By Mark Durivage, Quality Systems Compliance LLC
On March 2, 2022, the FDA's Center for Drug Evaluation and Research's (CDER) Office of Regulatory Affairs (ORA) finalized the July 2013 draft guidance Pre-Launch Activities Importation Requests (PLAIR). The guidance describes the FDA's policy regarding requests for the importation of unapproved finished dosage form drug products by applicants preparing products for U.S. market launch based on anticipated approval of a pending new drug application (NDA) or abbreviated new drug application (ANDA). The guidance also applies to unapproved biologics licensing applications (BLAs) regulated by CDER and unapproved combination products assigned to CDER for which NDA, ANDA, or BLA approval is anticipated.
The guidance describes the procedures for making requests for importation of unapproved finished dosage form drug products before final approval of the application and which factors FDA will consider in granting such requests.
Section 505(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) prohibits the introduction or delivery for introduction into interstate commerce of a new drug "unless an approval of an application filed pursuant to subsection (b) or (j) is effective with respect to such drug." Applicants who have a pending NDA, ANDA, or CDER-regulated BLA nearing an FDA application decision can submit a PLAIR to FDA seeking permission to import an unapproved finished dosage form drug product for reconditioning in the form of approval prior to the drug's arrival at the port of entry, eliminating the need to file a Form FDA 766 requesting reconditioning.
The FDA's granting of a PLAIR does not represent a statement about the approvability of the NDA, ANDA, or CDER-regulated BLA but facilitates the process for importing unapproved finished dosage form products to prepare for market launch based on anticipated approval of the pending application.
What Should Be Included In A PLAIR?
- The drug product name and how supplied (from product labeling per 21 CFR 201.56 and 201.80).
- The name of the CDER Office of New Drugs or Office of Generic Drugs regulatory project manager assigned to the pending application.
- The National Drug Code (NDC) number, if assigned.
- The name, address, registration number, and telephone number of the foreign manufacturer of the finished dosage form drug product.
- The name, address, registration number, and telephone number of the U.S. consignee.
- The application number for the finished dosage form drug product pending FDA approval.
- A letter from FDA officially documenting the user fee goal date.
- The precise quantities to be imported.
- The name, address, facility identification number (DUNS), and telephone number of any facility where the finished dosage form drug product in final packaged form will be stored pending approval.
- When the finished dosage form drug product is imported for minimal further processing, information regarding the facility where minimal further processing activities will occur, including the name, address, and registration number of the facility, and a description of the further processing activities. This facility should be identified in the pending application.
- A letter signed by an authorized representative of the applicant stating the following:
- The applicant's acknowledgment that the product is an unapproved new drug.
- That the PLAIR represents the applicant's request to recondition the product, under section 801(b) of the FD&C Act and 21 CFR 1.95, by obtaining product approval within six months.
- For an unapproved finished dosage form drug product that calls for minimal further processing, that the unapproved finished dosage form drug product will be delivered to a facility identified in the finished dosage form drug product's pending application to permit further processing. Following completion of those activities, the product will remain subject to the terms and conditions of the U.S. Customs and Border Protection (CBP) entry bond that covers the specific shipment.
- For an unapproved finished dosage form drug product in final packaged form that does not call for further processing, that the drug product should be delivered to a single facility used for warehousing. The product will remain subject to the terms and conditions of the CBP entry bond that covers the specific shipment.
- That the facility used for warehousing complies with any applicable current good manufacturing practices (CGMP) or if applicable, other federal or state requirements.
- That the applicant understands that the unapproved finished dosage form drug product must be exported or destroyed within 90 days of the date of any notice of refusal, if refused admission.
When Should A PLAIR Be Submitted?
The recommended timeframes help ensure that PLAIR requests are processed in time for FDA to review the underlying application.
- PLAIRs should be submitted at least 30 days prior to the proposed entry date of the shipment to allow time to process the submission.
