Refuse to Receive Standards (RTR) – Considerations on ANDA Submissions

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.

The response period will begin the day after notification is provided. If the 7^th calendar day falls on a Saturday, Sunday, or Federal holiday, the deadline for amending the ANDA to correct the deficiencies will be the next day that is not a Saturday, Sunday, or Federal holiday.

FDA determines that an ANDA contains ten or more minor deficiencies or one or more major deficiencies, FDA will not consider the ANDA to be a substantially complete application under 21 CFR 314.101(b)(1).

If the applicant decides to submit additional materials to correct the deficiencies, the resulting amended ANDA will be considered a new ANDA submission, received as of the date the amended ANDA is submitted (if deemed substantially complete), and the applicant will be required to pay a new ANDA fee.

Sufficiently Complete means that the ANDA contains all the information required under section 505(j)(2)(A) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and does not contain a deficiency described in 21 CFR 314.101(d) and (e).

If FDA determines that an ANDA contains fewer than ten minor deficiencies, 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 07 calendar days the requested information is not received, FDA will RTR the ANDA.

[The response period will begin the day after notification is provided. If the 7th calendar day falls on a Saturday, Sunday, or Federal holiday, the deadline for amending the ANDA to correct the deficiencies will be the next day that is not a Saturday, Sunday, or Federal holiday]

FDA determines that an ANDA contains ten or more minor deficiencies or one or more major deficiencies, FDA will not consider the ANDA to be a substantially complete application under 21 CFR 314.101(b)(1).

If an ANDA is not received and the applicant takes no action, FDA may consider the ANDA withdrawn after 01 year.

Lets learn what are the important items in an ANDA that leads to an RTR decision.

GENERAL

356h

• If this form is not included, or is not signed, which indicates that the applicant is not attesting to the material contained in the application, FDA will RTR the ANDA.

Format

• The ANDA should be formatted according to the eCTD format, and it should be submitted electronically for GDUFA metric goals to apply to the ANDA.

Non-Payment of GDUFA Obligations

• GDUFA ANDA or PAS – fee within 20 calendar days of submitting the application 
• Type II active pharmaceutical ingredient (API) Drug Master File (DMF) – Non-payment of the GDUFA DMF fee 
• Facility – Failure to pay the GDUFA facility fee(s) [arrears list ]
• Applicant is listed on the backlog arrears list
• Applicant is affiliated with an applicant on the backlog arrears list

Lack of a Designated U.S. Agent for a Foreign Applicant 

• FDA will RTR an ANDA if a foreign applicant does not designate a U.S. agent. 
• If the person signing the application form (i.e., Form FDA 356h) does not reside or have a place of business within the United States, the application form is required to contain the name and address of, and be countersigned by, an attorney, agent, or other authorized official who resides or maintains a place of business within the United States.

Citing a Pending Suitability Petition as a Basis of Submission 

• Pending suitability petition – Lacks a legal basis for the submission
• The changes (from the RLD) that can be requested in a suitability petition are: 
  • Change in route of administration 
  • Change in dosage form 
  • Change in strength 
  • One active ingredient is substituted for one of the active ingredients in a listed combination drug

In addition, the docket number and a copy of FDA’s correspondence approving the petition must be included in the ANDA submission

API

Starting Material 

• If the active pharmaceutical ingredient (API) review, whether in an ANDA or in a referenced drug master file (DMF), reveals that the starting material for the API is not justified according to the principles in the ICH Q11 guidance. 

Sterility Assurance Data 

• If the API review, whether in an ANDA or a referenced DMF, reveals that sterility assurance data are missing for a sterile API.

PRODUCT QUALITY DEFICIENCIES

Inactive Ingredients

Inactive Ingredients Exceeding the Inactive Ingredient Database Limit:

• An inactive ingredient is considered justified, for receipt purposes, if the proposed level is at or below the amount indicated in the IID for the corresponding route of administration of the drug product.
• If the submission proposes to use an inactive ingredient at a level that exceeds any of the inactive ingredient database (IID) listings without the justification described.
  • Submit complete pharmacology/toxicology information
  • Cite a specific example of a CDER-approved drug product
  • Refer to an FDA controlled correspondence response
• Inactive ingredient justification for oral liquid drug products should not be based on a listed percentage in the IID – Amount of inactive ingredient delivered per dose cannot be properly ascertained

• Applicant should calculate the amount of inactive ingredient that is delivered per dose or per day (MDI) based on dosing recommendations indicated in the RLD label.
• When justifying inactive ingredients for semi-solid and topical dosage forms, applicants can refer to listed percentages in the IID.
• The percent concentration of each inactive ingredient should be converted into an amount expressed in one of the following forms: mg/mL, mg/g, mL/mL.

