FDA Guidance Breakdown: Notifying the Agency of a Discontinuance or Interruption in Manufacturing of a Finished Drug Product or API
The draft guidance is intended to assist applicants and manufacturers in providing FDA timely, informative notifications about changes in the production of certain finished drug products.
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On February 5, 2024, the FDA issued a draft guidance intended to assist applicants and manufacturers in providing the FDA with timely, informative notifications about changes in the production of certain finished drugs and biological products as well as certain APIs that may, in turn, help the Agency in its efforts to prevent or mitigate shortages.
The draft guidance also explains how the FDA communicates information about products in shortage to the public.
This draft guidance comes in response to the ongoing issue of drug shortages; the U.S. Congress and the FDA have taken steps to enhance the agency's ability to prevent and mitigate shortages through legislation like The Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012 and the The Coronavirus Aid, Relief, and Economic Security (CARES) Act of 2020.
Section 506C of the FD&C Act mandates drug manufacturers to report permanent discontinuation or significant interruption in making certain drugs that could lead to a shortage.
This guidance aims to enhance communication between manufacturers and the FDA by clarifying notification requirements, who should notify, what information to include, and how the FDA communicates shortages to the public. The guidance is part of a broader strategy to ensure critical medications are available to patients who need them.
Here’s a quick breakdown of the key policy details:
Introduction and background
The guidance addresses the notification requirements under section 506C of the FD&C Act and FDA’s regulations.
It emphasizes the importance of timely notifications for preventing and mitigating drug shortages. It also outlines the legal foundations, including amendments from the FDASIA and CARES Act, aimed at addressing drug shortages.
Who must notify: The guidance specifies that notifications must come from manufacturers with approved NDAs, ANDAs, or BLAs for certain finished products, including those not requiring approval but meeting specific criteria.
What products are subject to notification: It details the criteria for which prescription drugs and biological products must be reported, focusing on those essential for sustaining life or treating severe conditions:
Life-supporting or life-sustaining products: These are products that are essential to, or that yield information essential to, the restoration or continuation of a bodily function important to the continuation of human life.
Products intended for use in the prevention or treatment of a debilitating disease or condition: This includes products intended for use in the prevention or treatment of diseases or conditions associated with significant mortality or morbidity, which substantially impact day-to-day functioning.
Products critical to public health during a public health emergency: This category includes any drug or biological product that is deemed critical to public health during a public health emergency declared by the Secretary under section 319 of the Public Health Service Act.
Exclusions: The criteria exclude radiopharmaceutical drug products and any other products specifically designated by the FDA.
When to notify: A six-month advance notice requirement aims to give the FDA sufficient time to act on potential disruptions. The guidance specifies scenarios where this timeline might not be feasible and outlines the expectations for "as soon as practicable" notifications.
What information to include: Notifications must contain detailed product information, reasons for the discontinuance or interruption, and any factors related to the supply of active or inactive ingredients.
FDA communication on drug shortages
The draft guidance outlines how the FDA communicates shortages to the public, using a standardized format that includes the product name, reasons for the shortage, and estimated duration.
Failure to notify
The guidance describes the repercussions of failing to notify the FDA, including the issuance of noncompliance letters and potential public disclosure:
Issuance of noncompliance letters: If a manufacturer fails to provide the required notification about a discontinuance or interruption in manufacturing, the FDA will issue a noncompliance letter to the manufacturer. This letter indicates that the manufacturer has not complied with the notification requirements under Section 506C of the FD&C Act.
Public disclosure: The FDA is required to publicly post the noncompliance letter and any response from the manufacturer on its website not later than 45 calendar days after the letter's issuance. However, this posting will be done with appropriate redactions to protect confidential commercial information and trade secrets. Public disclosure aims to inform stakeholders, including healthcare providers and patients, about potential drug shortages and the manufacturers' compliance status.
Response requirement: Manufacturers who receive a noncompliance letter must respond to the FDA not later than 30 calendar days after its issuance. The response must provide the reason for noncompliance and the required information about the discontinuance or interruption that was not initially provided as required.
Legal obligations of manufacturers
Timely notification: Manufacturers are legally obligated to notify the FDA at least six months in advance of a permanent discontinuance or an interruption in manufacturing that is likely to lead to a meaningful disruption in supply. If such advance notice is not feasible, manufacturers must notify the FDA as soon as practicable.
Comprehensive information: Notifications must include detailed information about the discontinuance or interruption, including the product name, reasons for the discontinuance or interruption, and the expected duration, among other details.
Avoidance of noncompliance: Manufacturers must ensure that they comply with these notification requirements to avoid receiving noncompliance letters and facing public disclosure. Compliance is not only a legal requirement but also a critical component of public health safety, as it enables the FDA to take timely action to prevent or mitigate drug shortages.
Beyond the minimum requirements, the guidance encourages manufacturers to provide comprehensive details about discontinuances or interruptions. This includes potential preventive actions, root cause analyses, and any steps taken to mitigate shortages. Such detailed communication can facilitate the FDA's response to shortages, including identifying alternative sources and expedited review processes for affected products.
Here are a few things drug firms may want to consider in light of this guidance:
Establish an early warning system(s). Develop internal systems to detect potential discontinuances or significant interruptions in manufacturing early. This can include monitoring supply chain issues, raw material shortages, manufacturing problems, or changes in demand that could lead to drug shortages. We suggest firms implement a supply chain monitoring system to track inventory levels, supplier performance, and lead times. Make sure to regularly review sales forecasts versus actual sales to identify unexpected increases in demand.