The issue of interest concerns the newly stated requirement for quantitative (Q1) and qualitative (Q2) sameness of the formulation of product beyond what has been required in the past. For most parenteral products, the regulations at 21 CFR 314.94(a)(9)(iii) permit changes in three types of inactive ingredients, preservative, buffer or antioxidant as long as the applicant “Identifies and characterizes the differences and provides information demonstrating that the differences do not affect the safety or efficacy of the proposed drug product.” In the case of propofol injection, historically, OGD has permitted differences in preservative for this product without requiring an in vivo bioequivalence study and would granted a waiver of the in vivo bioequivalence requirement if a series of in vitro tests were found acceptable (see review of ANDA BE study from Drugs@FDA here). However, in the newly issued Guidance, a waiver of in vivo requirements will only be granted if the formulations of the proposed product and reference listed drug (RLD) are both Q1 and Q2. When describing the in vivo study, a footnote found in the Guidance reads “[a]n in vivo pharmacokinetic bioequivalence study will also be requested for a test product which contains a different buffer, preservative or antioxidant.” And, of course, if any of the in vitro and or physicochemical testing does not demonstrate acceptable results, an in vivo study will be required. In addition, FDA is also asking applicants to demonstrate that the proposed product is stable in various IV fluids, cited in the labeling of the RLD. It is also not clear what prompted FDA to change its recommendations.
It is interesting that the RLD listed in the Orange Book is Diprivan, but the ANDA subject of a different preservative (see review linked above) is a listed approved product but not an RLD. It is not clear where the FDA will land relative to BE requirements should another applicant wish to formulate its product with the preservative used in the ANDA cited in the review linked above. The new propofol BE Guidance can be found here.
）。然而，在新发布的指南中，仅在产品配方与参照产品（RLD）Q1和Q2相同的情况下才准许体内豁免。在描述体内研究时，指南的一个脚注表明“对包含不同缓冲剂、防腐剂或抗氧化剂的待测产品也会要求体内药代动力学生物等效性研究”。当然，如果任何体外或物理化学研究不能证明可接受的结果，将要求体内研究。此外，FDA还要求申请人证明拟定的产品如RLD标签所述在不同的静脉输液中是稳定的。尚不清楚是什么原因促使FDA修改其BE指南。