a large dose range, as dosing typically escalates following each dose escalation meeting held throughout the trial. Depending on the clinical trial design, doses may vary from a few milligrams to more than a gram, resulting in a potential 10- to 100-fold increase between the starting dose and the final cohort. Flexibility in dose administration is therefore critical to accommodate this variability.⁴

As clinical development advances and the target dose becomes more clearly established, the need for dose flexibility decreases. Consequently, formulation efforts should be streamlined to conserve both time and cost during development.

Selecting Appropriate Dosage Forms

Given the wide dose range required in early trials, selecting an appropriate dosage form becomes critical. Solid dose formulations for early clinical trials are typically capsules or powder-in-bottle formulations due to the limited development requirements compared with tablets.

To support this variability, the formulation must allow for flexible dosing units. Initially, low-dose units are required, but as the trial progresses, higher-dose units become necessary. Using fixed-strength capsules or tablets requires multiple strengths to be available throughout the trial. Relying solely on low-dose units may offer flexibility but can place a burden on participants, who may need to ingest 15-20 capsules at higher dose levels.

Capsules can be filled with:

• Neat drug substance
• Powder blend
• Semi-solid

Neat drug substance capsules are often favored unless the drug substance properties require additional excipients, resulting in a powder blend or semi-solid filled capsule. Dissolution and absorption of the drug substance can be improved by the excipients.

Not all drug substances are suitable for capsule dosing, so liquid formulations should be considered. If the drug substance must be administered as a liquid but is unstable in aqueous environments, a powder-in-bottle formulation may be a suitable alternative. A powder-in-bottle formulation offers the benefits of a solid dosage form, particularly in terms of stability and dose adaptation. Prior to administration, the powder-in-bottle formulation must be reconstituted by clinical or pharmacy staff. The reconstitution process should be straightforward and equipment-free, enabling ease of use at clinical sites. It should yield either a clear solution or a homogeneous suspension to ensure accurate dosing. If the required dose is lower than the total drug substance in the bottle, part of the solution can be administered using an oral dosing syringe.

Liquid drug products offer greater dose adaptability through volume adjustment or dilution.⁵ In case of volume adjustments, the suspension or solution will not be directly taken from the bottle but administered by syringe.

To confirm compatibility with the syringe used for dose administration, additional compatibility assessments will be needed. Especially low concentrations are impacted by adsorption of the drug substance to different materials used in handling the drug product.

Vehicles for oral liquids may include:

• Water (most palatable)
• Cyclodextrin-based solutions (for solubility enhancement)
• PEG-based diluents (less palatable, used when necessary)

Designing Matching Placebos for Blinded Studies

In addition to active formulations, placebo design plays a vital role in maintaining trial integrity, especially in blinded studies.⁶ Early phase clinical studies often require placebo-controlled designs, necessitating the development of a matching placebo formulation. For solid oral dosage forms, placebo capsules can be manufactured identically to active capsules. A single fill weight of excipient in placebo capsules can be used to match all active strengths, eliminating the need for dose-specific placebo batches and simplifying manufacturing while blinding is guaranteed.

Capsules offer a practical advantage for blinding, as the capsule shell conceals the contents, preventing clinical staff and participants from visually identifying the formulation. To prevent unblinding caused by visual differences, opaque, colored capsules should be used when the drug substance itself is colored. Capsules also eliminate concerns about taste, as the drug substance is encapsulated.

In contrast, liquid formulations require more complex blinding strategies due to appearance and taste. Since the taste profile of the drug substance is often unknown in early trials, taste masking can be achieved by administering the drug product immediately after a peppermint strip or peppermint mouthwash. This method effectively reduces taste perception without altering the formulation itself.

To maintain blinding of appearance, dosing bottles or syringes can be wrapped in opaque foil, preventing visual identification of the liquid’s color or clarity. This simple, yet effective, approach supports blinding without requiring changes to the formulation.

Stability Testing to Support Dose Flexibility

Following the selection of both the active formulation and its matching placebo, stability studies must be conducted to ensure product integrity from the date of manufacture through the entire duration of the clinical trial.⁷ To ensure dose flexibility throughout the clinical trial, stability must be established across all strengths and concentrations of the drug product, or alternatively, through a bracketing approach.⁸ For example, when using neat drug substance in capsules, stability data for the lowest and highest strengths may be sufficient to justify the full dosing range, offering optimal flexibility while minimizing testing requirements. Stability data from active capsules can also support placebo shelf-life assignment, potentially reducing the extent of testing required for placebo formulations.

Drug product formulations used in early phase trials are often tailored to the dosing needs identified during the first-in-human study. These early formulations may not be suitable for later phase trials, when dosing is more defined. In such cases, simple formulations may be used to minimize development time and cost, and extensive stability studies may not be necessary. Stability testing under intended storage conditions is typically sufficient during early development.

As clinical development progresses, additional stability studies under accelerated conditions become important to support formulation refinement and regulatory requirements. If a formulation is intended for use in later phase trials, a long-term stability program, including accelerated testing, is recommended to support ongoing product development and ensure robustness of the formulation.⁹

Stability studies for the drug substance can be planned for mid- to long-term durations, as the drug substance is less likely to undergo significant changes compared with the drug product, which may evolve as formulation strategies are refined. However, not all investigational products will advance beyond early clinical phases, making it critical to balance the investment in large-scale manufacturing and extensive stability testing against the risk for project discontinuation.

Optimizing the Formulation Approach for Clinical Success

Formulation development in early clinical trials demands a strategic balance between flexibility, simplicity, and regulatory compliance. Careful selection of dosage forms, thoughtful placebo design, and tailored stability studies aligned with trial objectives help ensure reliable data generation while avoiding unnecessary complexity. Since not all investigational products advance beyond early clinical phases, strategic planning is essential to optimize resource use and uphold the integrity of clinical outcomes. Ultimately, a well-designed formulation approach provides a strong foundation for successful drug development and supports progression into later clinical stages.

References

1. EMA. Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on Clinical Trials on Medicinal Products for Human Use, and Repealing Directive 2001/20/EC Text with EEA Relevance. Accessed Dec 3, 2025.
2. Shen, J; Swift, B; Mamelok, R; et al. Design and Conduct Considerations for First-in-Human Trials. Clin Transl Sci. 2019;12(1):6-19.
3. EMA. Detailed Commission Guidelines on Good Manufacturing Practice for Investigational Medicinal Products for Human Use, Pursuant to the Second Subparagraph of Article 63(1) of Regulation (EU) No 536/2014. Accessed Dec 3, 2025.
4. van Hoogdalem, E; van Iersel, M; Winter, E; et al. Pharmacology-Guided Rule-Based Adaptive Dose Escalation in First-in-Human Studies. Clin Pharmacol Ther. 2021;109(5):1326-1333.
5. Chiang, C; Tang, S; Boonstra, J; et al. Development of an extemporaneous Preparation Formulation Using a Simple and Non-solubilizing Matrix for First in Human Clinical Study. Int J Pharm. 2024;653:123868
6. EFPIA. Innovation in Clinical Trial Design: A review of The Clinical Trial Design Landscape. Accessed Dec 3, 2025.
7. Ohnmnacht, C; Jansen, S. What’s Evaluated in a Stability Study?TheMedicineMaker.com. Aug 15, 2025.
8. EMA. Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products in Clinical Trials. Accessed Dec 3, 2025.
9. ICH. Q1A (R2) Stability Testing of New Drug Substances and Products. Accessed Dec 3, 2025.