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Injectables: 505j or 505(b)(2)?

Generic injectable drug products are treated differently than other routes of administration when it comes to permitted differences from the RLD. For most dosage forms, the sponsor is allowed to change excipients as long as the test product is bioequivalent to the RLD. No so for injectables, the excipients must be the same. If the excipients are not the same, the 505(b)(2) pathway must be used. Let’s look at a recent example.

APP Pharmaceuticals received approval of NDA 022536 Indomethacin for Injection on March 17, 2010 via 505(b)(2). The reference product is Ovation Pharmaceuticals’ Indocin® I.V., which is not buffered. The active ingredient in the RLD is indomethacin sodium and no excipients are listed in the labeling. AAP Pharma’s product uses indomethacin base and a phosphate buffer adjusted with sodium hydroxide, as needed. The use of a buffer required this product to be submitted under 505(b)(2) rather than as a generic under 505j.

In order to obtain approval under 505(b)(2), AAP Pharma had to request a biowaiver under 21 CFR Section 320.22(b). The Agency had to approve the biowaiver and review the CMC and microbiology of the product for approval; no studies were conducted by the sponsor.

A review issue was that the RLD is a USP article and the proposed product did not meet the USP pH specification. Thus, the approved product does not bear the USP designation. The sponsor can petition the USP to add its product.