INTRODUCTION:

This guidance is intended to assist applicants preparing to submitto FDA abbreviated new drug applications (ANDAs) and prior approval supplements(PASs) to ANDAs for which the applicant is seeking approval of a new strengthof the drug product. The guidance highlights deficiencies that may cause FDA to refuseto receive an ANDA. A refuse-to-receive decision indicates that FDA determined that anANDA is not sufficiently complete to permit a substantive review.

This guidance is not meant to be a comprehensive list of the deficienciesthat may or will lead to a refuse-to-receive determination by FDA. Instead,this guidance identifies certain deficiencies and certain recurrentdeficiencies that in FDA's experience have led FDA to refuse-to-receive anANDA. This guidance also describes how FDA will assess deficiencies identifiedduring FDA's filing review to determine whether an ANDA should be received. Wenote that industry is aware of many of the standards described in this guidancebecause FDA has historically applied many of these standards in itsrefuse-to-receive determinations.

BACKGROUND:

Recentdata underscore the need for improvement in the quality of original ANDAsubmissions. For example, between 2009 and 2012, FDA refused to receive 497ANDAs. Of all ANDA submissions, FDA refused to receive:

• 12%in 2009

• 18%in 2010

• 15.5%in 2011

• 9.4%in 201211

In 2012, of the 100 ANDAs that FDA refused-to-receive, 40 were refusedbecause of serious bioequivalence (BE) deficiencies; 36 because of seriouschemistry deficiencies; 13 because of format or organizational flaws; 6 becauseof clinical deficiencies; 4 because of inadequate microbiology (sterilityassurance) information; and 1 was refused because an incorrect reference listeddrug (RLD) was cited as the basis of submission. Despite evidence that themajority of deficiencies are related to BE and product quality standards(chemistry, manufacturing, controls (CMC)), FDA believes that clarification ofthese and certain other deficiencies (as discussed below) will help improve theoverall quality of ANDA submissions.

The following sections discussed deficiencies that FDA considers tobe major deficiencies:

GENERAL POLICY

A.     Form FDA 356h(356h)

B.     Organization/Format

C.     Non-Payment ofGDUFA Obligations

D.     Lack of aDesignated U.S. Agent for a Foreign Applicant

E.      Failure toProvide Environmental Assessment or Claim of Categorical Exclusion

F.      Citing a PendingSuitability Petition as a Basis of Submission

REVIEWS FOR API

A.     Starting Material

B.     B. SterilityAssurance Data

CHEMISTRY, MANUFACTURING, AND CONTROL DEFICIENCIES

A.     InactiveIngredients

B.     InadequateStability

C.     Packaging AmountConsiderations

D.     Batch Records

E.      MethodValidation/Verification Reports

F.      SpecialConsideration for Transdermal Patches

G.     Scoring andConditions of Use

H.     MicrobiologyConsiderations

BIOEQUIVALENCE AND CLINICAL DEFICIENCIES

A.    Failed In Vivo BE Studies

B.    Alternate BE Studies

C.    Q1/Q2 Sameness Requirement for Consideration of an In Vivo BEStudy Waiver

D.    Inadequate Dissolution Data (In Vitro Studies)

E.     Miscellaneous Factors

Further Please refer this guide:

ANDA Submissions -- Refuse-to-ReceiveStandards (PDF - 206KB)