Refuse to Receive (RTR) Determination for an ANDA – Standard Checklist

An RTR decision indicates that FDA determined that an ANDA is not substantially complete.

A substantially complete ANDA is “an ANDA that on its face is sufficiently complete to permit a substantive review“.

It identifies certain deficiencies and certain recurrent deficiencies that in FDA’s experience have led FDA to RTR an ANDA and also describes how FDA will assess deficiencies identified during FDA’s filing review to determine whether an ANDA should be received.

FDA evaluates each submitted ANDA individually to determine whether the ANDA can be received.

The receipt of an ANDA means that FDA made a threshold determination that the ANDA is a substantially complete application, that is, an ANDA that on its face is sufficiently complete to permit a substantive review.

FDA’s filing review of a submitted ANDA, FDA will determine if there are any major or minor deficiencies.

A major deficiency is one that in FDA’s judgment is significant in nature such as certain deficiencies found in 21 CFR 314.101(d) or 21 CFR 314.101(e);

A minor deficiency is one that in FDA’s judgment is minor in nature and can be easily remedied.

In particular, if FDA determines that an ANDA contains fewer than ten minor deficiencies (i.e., nine deficiencies or fewer), FDA will notify the applicant of the deficiencies, by phone, fax, or through the primary method for communication, which is email.

FDA, in its discretion, provides applicants with the opportunity to correct minor deficiencies or amend the ANDA, within seven (7) calendar days. If within 7 calendar days the requested information is not received, FDA will RTR the ANDA.

 

Module

RTR Standards

StatusRiskRemarks
General    
 ANDA is presented in eCTD formatYes/NoMinor 
Complete Dossier is presented in English.Yes/NoMinor 
Any language other than English is used in the dossierYes/NoMinor 
If yes, an accurate and complete English translation is provided (12 font)Yes/NoMinor 
The PDF files are according to the recommended PDF standards.

(page size: 8.5×11, No Security, Embed fonts, bookmarks and ToC for pages >5)

Yes/NoMinor 
GDUFA ANDA or PAS fee is paid or going to be paid.

ANDA fees should be paid within 20 calendar days of submission.

Yes/NoMajor 
No facility listed in application is on the facility arrears listYes/NoMajor 
Applicant/Affiliate listed in backlog arrear list.Yes/NoMajor 
Admin    
1.1.2Form 356h is filled and presented in the dossierYes/NoMajor 
 Form 356h is signed and dated by relevant person. (either applicant or U.S Agent)Yes/NoMajor 
1.1.3Debarment Certifications and list of conviction statement from all facilities included?Yes/NoMinor 
1.3.1.2Applicant have a place of business within the USYes/NoMajor 
 If not, U.S. agent is designated or the application form  signed by a person residing in USYes/NoMajor 
 Letter of Authorization for US Agent is includedYes/NoMinor 
1.3.4Does the submission includes Financial Disclosure Statements (Form 3454/3455)Yes/NoMinor 
1.3.5Relevant Patent & Exclusivity certification is included (PIV, PIII and/or section viii)Yes/NoMinor 
1.4.2Letter of Authorization from Type II, Type III and Type IV are includedYes/NoMajor 
 Does the LoA from DMF holder include Page No./Sequence No. and date of submissionYes/NoMinor 
1.12.11Suitability/Citizen Petition is cited as a Basis of SubmissionYes/NoMajor 
 If yes, is the petition approved by FDAYes/NoMajor 
 FDA docket number and correspondence attached.Yes/NoMajor 
1.12.12A statement that the conditions of use prescribed, recommended, or suggested in the labeling proposed for the generic is same as RLDYes/NoMajor 
1.12.14An EA or a claim of categorical exclusion is providedYes/NoMinor 
1.12.15Q1/Q2 Sameness Requirement for Consideration of an in-vivo BE Study WaiverYes/NoMajor 
1.14Container and carton (if applicable) labeling for each packaging configuration provided?Yes/NoMajor 
 Is the labeling is in congruent with submitted patent certificationYes/NoMajor 
1.16Is the product is covered under REMS?Yes/NoMajor 
1.16.2If Yes, does the proposed REMS protocol/ETASU is included?Yes/NoMajor 
Summaries    
2.3Summaries of validation studies are included in the submissionYes/NoMajor 
2.7Is the study information BE table is complete?Yes/NoMajor 
 BE table includes the study type and site locations and should be placed in Module 2.7Yes/NoMajor 
 Does the summary table include sample storage and long-term storage?Yes/NoMajor 
 Does the number of days of long-term storage stability (LTSS) coverage are equal to or more than the number of days for sample storage duration?Yes/NoMajor 
 Does the temperature (°C) reported for LTSS coverage should be within or less than the temperature range for sample storage?Yes/NoMajor 
 LTSS coverage and data location provided in Table 10 (including Module, section, subsection, page no. and hyperlink)Yes/NoMinor 
 Comparative Dissolution data between test and RLD is includedYes/NoMajor 
 Does the Certificate of Analysis (CoA) for test and RLD is includedYes/NoMajor 
 Is the product is delayed-release, does the submission include