- PLAIR-eligible ANDAs, NDAs, and CDER-regulated BLAs subject to standard review should be submitted no more than 60 days before the user fee goal date.
- For PLAIR-eligible NDAs and CDER-regulated BLAs subject to six-month (priority) review, the PLAIR should be submitted up to 120 days before the user fee goal date.
- For PLAIR-eligible ANDAs subject to priority review, the PLAIR should be submitted up to 80 days before the user fee goal date.
PLAIR submissions should be on the applicant's letterhead and submitted by email to: CDER-OC-PLAIR@fda.hhs.gov in a PDF file. The subject line of the submission should include the application number, drug product name, and strength(s). Only one PLAIR submission will be accepted per NDA, ANDA, or BLA.
What Action Will FDA Take On A PLAIR?
The CDER Office of Drug Security, Integrity, and Response (ODSIR), Division of Global Drug Distribution and Policy (DGDDP), will confirm receipt of the submission. CDER will review the submission and assess, among other things, the foreign facility's inspection history and conformity with applicable cGMPs. After that, the DGDDP will notify the applicant whether the PLAIR has been granted or denied.
Amended PLAIRs should be submitted to FDA with an explanation of the changes made and identify the document as an "amendment" to differentiate it from the initial PLAIR request. The DGDDP will review and notify the applicant whether it has granted the amendment.
Importation Of New Drugs Under An Approved PLAIR
The importer may provide a copy of the granted PLAIR to the ORA Import Division where the product is being imported. The importer should provide an affirmation of compliance indicating the product is covered under a granted PLAIR as well as the associated drug application number in the Automated Commercial Environment (ACE).
For approved PLAIRs, the FDA intends to detain the product as an unapproved new drug and to authorize the drug's reconditioning in the manner and under the conditions set forth in the PLAIR. If FDA approves the products in the application within six months of the date of entry of the shipment made under the PLAIR, the agency intends to issue a "Release after Detention" for the drug product.
When the FDA refuses to approve the application or six months otherwise elapse without FDA approval, the FDA may determine the product is subject to refusal. If FDA refuses admission into the United States, the finished dosage form drug product must be exported or destroyed within 90 days of the refusal.
Post-Approval Of Your NDA, ANDA, Or CDER-Regulated BLA
Upon receiving notice from FDA that a drug product application is approved, the applicant should immediately send a copy of the approval letter to the ORA Import Division where the product was detained and CDER-OC-PLAIR@fda.hhs.gov. The applicant should notify FDA of any deviation of the drug product detained under a PLAIR from the provisions in the approved drug application.
The FDA has encountered occurrences in which drug products that had been warehoused subject to a pending drug approval did not conform with late changes made to the approved drug product labeling or instances in which the application did not receive FDA approval. These products may be considered misbranded and/or constitute unapproved new drugs because they may differ from the approval of the NDA, ANDA, or BLA. Introduction or delivery for introduction into interstate commerce of any misbranded drug or any article in violation of the FD&C Act is prohibited, and the products are subject to refusal of admission.
Submit written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852 or electronic comments to https://www.regulations.gov. Please reference docket number FDA-2013-D-0836 with all comments.
About The Author:
Mark Allen Durivage has worked as a practitioner, educator, consultant, and author. He is managing principal consultant at Quality Systems Compliance LLC, an ASQ Fellow and SRE Fellow. Durivage primarily works with companies in the FDA regulated industries (medical devices, human tissue, animal tissue, and pharmaceuticals), focusing on quality management system implementation, integration, updates, and training. Additionally, he assists companies by providing internal and external audit support as well as FDA 483 and warning letter response and remediation services. He earned a BAS in computer aided machining from Siena Heights University and an MS in quality management from Eastern Michigan University. He holds several certifications, including CRE, CQE, CQA, CSSBB, RAC (Global), and CTBS. He has written several books available through ASQ Quality Press, published articles in Quality Progress, and is a frequent contributor to Life Science Connect. You can reach him at email@example.com with any questions or comments.