USFDA’s Refuse to Receive (RTR) standards for ANDA and PAS Filings

USFDA’s Refuse to Receive (RTR) standards for ANDA and PAS Filings

When an applicant submits an ANDA to agency, OGD (Office  Generic  Drugs)  first conducts a review to determine whether the application is sufficiently complete to permit a substantive review. OGD refers to this period as the filing review. The filing review takes approximately 60 days from the ANDA’s receipt date to complete it. If the submitted application is not complete or any deficiencies are identified, then "refuse to file letter" is issued by the OGD/CDER to the applicant. In case the application has found complete without any deficiencies then it's accepted & application is then sent to the internal review team for the identification of Bio-Equivalence, Chemistry/Microbiology, Plant inspection & Labeling review issues. Once the ANDA submission is complete and acceptable without any further queries, the applicant finally receives FDA approval letter.

  

Refuse To Receive (RTR)

RTRs, which apply both to ANDAs and to certain  prior approval supplements (PASs) to ANDAs (required when making a major manufacturing or other change to a previously approved ANDA), indicate that FDA does not consider the submitted information to be substantially complete. When an ANDA is submitted to the FDA, the agency evaluates each application to ensure that it is complete and contains all the required information as per the section 505 (j) (2) (A) of the Federal Food, Drug and Cosmetic Act (FD&C Act) and doesn’t contain any deficiency as described in 21 CFR 314.101 (a) and (e).

In applicants prospective issuance of an RTR determination will add financial burden, delayed market-entry, and loss of market share. During OGD review, an application can be refused to receive, based on:

• Inadequate stability data
• Incomplete response to screening deficiency
• Inadequate dissolution data
• Qualitatively (Q1) and quantitatively (Q2) dissimilarity from the innovator drug
• Response to screening deficiency delayed beyond the prescribed time limit.

RTR Scenarios: Major And Minor Deficiencies

When an ANDA is submitted for review, the FDA will determine if the application is complete from a high-level view. The FDA will check for any missing details, highlight deficiencies (both major and minor), and mark if any corrections are necessary. To ensure an application is correctly completed and filed, it is important to understand the differences between major and minor deficiencies.

• A major deficiency is one the FDA considers “significant in nature, such as some found in 21 CFR 314.101(d) and 314.101(e). If a major deficiency is identified, FDA will RTR the ANDA.
• A minor deficiency is one that the agency considers less critical in nature and can be remedied easily. If the ANDA contains fewer than 10 minor deficiencies, the FDA will notify the applicant via phone, fax, or email and give them seven calendar days to correct these deficiencies or amend the ANDA. If an ANDA applicant receives an IR (information request) from FDA listing minor deficiencies identified  during the filing review, and if the requested information is not submitted and received  within seven calendar days, FDA will RTR the ANDA. Responses to IRs should completely address all outstanding issues identified in the IR.

The below flow chart shows the FDA’s process for reviewing ANDAs and issuing RTRs, depending on the number and type of deficiencies found.

Deficiencies In ANDAs

This section provides example deficiencies, organized by module of the Common Technical Document (CTD), that could lead to an RTR.

Module 1

Minor Deficiencies:

• Incomplete Form FDA 356h, such as
• Field 11: Full chemical name not provided
• Field 20: Patent certification is inconsistent with the patent certification provided in Module 1.3.5.2
• Field 28: Establishment information does not match with the facilities information provided in Modules 3.2.S and 3.2.P
• Field 29: Typo in drug master file (DMF) number or failure to list all the DMFs referenced in module
• Basis for submission 21 CFR §314.94(a)(3)
• Failing to provide the appropriate basis of submission — designated reference listed drug (RLD) and reference standard (RS; if applicable) currently listed in the Orange Book
• If an ANDA suitability petition is required, failure to provide the docket number or FDA’s correspondence approving the petition
• Labeling (Module 1.14)  
• eCTD: Legibility of draft and RLD container labels
• Failing to provide the proposed container and carton labels for each strength and each packaging configuration (container size)
• Failing to provide the RLD container and carton label for each strength

Major Deficiencies:

• Unsigned Form FDA 356h
• Failure to submit Form FDA 356h

Module 2

Minor Deficiencies:

• Provide separate PDF and Word documents
• Missing summary data tables in module 2.7
• Failure to provide the certificate of analysis for each strength of the RLD
• Failure to provide the exact location of the long-term storage stability (LTSS) study reports and data (Table 10), along with working hyperlinks to respective information

Major Deficiencies:

• Inadequate dissolution studies, lacking:
• Minimum of 12 units
• Use of FDA-recommended test media
• ½ tablet dissolution for modified-release products with functional score marks

• General deficiencies of in-vitro dissolution (Table 5)
• Not conducted on 12 units
• Not conducted on all strengths (test vs. RLD)
• Not conducted in all test media

Module 3

Minor Deficiencies:

• Lack of legibility in documents/data
• Failure to translate non-English content into the English language
• Failure to follow the ANDA checklist
• Missing batch reconciliation and label reconciliation information
• Executed batch reconciliation tables don’t include theoretical, actual, and packaged yield
• Yield is not expressed in dosage or product units (e.g., number of tablets and bottles, number of vials, etc.)
• Potential impurities not listed in tabular format as per FDA recommendation

Major Deficiencies:

• Failure to demonstrate Q1/Q2 sameness for sterile drug products, ophthalmic, and otic solutions to the RLD
• Lack of justification for unknown/unspecified impurities
• Not providing method validation/verification reports
• Inconsistent functional scoring configuration with RLD
• Lack of compliance with inactive ingredient database (IID) limits for excipients for solid orals/parenterals/opthalmics/otics/topical drug products
• Lack of justification (supporting data and information) for impurities (specified identified or specified unidentified) where proposed acceptance criteria (AC) percentage exceeds qualification threshold (QT) or identification threshold (IT), respectively
• Proposed AC percentage exceeds QT or IT percentage, as applicable
• Failure to provide stability data on two discrete API lots for each strength of drug product, and on a minimum of three drug product batches of each strength
• Failure to provide six months (180 days) of stability data with a minimum three time points
• Accelerated and long-term stability studies
• Intermediate studies for all three batches of the specific strength if accelerated stability study shows significant change or failure of any attribute
• Failure to submit worst-case scenario and non-worst-case stability data related to container orientation
• Lack of verification for all stability start and pull dates

Impacts of FDAs RTR decision on submitted ANDA’s

When the FDA issues an RTR, agency returns 75 percent of ANDA fee already paid by applicant. Following are the major implications of RTR,

• Loss of 25 percent of the ANDA fee
• Loss of original submission date (Change in goal date)
• Loss of market exclusivity period (180 days) in the case of NCE-1 submissions
• Delay in product launch and loss of market share

If the applicant submits required information and material to correct the deficiencies, the FDA is all open to consider (if found substantially complete) the new and corrected version of ANDA. Upon such new submission, however, the applicant needs to pay the total ANDA submission fee, accordingly. The date of the revised submission will be considered as the new application date.

The applicant can request the FDA for a reconsideration, if the applicant disagrees with the major deficiencies identified and notified by the agency. Then the ANDA applicant can provide the relevant supporting information and material to the FDA and request for reconsideration. If the FDA does not agree even after submission of the supporting information, the applicant can request for a teleconference with the Agency for further evaluations. If the reconsideration issue remains unsolved, the applicant should refer to 21 CFR 314.103 and guidance for industry Formal Dispute Resolution.