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 | Status | Risk | Remarks |
| General | ||||
| ANDA is presented in eCTD format | Yes/No | Minor | ||
| — | Complete Dossier is presented in English. | Yes/No | Minor | |
| — | Any language other than English is used in the dossier | Yes/No | Minor | |
| — | If yes, an accurate and complete English translation is provided (12 font) | Yes/No | Minor | |
| — | 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/No | Minor | |
| — | GDUFA ANDA or PAS fee is paid or going to be paid. ANDA fees should be paid within 20 calendar days of submission. | Yes/No | Major | |
| — | No facility listed in application is on the facility arrears list | Yes/No | Major | |
| — | Applicant/Affiliate listed in backlog arrear list. | Yes/No | Major | |
| Admin | ||||
| 1.1.2 | Form 356h is filled and presented in the dossier | Yes/No | Major | |
| Form 356h is signed and dated by relevant person. (either applicant or U.S Agent) | Yes/No | Major | ||
| 1.1.3 | Debarment Certifications and list of conviction statement from all facilities included? | Yes/No | Minor | |
| 1.3.1.2 | Applicant have a place of business within the US | Yes/No | Major | |
| If not, U.S. agent is designated or the application form signed by a person residing in US | Yes/No | Major | ||
| Letter of Authorization for US Agent is included | Yes/No | Minor | ||
| 1.3.4 | Does the submission includes Financial Disclosure Statements (Form 3454/3455) | Yes/No | Minor | |
| 1.3.5 | Relevant Patent & Exclusivity certification is included (PIV, PIII and/or section viii) | Yes/No | Minor | |
| 1.4.2 | Letter of Authorization from Type II, Type III and Type IV are included | Yes/No | Major | |
| Does the LoA from DMF holder include Page No./Sequence No. and date of submission | Yes/No | Minor | ||
| 1.12.11 | Suitability/Citizen Petition is cited as a Basis of Submission | Yes/No | Major | |
| If yes, is the petition approved by FDA | Yes/No | Major | ||
| FDA docket number and correspondence attached. | Yes/No | Major | ||
| 1.12.12 | A statement that the conditions of use prescribed, recommended, or suggested in the labeling proposed for the generic is same as RLD | Yes/No | Major | |
| 1.12.14 | An EA or a claim of categorical exclusion is provided | Yes/No | Minor | |
| 1.12.15 | Q1/Q2 Sameness Requirement for Consideration of an in-vivo BE Study Waiver | Yes/No | Major | |
| 1.14 | Container and carton (if applicable) labeling for each packaging configuration provided? | Yes/No | Major | |
| Is the labeling is in congruent with submitted patent certification | Yes/No | Major | ||
| 1.16 | Is the product is covered under REMS? | Yes/No | Major | |
| 1.16.2 | If Yes, does the proposed REMS protocol/ETASU is included? | Yes/No | Major | |
| Summaries | ||||
| 2.3 | Summaries of validation studies are included in the submission | Yes/No | Major | |
| 2.7 | Is the study information BE table is complete? | Yes/No | Major | |
| BE table includes the study type and site locations and should be placed in Module 2.7 | Yes/No | Major | ||
| Does the summary table include sample storage and long-term storage? | Yes/No | Major | ||
| 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/No | Major | ||
| Does the temperature (°C) reported for LTSS coverage should be within or less than the temperature range for sample storage? | Yes/No | Major | ||
| LTSS coverage and data location provided in Table 10 (including Module, section, subsection, page no. and hyperlink) | Yes/No | Minor | ||
| Comparative Dissolution data between test and RLD is included | Yes/No | Major | ||
| Does the Certificate of Analysis (CoA) for test and RLD is included | Yes/No | Major | ||
| Is the product is delayed-release, does the submission include Alcohol dose-dumping data? | Yes/No | Major | ||
| If the proposed product has a functional score? | Yes/No | Major | ||
| If yes, half-tablet dissolution for modified-release drug products of test and RLD in the recommended media for each strength is included? | Yes/No | Major | ||
| Drug Substance | ||||
| Type II DMF is publicly available for reference? | Yes/No | Major | ||
| DMF fee has been paid and GDUFA cover sheet attached? | ||||
| Initial CA determination API DMF is completed? | Yes/No | Major | ||
| Starting material for the API is justified according to the principles in the ICH Q11? | Yes/No | Major | ||
| Two distinct lots of API is used in the manufacture of finished product? | Yes/No | Major | ||
| If Sterile API is used in the submission, sterility assurance data is included in the dossier? | Yes/No | Major | ||
| If the product is combination one, does separate (individual) substance sections are provided? | Yes/No | Major | ||
| 3.2.S.4.3 | Method validations (in-house)/verification (compendial)/Equivalency reports are included | Yes/No | Major | |
| Proposed limits are in consistent with ICH requirements Specified identified impurities >QT/Specified unidentified impurities >IT/unspecified impurities >IT | Yes/No | Major | ||
