Background/Objectives: Hospital compounding is essential for the delivery of patienttailored therapies—particularly for pediatric and oncology patients and other groups requiring precise dosing. Its role is expected to grow as, for instance, the UK MHRA’s new Guidance on Decentralised Manufacturing promotes alternative manufacturing pathways that integrate hospital preparation units. However, drug substances that remain stable in commercial oral formulations may undergo rapid degradation under alternative conditions (e.g., aqueous suspension, light exposure, or in the presence of specific excipients). Despite these risks, formulation strategies in hospital compounding often rely on empirical practices and lack structured guidance regarding stability, impurity control, and reproducibility. Methods: This study proposes a risk-based scientific framework for formulation design, integrating degradation profiling with predictive toxicology. Potential degradation pathways (hydrolytic, oxidative, and photolytic) are systematically identified through forced-degradation studies combined with ab initio modeling. These risks are translated into formulation strategies using a structured decision tree encompassing solvent selection, pH adjustment, excipient compatibility, and packaging considerations, even in the absence of a pharmacopeial monograph. The toxicological relevance of degradation products is evaluated using in silico approaches aligned with ICH M7 guidelines, thereby defining critical quality attributes (cQAs) and critical process parameters (CPPs). Results: The applicability of the framework is demonstrated through hospital compounding case studies, with further extension toward advanced applications such as semi-solid extrusion (SSE) 3D printing. Conclusions: By integrating mechanistic understanding of drug degradation into formulation planning, the proposed framework enhances the safety, reproducibility, and quality of compounded preparations. This approach reinforces Good Preparation Practices (GPPs) and is consistent with international quality-by-design (QbD) principles in the context of personalized medicine.
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