United States: FDA Publishes Final Guidance On Reporting Listed Drug Amounts

On Feb. 6, 2024, the U.S. FDA issued a final guidance, Reporting Amount of Listed Drugs and Biological Products Under Section 510(j)(3) of the FD&C Act, intended to assist registrants of drug establishments in submitting reports to FDA on the amount of each listed drug manufactured for commercial distribution by the registrant.¹ Such reports are required by section 510(j)(3) of the Federal Food Drug and Cosmetics Act (FD&C Act) as amended by section 3112(e) of the Coronavirus Aid, Relief, and Economic Security Act (CARES Act).²

New Reporting Guidance Rooted In Shortage Prevention

On March 27, 2020, Congress enacted the CARES Act to help address the health and economic effects of the COVID-19 pandemic. The CARES Act also included provisions to enhance FDA's ability to assess, prevent, and mitigate drug shortages, which can occur for various reasons, including manufacturing and quality problems, delays, and discontinuations, and which FDA is responsible for addressing to enhance product availability.³ While FDA had taken action to address drug shortages in the years prior, including by establishing the Drug Shortages Task Force in July 2018 and publishing a report on the causes and potential solutions to drug shortages in October 2019, the additional strain on drug supply chains during the COVID-19 pandemic predictably led to supply disruptions and drug shortages.⁴

Section 3112(e) of the CARES Act added section 510(j)(3) of the FD&C Act, which requires any company with a drug establishment registered with FDA to report to FDA annually on the amount of each listed drug that company manufactured for commercial distribution.

For purposes of FDA registration and listing requirements, to "manufacture" a drug in an establishment means to manufacture, repack, relabel, prepare, propagate, compound, or process a drug,⁵ and "commercial distribution" means "any distribution" of a drug, subject to limited exceptions, including drugs distributed for investigative use and internal or interplant transfers between registered establishments under common ownership and control.

Establishments that manufacture a drug in the United States and establishments in a foreign country that manufacture a drug imported or offered for import into the United States must register with FDA.⁶ These registrants must then list with FDA all the drugs manufactured in their registered establishments for commercial distribution, including unfinished drugs and active pharmaceutical ingredients (APIs), and provide certain information for each listed drug.⁷ FDA relies on registration and listing information to maintain a catalog of all drugs in commercial distribution in the United States. Registrants should submit these reports using FDA's NextGen Portal.⁸

FDA's Purpose For The New Reporting Requirements

FDA intends to use data reported from registrants per these requirements in its efforts to reduce drug shortage risks. Early notice of potential future supply chain disruptions can provide early notice of changes to the risk of drug shortage and facilitate an earlier and more informed response from FDA. Further, more comprehensive data from across the manufacturing industry can help FDA recognize and evaluate common and persistent supply chain vulnerabilities and facilitate more informed FDA actions intended to strengthen drug manufacturing supply chains.

FDA also intends to use reported data along with other information it collects about individual establishments as part of its quality surveillance oversight and to use the knowledge of the amount of drug product manufactured at each given establishment to better assess the potential risk of exposure from quality issues that may arise at the establishment. FDA acknowledged in the guidance that the information submitted to the agency in 510(j)(3) reports is generally considered confidential commercial information, which is exempt from disclosure under FDA disclosure regulations and the Freedom of Information Act.⁹

510(j)(3) Report Requirements

Section 510(j)(3) of the FD&C Act applies to each registrant of listed drugs in the drug supply chain. Registrants must report the amount of each listed drug, identified by National Drug Code (NDC), manufactured by each registered establishment during the reported calendar year. The drug amounts should be reported separately under each NDC. Registrants should organize these reports by the amount manufactured for commercial distribution in each month.

FDA advises that registrants, when reporting, should consider a listed drug "manufactured" during the month the drug is released and defines "released" to mean that the batch or lot has been determined to conform to final specifications.

Domestic registrants' 510(j)(3) reports must include any amount manufactured for commercial distribution within or outside the United States. Foreign registrants' reports must include any amount manufactured for importation or to be offered for importation into the United States, even if it is not ultimately distributed to the U.S. market. If a foreign registrant does not know how much of a listed drug was imported or offered for import in the U.S., it should report the total amount manufactured during the reporting period.

