When is an active ingredient not an active ingredient?

I was reviewing the Velcade litigation recently and found a nugget of FDA precedent that our readers might find of interest.  We blogged previously about a decision at the Federal Circuit, where the Federal Circuit reversed a district court decision invalidating a claim to the mannitol ester of bortezomib, the active ingredient in Velcade.  The mannitol ester formed when bortezomib was lyophilized, and the district court had improperly concluded that the compound could not be patented because it was the inherent result of an obvious process.

While it was pursuing its patent litigation, Takeda was also pursuing a parallel proceeding at FDA, when its partner Millennium Pharmaceuticals asked FDA to rule that the active ingredient in Velcade was the mannitol ester of bortezomib, even though it was only formed during the lyophilization process.  We suspect that some generic challengers had filed 505(b)(2) applications omitting mannitol from their formulations, since mannitol is a necessary ingredient in a 505(j) under the exception excipient rules.  Our suspicion appears to have been confirmed by FDA’s approval of Fresenius’ 505(b)(2) application for bortezomib for injection, which lists the following ingredients on its label, not including mannitol:

Bortezomib for injection is an antineoplastic agent available for intravenous injection. Each single-dose vial contains 3.5 mg of bortezomib, 10.5 mg boric acid, 25 mg glycine as a sterile lyophilized powder.

According to Millenium an active ingredient must, by definition, refer to a molecule’s state in the approved drug product.  As FDA stated in its citizen petition response:

The Petition asserts that "VELCADE is a lyophilized product that needs to be reconstituted prior to administration," and bortezomib "exists only after VELCADE is reconstituted into a solution." The Petition also asserts that, under FDA's regulatory framework, "the active ingredient must be identified in the form it exists in the lyophilized powder and not the reconstituted solution."  


FDA denied the petition because Millenium did not treat the mannitol ester as bortezomib as its active ingredient during development of its drug product.  According to FDA:

the Petition has not provided evidence that, during in-process, release, andstability testing of the drug product, Millennium controls for and specifies the amount of the mannitol ester of bortezomib, as would be necessary if the mannitol ester of bortezomib were the active ingredient in Velcade. We note that postapproval changes must be made in accordance with section 506A of the FD&C Act and 21 CFR 314.70. Accordingly, if Millennium wishes to identify the active ingredient as the mannitol ester of bortezomib, then Millennium would need to seek approval of a supplement to its NDA. This supplement would need to provide chemistry, manufacturing, and controls data and information to show that Millennium controls for the amount, content uniformity, purity, and stability during in-process, release, and stability testing, among other things (e.g., labeling updated to reflect active ingredient change in name and in dosing).

Interestingly, despite losing the petition, Millennium continues to list U.S. Patent No. 6,713,446, the patent covering the mannitol ester of bortezomib, as a “drug substance” patent in the Orange Book.