| 3.2.S.4.5 | Does the submission includes a justification in FDA recommended format | Yes/No | Major | |
| Drug Product | ||||
| 3.2.P.1 | Inactive ingredients in the composition is with-in IID listings for the proposed route of administration | Yes/No | Minor | |
| 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/No | Major | ||
| Proposed product has a component of iron? | Yes/No | Major | ||
| A daily elemental iron calculation is included? (5ppm) | Yes/No | Major | ||
| Does the proposed product has a functional score? | Yes/No | Major | ||
| Any inconsistencies observed in the scoring configuration between the RLD and test product | Yes/No | Major | ||
| Is the proposed product is Parenteral Dosage Form? | Yes/No | Major | ||
| · Is the Upper limit of Q1/Q2 is with-in the IID limits? | Yes/No | Major | ||
| Is the fill volume of generic drug is same as the RLD (overfill allowances that are within USP recommendations) | Yes/No | Major | ||
| If yes, it contains the same inactive ingredients and in the same concentration | Yes/No | Major | ||
| · Is the product Q1/Q2 as that of RLD (95-105%), · CC response is attached in the submission. | Yes/No | Major | ||
| If the fill volume deviates (change in strength), does any suitability petition filed? | Yes/No | Major | ||
| 3.2.P.3.1 | Does 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/No | Major | |
| 3.2.P.3.3 | Commercial (blank) batch records for the proposed scale-up batches or Blank batch record for pilot batches are included in 3.2.P.3.3 | Yes/No | Major | |
| 3.2.P.3.5 | Sterility 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/No | Major | |
| 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/No | Major | ||
| 3.2.P.5.3 | Method validations (in-house)/verification (compendial)/Equivalency reports are included | Yes/No | Major | |
| 3.2.P.5.5 | Proposed limits are in consistent with ICH requirements Specified identified impurities above QT/Specified unidentified impurities above IT/unspecified impurities above IT | Yes/No | Major | |
| 3.2.P.5.6 | Does the submission includes a justification in FDA recommended format | Yes/No | Major | |
| 3.2.P.7 | Does the proposed packing is in consistent with the RLD | Yes/No | Major | |
| Does the package finished drug product packaged in a minimum (threshold) amounts in the container/closure systems that are proposed for marketing? | Yes/No | Major | ||
| Does the submission proposes a bracketing or matrixing approach | Yes/No | Major | ||
| If yes, does the container/closure system information applicable to configurations that were excluded from stability studies included in 3.2.P.7 | Yes/No | Major | ||
| 3.2.3.P.8 | Stability data from 3 pilot-scale/2 pilot-scale and 1 small-scale batch is included | Yes/No | Major | |
| 6 months (180 days) – Accelerated and long-term data provided for each batch | Yes/No | Major | ||
| Does the data included have 3 time points (0, 3, and 6 months minimum) | Yes/No | Major | ||
| Stability data includes the initiation date, individual pull dates for each time point? | Yes/No | Major | ||
| Is the accelerated data show a significant change or failure of any attribute? | Yes/No | Major | ||
| 6M intermediate stability data included in the submission | Yes/No | Major | ||
| Is the product is liquid, solution, semi-solid or suspension? | Yes/No | Major | ||
| Worst-case orientation stability data included for 3 time points? | Yes/No | Major | ||
| Regional | ||||
| 3.2.R | Executed batch records with reconciliation sheets provided | Yes/No | Major | |
| Module 5 | ||||
| Does API is BCS class I and BE wavier is requested in the submission? | Yes/No | Major | ||
| Supporting data for BCS class I is included in the submission? | Yes/No | Major | ||
| Copies of individual CRF’s for patients enrolled in the study are included (at least 10%) | Yes/No | Major | ||
| Does any of the subjects removed from study analysis for any reason, CRF are included? | Yes/No | Major | ||
| 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/No | Major | ||
| Does the data sets and definition files (ADaM, SDTM) are provided in the submission | Yes/No | Minor | ||
| Misc | ||||
| Is the proposed product is Transdermal Patch? | Yes/No | Major | ||
| If Matrix, does the three batches of drug product manufactured from three distinct laminates? | Yes/No | Major | ||
| Does each batch of laminate is made using different lots of API, adhesives, backing? | Yes/No | Major | ||
| If reservoir, does the three batches of drug product manufactured from three distinct reservoir gels? | Yes/No | Major | ||
| Does each batch is made of different lots of API, adhesives, gel excipients, backing membrane, rate controlling membrane? | Yes/No | Major | ||
| 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/No | Major | ||
| Is the proposed product is Ophthalmic Solution? | Yes/No | Major | ||
| If yes, BE table – Comparative Physicochemical Data of Ophthalmic Solution Drug Products is included in Module 2.7 | Yes/No | Major |
Responses