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P116: Biopharmaceutics Evaluation for Approval of Parenteral Formulations: Biowaiver versus Establishing a Clinical Bridge

Poster Presenter

Tapash Ghosh

TL
FDA
United States

Objectives

Every submission of parenteral products is reviewed by FDA on a case-by-case basis. This presentation will describe the nature of possible regulatory submissions pathways especially on the requirements for biowaiver or establishing a clinical bridge from the Biopharmaceutics perspective.

Method

We used original regulatory submissions without disclosing any proprietary information. We used examples to explain differences between 505(b)(1) and 505(b)(2) NDAs and ANDAs and role of Biopharmaceutics in 505(b)(2) NDA in establishing a bridge with the reference parenteral products.

Results

Case Study 1: Waiver for Parenteral emulsion: A 505 (b)(2) application for an injectable emulsion was submitted using an approved injectable emulsion product as Listed Drug (LD). The proposed formulation differs in inactive ingredient(s) not listed as the “exception inactive ingredient.” Comparative formulation and physicochemical data, comparative in vitro drug release profiles, and population bioequivalence information were requested. The application is still under review. Case Study 2: Waiver for Parenteral Products with different presentation: The proposed drug product (PDP) is a frozen, premixed solution in single dose IV bag whereas the LD is a lyophilized powder for reconstitution. The PDP contains NaCl, and HCl and recommended to be stored frozen. The 505 (b)(2) NDA was approved based on the bridging to the LD mainly using: (1) Comparable pH and osmolality of thawed injectable solution and final diluted LD and (2) the justification that changing from mannitol to NaCl will not significantly impact the pharmacokinetics of the drug substance. Case Study 3: Waiver for Parenteral Solution: A biowaiver was requested for the proposed parenteral solution based on the applicant’s claim that a biobridge has been established with the submitted documents. Upon review, FDA approved the 505 (b)(2) NDA product. Case Study 4: Assessment for Exception Excipients: A parenteral solution (test) and the reference listed drug (RLD) differed in that the RLD contains sodium citrate (buffer) and sodium sulfite (antioxidant) and the proposed test contains mannitol as buffer and uses no antioxidant, making the PDP not Q1/Q2 to the RLD in exception excipients. As in a 505 (j) application, differences on exception excipients and their acceptable amounts are acceptable for the products using the same route of administration, upon review, the ANDA was approved.

Conclusion

The term reference listed drug (RLD) applies to ANDAs whereas 505(b)(2) NDAs rely on listed drug (LD). Parenteral drug products generally must contain the same inactive ingredients and in the same concentration as the LD. However, specific qualitative and quantitative changes from the RLD formulation are permitted in an ANDA for certain inactive ingredients (i.e., preservatives, buffers, and antioxidants) that are considered exception excipients. In case of addition of any excipient, not defined under exception excipients, the submission should come via 505 (b)(2). For example, a proposed parenteral drug product that contains an additional inactive ingredient which cannot be considered an exception excipient would not be permitted in an ANDA under the regulations at 21 CFR 314.94(a)(9)(iii) and may require clinical investigations to establish safety of the excipient in a 505(b)(2) application. In those cases, to support approval of proposed product, a scientific bridge needs to be established with the LD mainly using the following information: (1) comparative bioavailability or bioequivalence studies (BA/BE) comparing the proposed drug and the relied-upon listed drug(s); (2) with comparative physicochemical tests and bioassays, bridging toxicology studies, PK/PD data, clinical data; and (3) any other approach FDA deems adequate to establish a BA/BE bridge. As establishing the clinical bridge is a key component for parenteral 505 (b)(2) applications, it is important to cite the correct regulation when describing the bridge; 320.22(b)(1) is less common with a 505(b)(2) and 320.24(b)(6) is generally used to establish the clinical bridge and should not be described as a waiver of in-vivo BA or BE per se. More details of the above case studies along with more explanation will be presented.