A risk-based, QTPP-driven framework for semi-solid extrusion 3d printing of personalized medicines: Integrating hospital compounding and clinical trial regulation

• Risk-based framework for SSE 3D printing in hospital and clinical trial contexts. • Ink treated as a regulated intermediate, decoupling formulation from dose. • Structured risk tables define CQAs, CPPs, and IPCs, aligning with ICH and USP • Three paediatric case studies illustrate regulatory and technical feasibility. • Harmonized quality oversight for decentralized, personalized drug manufacturing. Semi-solid extrusion (SSE) 3D printing enables precise, patient-specific oral medicines, yet its uptake is constrained by fragmented regulatory pathways. This study develops an applied, risk-based framework grounded in empirical data from hospital compounding and early-phase clinical trial implementation, integrating both within a unified regulatory model through the concept of the printable ink as a pharmaceutical intermediate. Drawing from three pediatric use cases involving 5 different active pharmaceuticals ingredients (APIs), trimethoprim-sulfamethoxazole (Bactrim®), cyclophosphamide, tamoxifen (OPERA clinical trial) and isoleucine (Maple syrup urine disease) the framework applies quality-by-design principles (ICH Q8–Q11, USP <1220>) to define critical quality attributes (CQAs), critical process parameters (CPPs), and in-process controls (IPCs) suitable for both centralized and point-of-care production. Two complementary tables stratify APIs by risk and map them to actionable quality control strategies, enabling science-based decisions on when IPCs alone suffice versus when full GMP oversight is required. This harmonized model supports reproducible, traceable production across decentralized sites, addressing regulatory ambiguity while preserving flexibility for innovation in paediatric and rare disease care.