Changes to Non-Exception Inactive Ingredients in Parenteral, Ophthalmic, and Otic Products:

• Parenteral drug products generally must contain the same inactive ingredients and in the same concentration as the RLD
• For all other inactive ingredients, an ANDA whose subject is a parenteral drug product must be qualitatively and quantitatively the same (Q1/Q2 same) as the RLD, with certain allowable differences permitted under 21 CFR 314.94(a)(9)(iii)
• Sameness – within 95-105% of the RLD concentration

Inadequate Stability

Number of Batches and Length of Studies

• The applicant should provide three pilot-scale batches or two pilot-scale and one small-scale batch with both accelerated and long-term data provided for each batch covering a period of no less than 6 months (180 days), with data from three time points.
• The initiation date for each of the stability studies, along with individual pull dates (removal from the storage chamber) for each stability time point should also be provided as part of the data to verify that each study covers the recommended 6-month (180 days) minimum hold time.

Container Orientation

• ANDA must contain both worst-case scenario and non-worst-case stability data adhering to the recommendations.
• Drug product batches: liquids, solutions, semi-solids, and suspensions not required to submit above data.

Packaging Amount Considerations

• To qualify the dosage units that are packaged toward the applicable threshold, the following three recommended criteria for each container/closure configuration should be satisfied: 

Stability data

• Container/closure system information should be submitted in ANDA section 3.2.P.7. If bracketing or matrixing is used, an ANDA should include the container/closure system information applicable to configurations that were excluded from stability studies because of bracketing or matrixing.
• Container and carton (if applicable) labeling for each packaging configuration containing dosage units to be counted in the overall packaged total should be provided in section 1.14.1 of the ANDA. 

Batch Records 

• FDA will RTR an ANDA if blank and executed batch records are not provided, regardless of whether commercial scale-up is proposed. 
• For example, both commercial (blank) and executed (pilot) batch records for the pilot batches that are manufactured to support an ANDA should be submitted, along with any accompanying reconciliation sheets.

Method Validation/Verification Reports

• It is critical that method validation/verification reports for all analytical methods be provided in sections 3.2.S.4.3 and 3.2.P.5.3 of the ANDA, for both the drug substance (API) and drug product, respectively.
  • Pharmacopeial – Verification
  • In-House – Validation
  • In-House (lieu of compendial) – Comparison

Special Consideration

Matrix Systems

• ANDAs for matrix transdermal systems should be supported by stability data on three batches of drug product manufactured from three distinct laminates, where each batch of laminate is made using different lots of API, adhesives, backing, and/or other critical elements in the drug product

Reservoir Systems

• ANDAs for reservoir transdermal systems should be supported by stability data on three batches of drug product manufactured from three distinct reservoir gels. Each batch of drug product should use different lots of API, adhesives, gel excipients, backing membrane, rate controlling membrane, and/or other critical elements in the drug product. A bracket approach is usually not acceptable

Scoring and Conditions of Use

Functional Scoring Configurations that Are Inconsistent With the RLD 

• Scoring configurations often facilitate dose titration and other patient-specific regimens that would be imprecise because of the difficulty of splitting an un-scored tablet.

Fill Volumes for Parenteral Drug Products that Differ From the RLD

• A deviation from the fill volume of the RLD parenteral drug product may constitute a change in strength. 
• A change in strength must first be approved via the suitability petition process before it can be proposed in an ANDA submission.

Differences in Packaging and/or Labeling that May Be Associated With the Safe/Effective Use of the Drug Product 

• Generally, if the RLD is packaged with certain labeling in a manner to ensure its proper administration, the test product should be packaged and labeled similarly.

