Notifying FDA of a Discontinuance or Interruption in Manufacturing of Finished Products or Active Pharmaceutical Ingredients

The guidance document “Notification Requirements under Section 506C of the FD&C Act for Discontinuance or Interruption in Manufacturing of Finished Products or Active Pharmaceutical Ingredients" offers detailed instructions to applicants and manufacturers regarding the notification obligations outlined in section 506C of the Federal Food, Drug, and Cosmetic Act (FD&C Act).

Its goal is to facilitate prompt and informative notifications to the FDA concerning modifications in the manufacturing of specific finished drugs, biological products, and active pharmaceutical ingredients (APIs) to prevent and alleviate shortages.

?Under the provisions of section 506C of the FD&C Act and the FDA's regulations, specific individuals are required to inform the FDA about:

1. A permanent cessation of manufacturing for finished drug and biological products.
2. An interruption in manufacturing for certain finished drug and biological products that is expected to cause a significant disruption in their availability in the United States. For blood or blood components intended for transfusion, this disruption is considered significant.
3. A permanent halt in the production of active pharmaceutical ingredients (API) for specific finished drugs and biological products.
4. An interruption in the manufacturing of API for certain finished drugs and biological products that is likely to result in a significant disruption in the supply of the API for those products.

?Who must notify?

Those mandated to notify under section 506C, termed manufacturers in this guidance, encompass:

Applicants with approved NDAs or ANDAs for specific finished drugs.

• Applicants with approved BLAs for certain finished biological products, excluding blood or blood components.
• Applicants with approved BLAs for blood or blood components for transfusion, making a notable contribution to the U.S. blood supply.
• Manufacturers of specific finished drugs lacking approved NDAs or ANDAs.

The notification requirements for covered finished products apply to each manufacturer independently, without consideration of their market share, the number of other manufacturers selling similar products, or the quantity of product in distribution.

When to notify?

Typically, manufacturers of covered finished products should provide the FDA with a notification at least 6 months ahead for the mentioned four scenarios. If giving 6 months' notice isn't feasible, they should submit the notification as soon as possible afterward. Additionally, notifications about a permanent discontinuation or interruption in manufacturing of a covered finished product must be sent no later than 5 business days after the occurrence of the discontinuation or interruption.

If a manufacturer is unsure whether an interruption in manufacturing warrants FDA notification due to uncertain impacts on supply, FDA advises submitting a notification regardless. This enables FDA to monitor the market and intervene promptly if needed to prevent or lessen any potential shortages.

?What Information to Include in Notifications?

The minimum requirements for notifying FDA about a permanent discontinuance or interruption in manufacturing of covered finished products and API under section 506C of the FD&C Act include:

1. Name of the product, including the National Drug Code (NDC) number, or an alternative standard for identification and labeling for biological products.
2. ? Name of the applicant (for approved products) or manufacturer (for unapproved drugs).
3. Whether the notification relates to a permanent discontinuance of the product or an interruption in manufacturing of the product.
4. Disclosure of reasons for the discontinuation or interruption in manufacturing of the API.
5. Whether the notification relates to a permanent discontinuance of the API or an interruption in manufacturing of the API.
6. Expected duration of the interruption in manufacturing.
7. Description of the reason(s) for the discontinuation or interruption in manufacturing.

Manufacturers should initially notify within the timeframe specified in section 506C(b) of the FD&C Act and related regulations (refer to section III.B for more details), and FDA suggests updating these notifications with any new information as it becomes known.

?How to Notify FDA?

Manufacturers of covered finished products under CDER should initially notify about these products and their API through email to [email protected] or the CDER Direct NextGen Portal. For covered finished products regulated by CBER, the initial notifications should be sent via email to [email protected]. Updates should be emailed to the relevant center (CDER or CBER), not through the NextGen Portal.

Each permanent discontinuance or interruption in manufacturing requires a separate notification. A single initial notification can list all affected products or API. However, manufacturers should not include newly affected products in updates; instead, they should submit separate initial notifications for proper tracking. Notifications for other reporting requirements are not substitutes for those needed under section 506C.

If a manufacturer doesn't notify FDA as per section 506C(a) of the FD&C Act within the set timeframes, FDA will send a "noncompliance letter" indicating the missing notification. Similarly, if an applicant faces an unexpected manufacturing interruption, they couldn't predict six months ahead but doesn't inform FDA promptly, they'll receive a noncompliance letter too. The manufacturer has 30 days to explain the noncompliance and provide required information.

?FDA will post the noncompliance letter and responses on their website within 45 days unless it's determined to be an error or if the manufacturer had a valid reason for not notifying as required.

FDA keeps current, publicly available lists of finished drugs and biological products that are confirmed to be in shortage within the United States. FDA regularly updates its lists and aims for real-time communication to ensure patients and healthcare providers have the latest information on product shortages in the United States. FDA evaluates market conditions to determine if a shortage is resolved and removes products from the "current shortage" section based on factors like market share, alternate manufacturing capacity, and market stability. These lists don't include confidential information or trade secrets.

?Before posting publicly, FDA verifies information with manufacturers. It will continue posting information consistent with regulations, regardless of additional details manufacturers provide based on FDA guidance.

Reference:

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/notifying-fda-discontinuance-or-interruption-manufacturing-finished-products-or-active