FDA Review of Inavolisib Tablets: Established Conditions and Formulation Change Bridging

Formulation Bridging

The proposed commercial formulation for Inavolisib tablets at 3 mg and 9 mg has evolved from multiple clinical formulations, with the applicant making minor adjustments to accommodate different dosage strengths (b)(4), as shown in Figure 1. A film coating (b)(4) was introduced, and the color of the proposed commercial formulation was optimized for sufficient market acceptance.

Module 3.2.P.2 provides a qualitative and quantitative comparison of all clinical formulations with the primary stability study formulations. Table 4 shows the formulation comparison for Phase I clinical, Phase III clinical, primary stability studies, and the proposed commercial formulation. The dissolution testing of critical clinical batches (formulations F08/09 and F14/15) was conducted using the proposed paddle method at the specified rotation speed. During the formulation bridging study, representative critical batches were also tested using the proposed quality control method at 50 rpm.

The applicant conducted bridging studies for formulations at various clinical development stages through in vitro dissolution tests under different pH conditions (pH1.1, pH4.5, and pH6.8). The specific results are shown in Figures 12A, B, and C.

From the early prescription development stage to Phase II and the main stability study stage, the tablets showed similar dissolution behavior in the pH range of 1.1 to 6.8, consistent with the characteristics of immediate-release formulations. Additionally, Figures 13A, B, and C show the dissolution profile comparisons between Phase III batches and main stability batches using the commercial testing method (USP Apparatus 2 (paddle method) at 50 rpm) in 0.1N hydrochloric acid medium, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer, respectively (Note: Formulation F15 was not tested under the 50 rpm condition. Since F15 has the same formulation composition as F09, their dissolution profiles are expected to be consistent).

In 0.1 N HCl, all formulations exhibited similar extremely rapid dissolution behavior, dissolving within 30 minutes (4)(6). In pH 4.5 acetate buffer and pH 6.8 phosphate buffer, all formulations showed similar dissolution profiles (f2 > 50).

Conclusion:The applicant has fully bridged the formulation changes during the clinical development phase through in vitro dissolution comparative tests, demonstrating the similarity between the formulations (*（4）% released within （4） minutes*).

General Recommendations of Biopharmaceutics: Based on the completeness of the submitted information and evaluated from a biopharmaceutical perspective, it is recommended to approve the dissolution method for Inavolisib Tablets (3 mg and 9 mg) for NDA 219249: Use USP Dissolution Apparatus 2 (500 mL of 0.1 N HCl for the 3 mg strength, 900 mL of 0.1 N HCl for the 9 mg strength), at a speed of 50 rpm. The acceptance criteria for batch release and stability testing is Q = dissolution within 30 minutes (4)%.