Accelerating Formulation Paths to First-in-Human: Why Fit-for-Purpose is the Smart Strategic Choice

Transitioning from a nominated preclinical candidate to a First-in-Human (FIH) study represents a critical, high-risk, and resource-intensive phase in drug development. Traditional reliance on commercial-ready formulations at this stage often incurs avoidable delays, costly procedures, and operational complexity, especially given the high attrition rate common in early development. A Fit-for-Purpose (FFP) formulation strategy, grounded in scientific rigor and risk-based decision-making aligned with early clinical objectives, offers a streamlined and efficient pathway. By focusing on what is essential for FIH—namely safety, dose accuracy, exposure, short-term stability, and clinical readiness—FFP facilitates accelerated clinical entry, optimized resource utilization, and informed early decision-making, all without compromising scientific robustness or regulatory compliance.

Reducing time to FIH confers significant advantages, including preservation of substantial R&D capital and earlier patient access to novel therapies. Yet, many drug development programs expend excessive resources developing elaborate commercial formulations prematurely, resulting in delayed proof-of-concept milestones. Given high candidate attrition rates, this traditional approach leads to inefficient consumption of drug substance, labor, and capital.

The alternative is an agile FFP approach that aims for the simplest, most reliable formulation sufficient for early clinical use. This approach strategically aligns formulation design with the immediate clinical needs, focusing on delivering safe and precise dosing, facilitating clear interpretation of initial human pharmacokinetics (PK) and safety data in FIH studies.

FFP formulations are developed using a rigorous scientific framework, focusing on enabling the molecule’s advancement through early clinical phases with clearly defined success criteria:

• Safety: Incorporating excipients with Generally Recognized As Safe (GRAS) status or established clinical precedence to mitigate toxicological risks.
• Adequate Exposure:  Achieving sufficient systemic exposure in toxicology species is essential to support safe and effective FIH formulations.
• Phase-Appropriate Analytical Validation: Employing analytical methods rigorously validated for the current development stage to ensure reliable dose quantification and stability assessment.
• Short-Term Stability: Guaranteeing molecular stability over the relevant clinical trial duration (typically weeks to months).
• Trial-Ready Scalability: Designing manufacturing processes that are practical, reproducible, and scalable for early-phase clinical material supply.

The key question guiding FFP formulation design is identifying the most straightforward, platform-enabled approach that addresses the molecule’s physicochemical and biopharmaceutical properties. This determination also considers the intended route of administration, dosing regimen, and clinical study design to ensure an effective and practical formulation for early clinical use. Common FFP strategies include:

Oral Dosage Forms

• Direct-in-Capsule (DiC) / Powder-in-Bottle (PiB): Simple encapsulation of neat Drug Substance (DS) or simple DS–excipient blends, enables dose flexibility, rapid manufacturing, and minimal excipient risk—often the preferred Phase I strategy.
• Precision Micro-Dosing: Technologies such as Harro Höfliger capsule filling systems or Xcelodose® ensure accurate low-dose fills, reducing variability in dose-escalation studies.
• Powder-in-Capsule with Excipients (Blend-in-Capsule): Enhances dose uniformity and manufacturability.
• Enabling technology for augmentation of solubility and/or dissolution and converting them to a downstream unit solid dosage form, capsule, roller compaction following tabletting.
  • Amorphous Solid Dispersions (ASD): Spray-Dried Dispersions (SDD) or hot-melt extrudates combined with polymeric carriers (HPMC-AS, PVPVA) to improve solubility of poorly soluble New Chemical Entities (NCEs), especially BCS Class II molecules. Quick and pragmatic for early development.
  • Nanosuspensions: Particle size reduction via wet milling or high-pressure homogenization to enhance dissolution. Can be administered as liquids or solidified using top spray/DS for easier handling.
• Solutions & Soft Gels: Co-solvent or pH-modified solutions encapsulated in soft gelatin capsules for rapid drug release.
• Suspensions: Suitable for low-dose or titration studies, enabling flexibility in early pharmacokinetic work.
• Salt/Co-Crystal Screening: Rapid screening to improve solubility or permeability without complex formulation development.

