Why, Who, When, Where and More: New Draft Guidance on Notifying FDA about Discontinuance or Interruption in Manufacturing

On February 6, 2024, FDA issued a draft guidance titled Notifying FDA of a Discontinuance or Interruption in Manufacturing of Finished Products or Active Pharmaceutical Ingredients Under Section 506C of the FD&C Act. The draft guidance provides recommendations for applicants and manufacturers about the requirements for notifications about production changes of certain finished drugs and biological products and certain active pharmaceutical ingredients (API), and outlines information FDA would like to receive in addition to the requirements.

Why?

Given the disruptions in supply that have continued to occur even beyond the end of the pandemic crisis, it is not surprising that FDA has issued a draft guidance on this subject. Early notification can play a role in decreasing the impact and duration of such supply disruptions and product shortages. Since the enactment of the Food and Drug Administration Safety and Innovation Act (FDASIA) in 2012, manufacturers have been required to notify FDA of product changes affecting certain finished drugs and biological products. In 2020, the Coronavirus Aid, Relief, and Economic Security Act (CARES Act) expanded the notification requirement to include reasons contributing to the discontinuance or interruption (e.g., API and its source and any alternative sources; associated medical devices), and expected duration of the interruption.

Who?

The notification requirements under section 506C apply to:

• Applicants with approved new drug applications (NDAs) or approved abbreviated new drug applications (ANDAs) for certain finished drug products (see below for description of covered products);
• Applicants with approved biologics license applications (BLAs) for certain finished biological products other than blood or blood components;
• Applicants with approved BLAs for blood or blood components for transfusion that manufacture a significant percentage of the U.S. blood supply; and,
• Manufacturers of certain finished drug products marketed without an approved NDA or ANDA.

Others involved in the drug supply chain, such as third-party API manufacturers and suppliers, are not required to submit such notifications.

The notification requirements apply to each individual manufacturer regardless of market share, the number of competitors making therapeutically equivalent products, or the amount of product in distribution. FDA stresses, however, that the relevant analysis is whether a change in production is likely to lead to reduction in supply of a product by that manufacturer. The assessment is to be based solely on the reporting manufacturer’s capacity and supply without regard to other manufacturers’ capacity or market demand.

For purposes of these notification requirements, finished products are prescription drugs and biological products that are (1) life supporting, life sustaining, or intended for use in the prevention or treatment of a debilitating disease or condition, and (2) not radiopharmaceutical drug products or any other products specifically designated by FDA.

FDA considers a permanent discontinuance to be a manufacturer’s decision to stop manufacturing and distributing its product indefinitely. Interruptions are those where a production change is likely to lead to a meaningful disruption in the supply of the product or API such that it impacts the manufacturer’s ability to fill orders or meet demand.

When?

Applicants and manufacturers are required to notify FDA at least six months in advance of a permanent discontinuance of certain finished drugs or API for such products or an interruption in manufacturing that may cause a disruption in the supply of the drug or API.  If it is not possible to provide advanced notice, notification must be provided as soon as practicable.

For a permanent discontinuance or interruption in manufacturing of a covered finished product, the notification must be submitted no later than five business days after such production change in manufacturing occurs.

In all cases, FDA should be notified by manufacturers before their own supply of a finished product or API for those products is meaningfully disrupted (e.g., interrupted).

Manufacturers are urged to notify FDA even if the manufacturer is unsure whether manufacturing interruption could lead to a meaningful disruption in order to allow FDA to monitor the market and help or prevent any resulting shortage.

FDA stresses in the draft guidance that other notifications to the agency such as a field alert report or report of marketing status do not substitute for notifications of discontinuance or disruption.

It is worth noting that although not a requirement, FDA requests that manufacturers contact the Agency in instances when supply cannot meet demand for covered finished products. Doing so creates a signal to FDA about a potential shortage and allows the Agency to mitigate against the potential shortage.

A separate notification for each permanent discontinuance or interruption in manufacturing is expected. The initial notification may include a list of all affected covered finished products or API. Subsequent updates should not include a newly affected product (e.g., a new strength). A separate notification should be submitted to ensure that the newly affected product is tracked appropriately.

What?

Covered Finished Products

At a minimum, a notification for a permanent discontinuance or interruption in the manufacturing of a covered finished product must identify:

• Product name;
• Applicant name;
• Whether it is a permanent discontinuance of the product or an interruption in the manufacturing;
• Reason for the discontinuation or interruption;
• Estimated duration of the interruption;
• Whether an API is a reason for, or risk factor in, the discontinuation or interruption, and, if so, the API source and any alternatives; and,
• Whether a device used for preparation or administration is a reason for, or risk factor in, the discontinuation or interruption.

APIs

At a minimum, a notification for a permanent discontinuance or interruption in the manufacturing of an API must identify the reason for the discontinuation or interruption, API source and alternatives, and expected duration of the interruption.

For both covered finished products and APIs, FDA recommends including a laundry list of additional information, most of which many manufacturers will not object to sharing with FDA.

What if?

Failure to provide notification of a discontinuance or interruption to FDA potentially could, among other things, land a manufacturer on the Drug Shortages: Non-Compliance With Notification Requirement website.

FDA will send a letter to the manufacturer noting that the applicable notification requirement was not met (a noncompliance letter). The draft guidance states that if FDA determines that an applicant could not have reasonably expected a reportable interruption six months in advance but failed to notify FDA “as soon as practicable,” a noncompliance letter will be issued. The manufacturer has an opportunity to respond, and both the noncompliance letter and response letter(s) will be posted on the website unless FDA determines it was issued in error or determines the manufacturer had a reasonable basis for not meeting the notification requirement.

We note there have been seven instances where FDA has posted the noncompliance letter and response letter over the last eight years, suggesting that manufacturers have mostly self-reported any production changes in manufacturing of finished products or APIs, or this was not a priority for FDA.

Where to look

FDA communicates shortage information about drugs and biological products through public, daily updated lists (e.g., CDER shortages and CBER shortages).

A product is added to a list only after FDA has determined it to be in shortage. Conversely, if a shortage is resolved based on FDA’s market assessment, which considers whether all backorders have been filled and supply is either meeting or exceeding demand, affected market share, alternative manufacturers to cover demand, and confirmed market stabilization, the affected product is removed from the list.

FDA informs the public of both shortages and extended use dates to assist with drug shortages. By actively updating the information related to shortages, FDA intends to allow the public and prescribers to develop alternative treatment plans before learning a prescription cannot be filled at the pharmacy when there is a supply issue.