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| Excipient Grade Change Under SUPAC |
Under the SUPAC (Scale-Up and Post-Approval Changes) framework, a grade change of an excipient refers to using the same chemical type from the same manufacturer but of a different physical grade — for example, changing from microcrystalline cellulose 101 to 102 or from lactose monohydrate to anhydrous lactose. Such changes do not alter the chemical composition but can affect physical properties like particle size, flowability, compressibility, or moisture content, which may influence the performance of the dosage form.
According to SUPAC-IR (Immediate Release), SUPAC-MR (Modified Release), and SUPAC-SS (Semisolid) guidelines, the regulatory impact of such a change depends on its potential to affect product quality or performance. If the new grade is functionally equivalent and does not alter the formulation’s performance, it is considered a Level 1 change, requiring only documentation in the annual report. However, if the grade has a measurable effect on formulation parameters such as dissolution or stability, it is categorized as a Level 2 change, necessitating submission of a Changes Being Effected (CBE-30) supplement supported by comparative dissolution and characterization studies. When the change may significantly affect the release profile or clinical performance, it is treated as a Level 3 change, requiring a Prior Approval Supplement (PAS) and complete validation, including potential bioequivalence studies.
When implementing a grade change, it is essential to evaluate Critical Material Attributes (CMAs) — such as particle size distribution, surface area, moisture content, viscosity, and bulk density — as these influence the Critical Quality Attributes (CQAs) of the finished product, including blend uniformity, dissolution, hardness, and stability. A risk-based justification following ICH Q8 (Pharmaceutical Development) and ICH Q9 (Quality Risk Management) should be provided to confirm that the new excipient grade lies within the established design space and maintains product quality.
Supporting studies should generally include comparative dissolution profiles in multiple media (ensuring an f₂ similarity factor ≥ 50), short-term and accelerated stability studies, and manufacturability evaluations such as flow and compressibility assessments. If equivalence is demonstrated, a Level 1 or Level 2 submission is sufficient. However, if differences are observed in dissolution or stability, a higher-level submission becomes mandatory.
In conclusion, a change in excipient grade under SUPAC is permissible provided that functional equivalence is scientifically justified, supported by comparative testing, and documented appropriately in line with the level of change.