Alcohol dose-dumping data?

Yes/NoMajor 
 If the proposed product has a functional score?Yes/NoMajor 
 If yes, half-tablet dissolution for modified-release drug products of test and RLD in the recommended media for each strength is included?Yes/NoMajor 
     
Drug Substance    
 Type II DMF is publicly available for reference?Yes/NoMajor 
 DMF fee has been paid and GDUFA cover sheet attached?   
 Initial CA determination API DMF is completed?Yes/NoMajor 
 Starting material for the API is justified according to the principles in the ICH Q11?Yes/NoMajor 
 Two distinct lots of API is used in the manufacture of finished product?Yes/NoMajor 
 If Sterile API is used in the submission, sterility assurance data is included in the dossier?Yes/NoMajor 
 If the product is combination one, does separate (individual) substance sections are provided?Yes/NoMajor 
3.2.S.4.3Method validations (in-house)/verification (compendial)/Equivalency reports are includedYes/NoMajor 
 Proposed limits are in consistent with ICH requirements

Specified identified impurities >QT/Specified unidentified impurities >IT/unspecified impurities >IT

Yes/NoMajor 
3.2.S.4.5Does the submission includes a justification in FDA recommended formatYes/NoMajor 
     
Drug

Product

    
3.2.P.1Inactive ingredients in the composition is with-in IID listings for the proposed route of administrationYes/NoMinor 
 If Not,

·         Controlled Correspondence has been file and accepted; CC response is attached in the submission.

·         Excipients levels are used in a CDER approved Product

·         Complete Pharmacology/toxicology information is submitted in the ANDA.

Yes/NoMajor 
 Proposed product has a component of iron?Yes/NoMajor 
 A daily elemental iron calculation is included? (5ppm)Yes/NoMajor 
 Does the proposed product has a functional score?Yes/NoMajor 
 Any inconsistencies observed in the scoring configuration between the RLD and test productYes/NoMajor 
 Is the proposed product is Parenteral Dosage Form?Yes/NoMajor 
 ·         Is the Upper limit of Q1/Q2 is with-in the IID limits?Yes/NoMajor 
 Is the fill volume of generic drug is same as the RLD

(overfill allowances that are within USP recommendations)

Yes/NoMajor 
 If yes, it contains the same inactive ingredients and in the same concentrationYes/NoMajor 
 ·         Is the product Q1/Q2 as that of RLD (95-105%),

·         CC response is attached in the submission.

Yes/NoMajor 
 If the fill volume deviates (change in strength), does any suitability petition filed?Yes/NoMajor 
3.2.P.3.1Does all the facilities used in the manufacturing and testing are included in manufacturer and Form 356h?

