The Food and Drug Administration (FDA) is issuing this revised draft guidance to incorporate program enhancements related to the content, timing, and assessment of a pre-submission facility correspondence (PFC) within the abbreviated new drug application (ANDA) assessment program agreed upon by the Agency and industry as part of the reauthorization of the Generic Drug User Fee Amendments (GDUFA III), as described in GDUFA Reauthorization Performance Goals and Program Enhancements, Fiscal Years 2023 through 2027 (GDUFA III22 commitment letter). This guidance replaces the November 2017 draft guidance for industry on ANDAs: Pre-Submission of Facility Information Related to Prioritized Generic Drug Applications (Pre-Submission Facility Correspondence).
The Generic Drug User Fee Amendments of 2012 (GDUFA I) amended the FD&C Act to authorize FDA to assess and collect user fees to provide FDA with resources to help ensure patients have access to quality, affordable, safe, and effective generic drugs. GDUFA fee resources bring greater predictability and timeliness to the review of generic drug applications. GDUFA has been reauthorized every 5 years. New enhancements to the program are designed to maximize the efficiency and utility of each assessment cycle, with the intent of reducing the number of assessment cycles for ANDAs and facilitating timely access to generic medicines for American patients.
Assessment of a PFC for a priority ANDA that will be eligible for priority review under the provisions of the GDUFA III commitment letter. This describes:
The content and format of the facility information that should be submitted to enable FDA’s assessment of facilities listed in the PFC;
Timeframes for the PFC, and the intersection of these timeframes with submission of an AND;
The possible outcomes of the Agency’s assessment of a PFC; and,
When and how the Agency communicates with an applicant about receipt of the PFC and
assignment of a goal date for the ANDA.
PRE-SUBMISSION FACILITY CORRESPONDENCE – CONTENTS
A complete and accurate PFC should contain all information needed to inform FDA’s decision regarding the need for facility inspections that support the assessment of an ANDA. The PFC provides the information FDA needs to assess the facilities involved in manufacturing processes and testing of the drug product, including facilities in corresponding Type II active pharmaceutical ingredient drug master files (API DMFs) referenced in an ANDA, and all sites or organizations involved in bioavailability/bioequivalence analytical and clinical studies used to support an ANDA.
FDA assesses facility information submitted in a PFC to determine earlier in the review cycle for the subsequent application submission whether an inspection is necessary. In order to qualify for a priority review goal, an applicant should submit a PFC no later than 60 days prior to the date of ANDA submission. In general, under the terms of the GDUFA III commitment letter, if the PFC is found to be incomplete or inaccurate, or there are significant changes to information contained in a PFC when submitted in the ANDA, or if information received in a final bioequivalence study report included in the ANDA leads FDA to a decision that an inspection is necessary, the 10-month standard review goal will generally apply instead of the priority review goal. The complete and accurate PFC must be submitted in the electronic common technical document (eCTD) format.
A. Drug Substance and Drug Product Manufacturing and Testing Facilities
Preapproval evaluations and inspections support the assessment of an ANDA by ensuring that any facility named or referenced in support of an ANDA can perform a proposed manufacturing operation as described in the application. FDA utilizes a risk-based approach to assess whether a preapproval inspection (PAI) is needed before an ANDA can be approved from a quality perspective. A complete and accurate PFC should provide the information necessary for FDA to determine each facility’s manufacturing operation capabilities for drug product or API and to identify the need for a PAI. This information should include a description of the manufacturing process, controls of critical steps, and anticipated differences between pilot/exhibit scale and commercial scale processes. Information regarding the conformance of exhibit batches to specifications should be provided. For each manufacturing facility, an applicant should also provide the following: facility name, operation(s) performed, facility contact name, address, FDA Establishment Identifier (FEI) number (if a required registrant or one has been assigned), DUNS number, registration information (for required registrants), confirmation that the facility is ready for inspection, and certification that any Type II DMF has similarly complete and accurate facility information.
B. Clinical Bioequivalence Study Sites and Organizations
Sites or organizations that perform the clinical portions of BE studies used to support an ANDA are subject to inspection to evaluate the overall quality of subject safety and data integrity at the site. A complete and accurate PFC should contain the information needed to inform FDA’s decision regarding the need for a bioresearch monitoring inspection of these sites, including the site name, address, and website; study numbers; a list and description of all study investigators consistent with section 16.1.4 of the guidance ICH E3 Structure and Content of Clinical Study Reports (July 1996); study conduct dates; and study protocols and any available amendments.
