FDA Grants Petitions and Approves Generic ZOSYN; Petition Decision Reaffirms FDA Policy on Inactive Ingredient Changes

September 16, 2009

By Kurt R. Karst –      

On September 15, 2009, FDA issued its long-awaited decision responding to several citizen petitions submitted in 2005 and 2006 (available here, here, here, and here) concerning the approval of ANDAs for generic versions of Wyeth Pharmaceuticals’ ZOSYN (piperacillin sodium; tazobactam sodium) Injection.  FDA’s decision to grant the petitions (and largely deny a Wyeth petition) and approve ANDAs reaffirms an Agency policy that FDA will, in the context of discontinued drug product formulations, waive its so-called “exception excipient regulations” to permit the receipt and approval of an ANDA for a drug product containing a so-called “non-exception excipient” change from the Reference Listed Drug (“RLD”).
FDC Act § 505(j)(4)(H) states that FDA must approve an ANDA unless, among other things:

information submitted in the application or any other information available to [FDA] shows that (i) the inactive ingredients of the drug are unsafe for use under the conditions prescribed, recommended, or suggested in the labeling proposed for the drug, or (ii) the composition of the drug is unsafe under such conditions because of the type or quantity of inactive ingredients included or the manner in which the inactive ingredients are included.

FDA’s regulations implementing FDC Act § 505(j)(4)(H), generally, are found in the Agency’s ANDA content and format regulations at 21 C.F.R. 314.94.  Pertinent regulations on inactive ingredient changes for certain types of generic drug products are set forth in 21 C.F.R. § 314.94(a)(9).  FDA’s regulations for parenteral drug products at 21 C.F.R. § 314.94(a)(9)(iii) state:

Generally, a drug product intended for parenteral use shall contain the same inactive ingredients and in the same concentration as the [RLD] identified by the applicant under paragraph (a)(3) of this section.  However, an applicant may seek approval of a drug product that differs from the reference listed drug in preservative, buffer, or antioxidant provided that 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.

Preservative, buffer, and antioxidant changes in generic parenteral drug products are referred to as “exception excipients,” which may qualitatively or quantatively differ from the RLD formulation.  Other regulations at § 314.94(a)(9)(iv) identify exception excipients for generic ophthalmic and otic drug products (i.e., preservative, buffer, substance to adjust tonicity, and thickening agent).  Excipients not identified in these regulations are referred to as “non-exception excipients.”  These regulations find their parallel in 21 C.F.R. § 314.127(a)(8)(ii), which addresses the grounds for an FDA refusal to approve an ANDA for a parenteral, ophthalmic, or otic drug product.  For example, 21 C.F.R. § 314.127(a)(8)(ii)(B) states: “FDA will consider an inactive ingredient in, or the composition of, a drug product intended for parenteral use to be unsafe and will refuse to approve the [ANDA] unless it contains the same inactive ingredients, other than preservatives, buffers, and antioxidants, in the same concentration as the listed drug. . . .”

Notwithstanding FDA’s exception excipient regulations, the Agency has, on occasion, but only in very limited circumstances, waived its exception excipient regulations to permit the receipt and approval of an ANDA for a drug product containing a non-exception excipient change from the RLD.  Specifically, FDA has granted waivers under 21 C.F.R. § 314.99(b), which states that a generic applicant “may ask FDA to waive . . . any requirement that applies to the applicant under §§ 314.92 through 314.99.”  FDA can grant such a waiver if the Agency finds: “(1) the applicant’s compliance with the requirement is unnecessary for the agency to evaluate the application or compliance cannot be achieved; (2) the applicant’s alternative submission satisfies the requirement; or (3) the applicant’s submission otherwise justifies a waiver.”  21 C.F.R. § 314.90(b).

FDA has historically granted § 314.99(b) waivers when an ANDA applicant seeks approval to market a drug product containing a non-exception excipient used in a discontinued RLD formulation that is not used in the currently-marketed RLD formulation.  For example, in 2005, FDA granted a petition permitting generic applicants seeking approval to market generic SANDOSTATIN (octreotide acetate) Injection to substitute a different tonicity agent (a non-exception excipient change) and buffer system because “the inactive ingredients (including the buffer system and tonicity agent) used in the discontinued formulation of Sandostatin do not make that formulation unsafe. . . [and because] the discontinued formulation of Sandostatin is no less safe and effective than the new formulation.” 

FDA’s ZOSYN petition decision is in the same vein as the SANDOSTATIN petition response.  In September 2005, FDA approved an NDA supplement for a new formulation of ZOSYN containing edetate disodium dihydrate (“EDTA”) and citric acid monohydrate, which reportedly function in the drug product as a chelator (a non-exception excipient) and a buffer, respectively.  Several petitions were submitted to FDA requesting that the Agency: (1) determine that the formulation of ZOSYN originally approved by FDA was not discontinued for safety or efficacy reasons; and (2) accept ANDAs for generic versions of ZOSYN duplicating the discontinued formulations (i.e., without EDTA and citric acid).  In granting these petitions, FDA stated:

The Agency may rely on § 314.99(b) (21 CFR 314.99(b)) to grant a waiver of the regulation requirement – that the ANDA and NDA formulations contain the same inactive ingredients in the same concentrations as the RLD, with limited exceptions for preservatives, buffers, and antioxidants – insofar as the statutory requirement regarding safety of inactive ingredients has been met. . . .  FDA may approve ANDAs for piperacilin and tazobactam for injection duplicating the original Zosyn formulation.  Such ANDAs would differ from the reformulated Zosyn with respect to the inactive ingredient EDTA, which is not a preservative, buffer, or antioxidant.  Here, experience with Wyeth's original Zosyn formulation and FDA’s recent analysis has shown that the inactive ingredients in the ANDA for piperacilin and tazobaetam for injection duplicating the original Zosyn formulation are safe. . . .  Because the original Zosyn formulation clearly meets the statutory safety standard with respect to inactive ingredients, the Agency may rely on § 314.99(b) to grant a waiver of the regulation requirement that the ANDA formulation contain the same inactive ingredients in the same concentration with the limited exceptions for preservatives, buffers, and antioxidants.

It is also noteworthy that ZOSYN contains an old antibiotic drug and is subject to § 4 of the “QI Program Supplemental Funding Act of 2008” (the “QI Act”).  The QI Act was enacted on October 8, 2008 and amended the FDC Act to add new § 505(v) – “Antibiotic Drugs Submitted Before November 21, 1997” – to create Hatch-Waxman benefits for old antibiotics.  Under a transition provision included in the QI Act, NDA holders and patent owners can list patents in the Orange Book, and generic applicants can qualify for 180-day exclusivity.  Shortly after the enactment of the QI Act, a patent was listed in the Orange Book covering ZOSYN.  Those generic applicants who timely amended their pending ANDAs for generic ZOSYN to include a Paragraph IV Certification to that patent are eligible for shared 180-day exclusivity.

Categories: Hatch-Waxman