Microbiology Considerations

• An ANDA should contain all sterility assurance validation studies for terminally sterilized drug products and aseptically filled drug products, as described below

Terminally sterilized drug products 

• Validation of production terminal sterilization process 
• Validation of depyrogenation of product containers and closures 
• Validation of container-closure package integrity 

Aseptically filled drug products 

• 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

BIOEQUIVALENCE AND CLINICAL DEFICIENCIES

Failed In Vivo BE Studies

• Typically, a failed study is one that does not satisfy the 90% confidence interval (CI) criterion (e.g., falls outside of the 0.8-1.25 acceptance criterion limits) for either the area under curve (AUC) or peak plasma concentration (C_max) parameter. FDA will RTR an ANDA if only a failed in vivo BE study is submitted.

Alternate BE Studies

• FDA will RTR an ANDA if the ANDA contains one or more in vivo studies that were not recommended in the BE guidance, without adequate justification.

Q1/Q2 Sameness Requirement for Consideration of an In Vivo BE Study Waiver

• Certain drug products may be eligible for a waiver from conducting in vivo BE studies, Parenteral drug products, in addition to both ophthalmic and otic solutions, may be eligible for a waiver of BE studies, provided that their formulations are considered Q1/Q2 same as the RLD.

Inadequate Dissolution Data (In Vitro Studies)

• For any recommended dissolution study, it is critical that appropriate comparison data (i.e., test product and RLD) be provided.

Miscellaneous Factors

Study Information BE Table:

• FDA will RTR an ANDA if the Study Information BE table is incomplete
• Receipt of the ANDA is also predicated on the following information that is captured in the table: 
• The number of days of long-term storage stability (LTSS) coverage should be equal to or more than the number of days for sample storage duration. 
• The temperature (°C) reported for LTSS coverage should be within or less than the temperature range for sample storage

Waiver of In Vivo BA or BE Studies for BCS Class I Drugs

• If the applicant requests a Bio-pharmaceutics Classification System (BCS) Class 1 BA/BE waiver, FDA will RTR the ANDA if any of the data needed to support such a waiver request are missing from the ANDA at the time of submission.

Missing Case Report Forms 

• FDA will RTR an ANDA if a clinical study conducted does not contain copies of individual case report forms for patients enrolled in the study

• Applicants should provide a random selection of at least 10% of all case report forms for any study that enrolls patients.

A BRIEF REFUSE TO RECEIVE (RTR) CHECK-LIST

9 Minor Deficiencies or 01 Major Deficiency

• Completeness of 356h
• eCTD format, with Bookmarking & Hypertext linking, English
• Non Payment of GDUFA Fees
• Lack of a Designated U.S. Agent for a Foreign Applicant 
• Citing a Pending Suitability Petition as a Basis of Submission 
• Starting material for the API is not justified according to the principles in the ICH Q11 guidance
• Sterility assurance data are missing for a sterile API.
• Inactive Ingredients Exceeding the IID Limit
• Q1/Q2 – within 95-105% of the RLD concentration
• Stability Data – 03 Pilot (02 pilot +01 small) with 6 M ACT + 6 M LT (180 days in the stability chamber)
• Container Closure information
• Blank and Executed batch records
• Method Validation/Verification Reports
  • 3.2.S.4.3 and 3.2.P.5.3 
    • Pharmacopeial – Verification
    • In-House – Validation
    • In-House (lieu of compendial) – Comparison
• Reservoir Systems – A bracket approach is usually not acceptable
• Functional Scoring Configurations that are Inconsistent with the RLD
• Fill Volumes for Parenteral Drug Products that Differ from the RLD
• Differences in Packaging and/or Labeling that May Be Associated With the Safe/Effective Use of the Drug 
• Sterility assurance validation studies
• Failed In Vivo BE Studies (90% CI – 0.8-1.25)
• Alternate BE Studies
• Q1/Q2 Sameness Requirement for Consideration of an In Vivo BE Study Waiver
• Inadequate Dissolution Data (In-Vitro Studies)
• BE tables
• Waiver of In-Vivo BA or BE Studies for BCS Class I Drugs
• Missing Case Report Forms
• Requested information is not received, with in 07 calendar days