C. Analytical Bioequivalence Sites and Organizations
Sites or organizations that perform the analytical portions of clinical bioequivalence studies or in vitro bioequivalence studies (collectively referred to as analytical sites), are subject to inspection to ensure that these studies are conducted using the highest laboratory standards and in accordance with applicable regulations. A complete and accurate PFC should contain the information needed to inform FDA’s decision regarding the need for a bioresearch monitoring inspection of analytical sites, including the site name, address, and website. For those analytical studies that were initiated no later than 60 days prior to the ANDA submission, additional recommendations are: a list of investigator name(s); study conduct dates; and the analytical method validation, if completed before dosing.
RECEIPT AND ASSESSMENT PROCESS FOR PRE-SUBMISSION FACILITY CORRESPONDENCE
A. Submitting the PFC through FDA’s Electronic Submissions Gateway (ESG)
1. Obtaining a Pre-Assigned ANDA Number (if applicable): For original ANDAs, the applicant should request a pre-assigned ANDA number before submitting the PFC. For PASs, PAS amendments, and ANDA amendments, the applicant should use the relevant ANDA application number on the Form FDA 356h.
2. Transmitting the PFC through FDA’s ESG: The PFC must be submitted electronically in eCTD format through the FDA ESG following the Agency’s instructions. When transmitting the PFC through the ESG, choose “CDER” when selecting the appropriate Center, and choose “eCTD” when selecting the submission type. The applicant should submit the priority ANDA consistent with the “ANDA Submission Timing”. If the applicant decides not to submit the ANDA after submitting the PFC, FDA should be notified in writing. The notice of decision not to submit it the ANDA should reference the submission number and be submitted to eCTD section 1.2, Cover Letter.
3. FDA’s Assessment of the PFC: The Agency will begin assessment of the PFC upon receipt. FDA will send a letter to the applicant to acknowledge receipt of the PFC. FDA will assess priority status and assign the appropriate review goal date after the ANDA is submitted.
B. ANDA Submission Timing
In order for an ANDA to be eligible to receive priority review, the PFC should be submitted not later than 60 days prior to the submission of the ANDA itself. This timing allows the Agency to begin assessing the facility information before receiving the ANDA. Additionally, an ANDA should not contain any significant changes to the information submitted in the PFC. To minimize the possibility of significant changes to facility information between submission of the PFC and the ANDA (and consequently loss of the priority review goal), FDA recommends applicants submit the PFC not earlier than 90 days before submission of the ANDA.
The applicant should submit a signed certification statement during ANDA submission (in eCTD section 1.2) stating that the applicant has 1) made no significant changes (as described in the GDUFA III commitment letter) to the information contained in the PFC or 2) has made no changes except to exclude a facility not involved in generating data for the application as described in section 505(j)(11)(B) of the FD&C Act. Significant changes between PFC and ANDA submission will result in assignment of the standard review goal. Such significant changes should be made by including information regarding the significant changes in the appropriate eCTD module with the ANDA submission. Such significant changes should be identified in the cover letter.
FDA’s review of the ANDA, which will include an assessment and determination of whether the ANDA meets the priority designation criteria, will be performed in accordance with its applicable statutory and regulatory authorities and policies, and procedures for ANDA reviews. At the time of receipt, FDA will notify the applicant in the ANDA acknowledgement letter whether the ANDA or PAS is subject to priority review.
NOTIFICATIONS TO THE APPLICANT
A. Pre-Submission Facility Correspondence Acknowledgement Letter
The Pre-Submission Facility Correspondence Acknowledgement Letter simply acknowledges receipt of the PFC by the Agency. Eligibility for the priority review goal based on the PFC is determined by FDA when an ANDA is submitted.
B. Determining Whether an ANDA Qualifies for the Priority Review Goal
After receiving the ANDA, FDA will determine the applicable goal date for the submission. Establishing the applicable goal date for the ANDA is based on the Agency’s priority designation determination at the time of ANDA submission; assessment of whether the applicant submitted a complete and accurate PFC, including confirmation that all facilities are ready for inspection; and determination that the information submitted in the ANDA does not differ significantly from what was submitted in the PFC. The Agency will convey the outcome and resulting goal date in the ANDA acknowledgement letter.