The FDA has issued draft guidance that outlines how drug makers should notify the agency of a discontinuance or interruption in manufacturing finished products and APIs to reduce the impact of drug shortages. What is it proposing to address the problem? 

The US Food and Drug Administration (FDA) has issued draft guidance to assist applicants and manufacturers in providing FDA timely, informative notifications about changes in the production of certain finished drugs and biological products as well as certain active pharmaceutical ingredients (APIs) that may, in turn, help the agency in its efforts to prevent or mitigate shortages. The draft guidance also explains how FDA communicates information about products in shortage to the public. Input on the draft guidance is due June 5, 2023.

FDA’s regulations generally require certain applicants and manufacturers to notify FDA of: (1) a permanent discontinuance in the manufacture of certain products; (2) an interruption in the manufacture of certain products that is likely to lead to a meaningful disruption in supply of those products in the United States; (3) a permanent discontinuance in the manufacture of APIs for certain products; or (4) an interruption in the manufacture of APIs for certain products that is likely to lead to a meaningful disruption in the supply of the API for those products. The draft guidance, when finalized, would recommend that applicants and manufacturers provide additional details and follow additional procedures to ensure FDA has the specific information it needs to help prevent or mitigate shortages.

Among other things, the draft guidance, when finalized, would explain: (1) who must notify FDA and what products are subject to the notification requirements; (2) when to notify FDA; and (3) what details to include in notifications that will ensure FDA has information that would be helpful to assess the potential for a supply disruption or shortage.

The draft guidance specifies information that must be included in notifications concerning permanent discontinuances or interruptions in the manufacturing of covered finished products and APIs. For example, the draft guidance states that notifications must include:

• If an API is a reason for, or risk factor in, the discontinuation or interruption in manufacturing of a covered finished product, the source of the API and any alternative sources for the API known by the manufacturer; and
• Whether any associated device used for preparation or administration included in the product is a reason for, or risk factor in, the discontinuation or interruption in manufacturing of the covered finished product.

The following are some examples of additional information that FDA recommends be included in notifications of a permanent discontinuance or interruption in manufacturing concerning a covered finished product:

• The anticipated time frame for all existing product (on hand and in distribution channels) to be exhausted if the notification is for a permanent discontinuance;
• The estimated market share for the product and whether the entire market share is affected by this issue;
• Amount of current inventory of product at the manufacturing facility or warehouse; and
• Whether a proposal is available for FDA to review to expedite availability of the product or suggestions for FDA actions that may help prevent or mitigate a supply disruption or shortage.

In general, the notification requirements for covered finished products apply to each individual manufacturer regardless of market share, number of other manufacturers marketing products that are therapeutically equivalent, or the amount of product that may be in distribution. Similarly, with respect to notifications for an API, FDA recommends that a manufacturer consider its current API manufacturer’s supply of the API, regardless of the API manufacturer’s market share, the number of other API manufacturers marketing the same or similar APIs, or the amount of the API that may be in distribution.

Notifications for finished products
The draft guidance specifies that notifications concerning a permanent discontinuance or interruption in the manufacture of a covered finished product that is likely to lead to a meaningful disruption in supply must include, at a minimum:

• Name of the product, including the National Drug Code (NDC) number, or, for biological products, an alternative standard for identification and labeling if one has been recognized as acceptable by the Center Director.

• Name of the applicant (for approved products) or manufacturer (for unapproved drugs).

• Whether the notification relates to a permanent discontinuance of the product or an interruption in manufacturing of the product.

• Description of the reason(s) for the discontinuation or interruption in manufacturing.

To ensure that FDA is better equipped to help prevent or mitigate a drug shortage, FDA recommends that manufacturers provide additional details about the situation and has included types of additional information for manufacturers to consider providing in their notifications to FDA. FDA says this list is not intended to be exhaustive, but it provides information that FDA generally finds helpful in assessing the situation and determining appropriate steps to help prevent or mitigate a shortage. FDA says manufacturers need not have all of these additional details available before submitting a notification and that notifications can be updated at any time to include such additional information. The list below identifies additional information for notifications for covered finished products.