Parenteral Dosage Forms

• Powder-Filled in Vials: Preferred in FFP formulations for their sterility and ease of reconstitution at clinical site, enabling quick dosing.
• Aseptically Manufactured Liquid Fill-Finish: Includes terminal sterilization by ionizing radiation or e-beam sterilization for immediate clinical use.
• Solubility-Enabling Formulations: Improve DS solubility using methods such as pH adjustment, co-solvent systems (e.g., ethanol, PEG, propylene glycol with or without surfactants), cyclodextrin complexes (like SBE-β-CD), and fill-finish or lyophilized processes.
• Exploratory Routes: Sublingual or nasal formulations designed for rapid systemic exposure.

• Time to clinic: FFP can reduce pre-FIH timelines by 3–6 months, expanding decision-making and accelerating first-in-class opportunities.
• Resource Efficiency: Requires minimal DS and leverages platform templates, allowing parallel development of multiple assets.
• Risk Mitigation: Supports a “fail fast, fail cheap” approach—limiting sunk costs until clinical viability is demonstrated.
• Data-Centricity: Generates real human PK and food-effect data early, guiding subsequent formulation decisions.

• Developability Assessment: Characterize DS properties that impact pharmaceutical and biopharmaceutical behaviour (pKa, logP, solubility profile, permeability, solid-state form, flow, particle size, excipient compatibility).
• Use Enabling Platforms: Utilize enabling technologies to improve oral exposure and solubility/dissolution using high-energy systems such as SDD, nano-sizing, lipids, cyclodextrin systems amongst others.
• Phase-Appropriate Analytical Method Development: Develop and validate analytical methods appropriate for supporting accelerated FIH strategies; for example, adapting DS analytical methods for DiC or DiB strategies with necessary verifications.
• Regulatory Alignment: Frame FFP within IND/IMPD submissions as a temporary, safe, and justified bridge to Phase II. This pragmatic approach is encouraged by both FDA and EMA.
• Plan the Pivot: Establish criteria and timelines for transitioning from FFP to patient-centric, commercial-ready formulations including parallel stability, manufacturability insights, excipient compatibility.

This case example showcases our client’s rapid development of a formulation for a challenging BCS Class IV molecule with extremely high logP, poor solubility and permeability. To avoid delays from complex soft-gel or lipid-based systems, a spray-dried amorphous dispersion combined with a permeability enhancer was advanced as a DiC strategy. Stability was adequate for toxicology and Phase I supply, and IND filing occurred in 6 months—nearly a year faster than a traditional path.

Fit-for-Purpose formulations combine scientific rigor with strategic pragmatism. They reduce development time, conserve DS, de-risk investment, and accelerate access to human data. Industry examples highlight the value of the value of precision dosing, DiC/PiB approaches, simple solutions, and integrated clinical packaging. Embedding these approaches in platform toolkits aligned with regulatory expectations enables a Contract Research, Development, and Manufacturing Organization (CRDMO) to deliver smarter, faster medicine to patients.

At Aragen, we understand that speed, simplicity, and scientific rigor are the cornerstones of Fit-for-Purpose development. Our integrated CRDMO platform brings together discovery-to-clinic expertise, cutting-edge formulation science, and phase-appropriate GMP manufacturing to accelerate First-in-Human studies.

We offer a range of formulation strategies, from straightforward strategies like drug- or blend-in-capsules or powder-in-bottle, tablets, and capsules, to enabling solutions for CMC-challenging compounds, such as spray-dried dispersions, nanosuspensions, and solubility-enhancing systems. Each formulation is designed to be fast, reliable, and optimized for early clinical success.

With deep capabilities in formulation, analytics, material science, and manufacturing, we help our clients conserve drug substance, minimize risk, and achieve IND/IMPD milestones faster.

Partnering with Aragen means choosing a smarter, more agile path—one that transforms promising science into patient impact, faster.