Unfinished drugs and API are included in this report requirement. Registrants should report the amount of a finished package form drug by the number of packages manufactured, the amount of a drug product not yet in finished package form by the number of dosage form units manufactured, and the amount of an API by mass or volume manufactured (e.g., kilograms or liters). Contract manufacturer registrants should provide the amount of drug they manufactured themselves, not the amount other registrants further downstream in the supply chain manufactured.

Packaging And Labeling Requirements

If a finished package product's packaging involves multiple layers of packaging, and it is not a kit product, the product should be reported using the NDC of the outermost layer, and the report should include amounts manufactured of the package type for each of the layers.¹⁰ If the product is listed as a kit, the amount reported should be based only on the outermost layer of packaging with the NDC assigned to the kit.

Registrants should identify in their 510(j)(3) reports the business operation (i.e., manufacturer, repacker, labeler, etc.) that best describes the activity performed at the establishment for the relevant listed drug, which should generally match the business operation for the establishment included in the drug listing.

Other Important Reporting Requirements And Exemptions

These reports are required regardless of whether a registrant also submits reports containing distribution data to satisfy post-marketing requirements associated with a drug or biologic application under 21 CFR 314.81(b)(2)(ii)(a) and/or 21 CFR 600.81(a), as such reports are not establishment-specific and are limited to finished drug product. However, FDA did express in the guidance its intention not to take action against an applicant for failure to submit distribution data required under 21 CFR 314.81(b)(2)(ii)(a) where each registrant subject to such requirement:

• submits a timely and complete 510(j)(3) report,
• adds the amount of listed drug product distributed for foreign use during the reporting period, and
• provides the NDC number(s) and strength(s) of drug product of the products for which the registrant will submit a 510(j)(3) report and the date on which they submit such report.

A registrant may have an authorized agent submit the 510(j)(3) report on its behalf, including a contract manufacturer registrant. There is no exemption for drug amounts recalled or returned. A registrant still must submit a 510(j)(3) report if the amount of a listed drug manufactured is zero.

FDA has exempted from 510(j)(3) reporting requirements:

• blood and blood components for transfusion and
• cell and gene therapy products, where one lot treats a single patient.¹¹

The deadline for 2023 510(j)(3) reports is July 1, 2024, and reports for subsequent years should be submitted no later than March 31 of the following year. Each report should include information regarding the amount of drug manufactured for the previous calendar year. Failure to provide information respecting a drug as required by section 510(j)(3) renders the drug misbranded and subject a manufacturer to various advisory and enforcement actions such as untitled letters or warning letters, recalls, product seizures, or criminal prosecution.¹²

Footnotes

1 Food and Drug Admin., Reporting Amount of Listed Drugs and Biological Products Under Section 510(j)(3) of the FD&C Act Guidance for Industry (Feb. 2024).

2 Pub. L. No. 116-136, § 3112(e), 134 Stat. 363 (2020).

3 Food and Drug Admin., Coronavirus Aid, Relief, and Economic Security Act (CARES Act) Drug Shortage Mitigation Efforts, FDA.GOV, https://www.fda.gov/drugs/drug-shortages/coronavirus-aid-relief-and-economic-security-act-cares-act-drug-shortage-mitigation-efforts (last updated March 1, 2024).

4 Food and Drug Admin., Report to Congress - Drug Shortages for Calendar Year 2020, https://www.fda.gov/media/150409/download?attachment. p>

5 21 CFR § 207.1.

6 Section 510(j)(1) of the FD&C Act; § 207.41 (21 CFR 207.41).

7 21 CFR § 207.49.

8 In February, FDA also provided technical guidance for registrants' reference in a separate guidance document. See Food and Drug Admin., Reporting Amount of Listed Drugs and Biological Products Technical Conformance Guide Guidance for Industry (Feb. 2024).

9 21 CFR § 20.61.

10 In other words, if a the total amount manufactured of a finished package drug packaging consists of 10 cases, each containing 10 bottles, the report should include both the number of cases (10) and the number of bottles (100) manufactured.

11 88 Fed. Reg. 22454 (Apr. 13, 2023).

12 Section 502(o) of the FD&C Act.

Previously published in Bioprocess Online, April 10, 2024.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.