(Bioequivalence Sites, Excipient/Container Closure Testing sites are not required to include in form 356h)

Yes/NoMajor 
3.2.P.3.3Commercial (blank) batch records for the proposed scale-up batches or Blank batch record for pilot batches are included in 3.2.P.3.3Yes/NoMajor 
3.2.P.3.5Sterility assurance validation studies for terminally sterilized drug products included?

·         Validation of production terminal sterilization process

·         Validation of depyrogenation of product containers and closures

·         Validation of container-closure package integrity

Yes/NoMajor 
 Sterility assurance validation studies for aseptically filled drug products included

·         Validation of the sterilizing grade filters (bacterial retention studies)

·         Validation of the sterilization of sterile bulk drug or product contact equipment, components, containers, and closures

·         Validation of the depyrogenation of product containers and closures

·         Validation of the aseptic filling process/line/room (media fills/process simulations)

·         Validation of container-closure package integrity

Yes/NoMajor 
3.2.P.5.3Method validations (in-house)/verification (compendial)/Equivalency reports are includedYes/NoMajor 
3.2.P.5.5Proposed limits are in consistent with ICH requirements

Specified identified impurities above QT/Specified unidentified impurities above IT/unspecified impurities above IT

Yes/NoMajor 
3.2.P.5.6Does the submission includes a justification in FDA recommended formatYes/NoMajor 
3.2.P.7Does the proposed packing is in consistent with the RLDYes/NoMajor 
 Does the package finished drug product packaged in a minimum (threshold) amounts in the container/closure systems that are proposed for marketing?Yes/NoMajor 
 Does the submission proposes a bracketing or matrixing approachYes/NoMajor 
 If yes, does the container/closure system information applicable to configurations that were excluded from stability studies included in 3.2.P.7Yes/NoMajor 
3.2.3.P.8Stability data from 3 pilot-scale/2 pilot-scale and 1 small-scale batch is includedYes/NoMajor 
 6 months (180 days) – Accelerated and long-term data provided for each batchYes/NoMajor 
 Does the data included have 3 time points (0, 3, and 6 months minimum)Yes/NoMajor 
 Stability data includes the initiation date, individual pull dates for each time point?Yes/NoMajor 
 Is the accelerated data show a significant change or failure of any attribute?Yes/NoMajor 
 6M intermediate stability data included in the submissionYes/NoMajor 
 Is the product is liquid, solution, semi-solid or suspension?Yes/NoMajor 
 Worst-case orientation stability data included for 3 time points?Yes/NoMajor 
Regional    
3.2.RExecuted batch records with reconciliation sheets providedYes/NoMajor 
Module 5    
 Does API is BCS class I and BE wavier is requested in the submission?Yes/NoMajor 
 Supporting data for BCS class I is included in the submission?Yes/NoMajor 
 Copies of individual CRF’s for patients enrolled in the study are included (at least 10%)Yes/NoMajor 
 Does any of the subjects removed from study analysis for any reason, CRF are included?Yes/NoMajor 
 Does any of the patients died during a clinical study or who did not complete the study because of an adverse event?  CRF are included?Yes/NoMajor 
 Does the data sets and definition files (ADaM, SDTM) are provided in the submissionYes/NoMinor 
     
Misc    
 Is the proposed product is Transdermal Patch?Yes/NoMajor 
 If Matrix, does the three batches of drug product manufactured from three distinct laminates?Yes/NoMajor 
 Does each batch of laminate is made using different lots of API, adhesives, backing?Yes/NoMajor 
 If reservoir, does the three batches of drug product manufactured from three distinct reservoir gels?Yes/NoMajor 
 Does each batch is made of different lots of API, adhesives, gel excipients, backing membrane, rate controlling membrane?Yes/NoMajor 
 A drug-device combination product if a device used to deliver the drug is not sufficiently similar to the device used to deliver the RLD?Yes/NoMajor 
 Is the proposed product is Ophthalmic Solution?Yes/NoMajor 
 If yes, BE table – Comparative Physicochemical Data of Ophthalmic Solution Drug Products is included in Module 2.7Yes/NoMajor 

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