• Whether the notification concerns an unavoidable supply disruption or a supply disruption that may be preventable.

• The underlying reason or root cause leading to this notification.

• The estimated date of onset of the interruption in manufacturing or supply disruption for this product. If a supply disruption has already occurred, FDA says to provide the estimated duration.

• The anticipated time frame for all existing product (on hand and in distribution channels) to be exhausted if the notification is for a permanent discontinuance.

• The estimated market share for the product and whether the entire market share is affected by this issue.

• The estimated volume of historic monthly sales, usage, or demand, as applicable, for this product.

• Whether the product is manufactured on multiple lines or in multiple facilities.

• Amount of current inventory of product at the manufacturing facility or warehouse.

• If the notification is for an interruption in manufacturing, the date when the last remaining batch of finished product was or will be released into distribution and how long the supply is expected to last in the market without additional releases based on current demand.

• Whether there is an emergency or reserve supply of this product and whether allocation of supply on hand or reserve supply is an option.

• Whether a redundancy risk-management plan that identifies and evaluates risks to the supply of the drug is in place.

• Whether public information has been provided or will be provided for stakeholders and patients regarding this actual or potential shortage

• Whether a proposal is available for FDA to review that may help to expedite availability of the product or suggestions for FDA actions that may help prevent or mitigate a supply disruption or shortage.

Notifications concerning APIs
The draft guidance specifies that notifications concerning APIs must at minimum include the following:

• Disclosure of reasons for the discontinuation or interruption in manufacturing of the API.

• Source of the API and any alternative sources for the API known by the finished product manufacturer.

• Expected duration of an interruption in manufacturing of the API.

To ensure these notifications provide information that is helpful to FDA in assessing the potential for a supply disruption or shortage for APIs, FDA further recommends that manufacturers also include additional information on APIs as outlined below:

• Name(s) of the finished product(s) for which the API is used, including the National Drug Code number(s), or, for biological products, an alternative standard for identification and labeling if one has been recognized as acceptable by the Center Director.

• Name of the application holder (for approved products) or manufacturer (for unapproved drugs) of the covered finished product(s) for which the API is used.

• Number of any drug master file associated with the API.

• Whether the notification relates to a permanent discontinuance of the API or an interruption in manufacturing of the API.

• Estimated date of onset of the interruption in manufacturing or supply disruption for the API. If a supply disruption has occurred, FDA requests to provide the estimated duration.

• Whether the discontinuance or interruption in manufacturing of the API has impacted or is expected to impact the supply of the covered finished product or ability to fill orders for the covered finished product.

Communication to the public
FDA maintains public, up-to-date lists of finished drugs and biological products that FDA has determined to be in shortage in the United States. These lists include:

• Established name of the product in shortage; brand name of the product in shortage, if applicable; the National Drug Code number, presentation, strength(s), and package size, as available.

• Name of each application holder (for approved products) or manufacturer (for
unapproved drugs).

• Name of the distributor, if different from the application holder (for approved products) or manufacturer (for unapproved drugs).

• Reason for the shortage from the following categories: GMP compliance; regulatory delay; shortage of an active ingredient; shortage of an inactive ingredient component; discontinuation of the manufacture of the product; delay in shipping; demand increase; and other reason.

• Estimated duration of the supply disruption or shortage, anticipated date of availability, and resolution dates (based on information provided by the manufacturer).

• Any additional information related to the shortage that the manufacturer chooses to share.

FDA says it updates its lists regularly and strives to communicate in real-time so that patients and healthcare providers have the most current information on product shortages in the United States. A product is added to the drug shortage list maintained by the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research only after the agency determines that it is in shortage; products are not added to the list(s) immediately upon receipt of a notification regarding a discontinuance or interruption in manufacturing. In cases where a shortage does not occur or is prevented through FDA or stakeholder intervention, the product will not be posted on the list. FDA generally considers a shortage to be resolved and removes the product from the “current shortage” section of the list based on an evaluation of the entire market, assessing whether all backorders have been filled and supply is meeting or exceeding demand. In making this evaluation, FDA may consider, among other factors, affected market share, ability of alternate manufacturers to cover the demand, and confirmed market stabilization.