Manufacturers seek clarity on FDA’s drug shortage notification guidance

Public comments submitted to the US Food and Drug Administration’s (FDA) draft guidance on how and when to inform the agency of certain drug and biologic product manufacturing shortages mainly came from manufacturers wanted to know more about the notification process and what constitutes a discontinuation in the eyes of the agency.

FDA’s draft guidance instructs manufacturers to notify the agency at least 6 months in advance of when they have permanently discontinued the manufacturing of certain finished products or active pharmaceutical ingredients (APIs), or when an interruption in the manufacturing of certain finished products or APIs “likely to lead to a meaningful disruption in supply” in the United States.

The draft guidance also recommends manufacturers provide additional information in the notifications to the agency to give FDA the information it needs to help prevent or lessen shortages, such as the names of the finished products, alternative standards for identification and labeling, application holder name or manufacturer and drug master file number.

“While some supply disruptions and product shortages cannot be predicted or prevented, early communication and detailed notifications from manufacturers to the Agency play a significant role in decreasing the incidence, impact, and duration of supply disruptions and product shortages,” FDA wrote in a Federal Register notice.

The draft guidance is intended to replace a previous guidance document released in March 2020 discussing section 506C of the Federal Food, Drug, and Cosmetic Act (FD&C Act), which was amended by the Coronavirus Aid, Relief, and Economic Security Act (CARES Act).

Under section 506C, FDA said manufacturers should notify FDA of permanent or temporary manufacturing interruptions if they are applicants of certain finished drug products submitted through new drug applications (NDAs), approved abbreviated drug applications and approved biologics license applications (BLAs). In the case of approved BLAs, finished biological products that do not contain blood or blood components are subject to notifications as well as transfusion products under approved BLAs for blood or blood components that “manufacture a significant percentage of the US blood supply.” Other applicants required to notify FDA are those with finished drug products marketed without approved NDAs or abbreviated NDAs.

FDA said the “certain finished products” in the draft guidance are prescription drugs and biological products that are life sustaining or life supporting, or used to prevent or treat debilitating diseases and conditions such as in emergency care or surgery settings. Finished products deemed critical to public health during a public health emergency also fall under this label, FDA noted, whereas manufacturers of radiopharmaceutical products or “any other products designated by FDA” are not subject to notification requirements under section 506C.

“The notification requirement regarding discontinuances and interruptions in manufacturing of API under section 506C of the FD&C Act applies only to the manufacturers that are listed above; other entities in the supply chain for a drug, including third-party API manufacturers and suppliers, are not required to submit such notifications,” the agency wrote.

Leukemia & Lymphoma Society

In their comment, the Leukemia & Lymphoma Society (LLS) said they had become “increasingly concerned” about drug shortages, particularly in the area of blood cancer, that have affected patients’ access to medications. They noted as of May 2023, there had been 17 oncology-related drug shortages.

“LLS agrees that early communication and detailed notifications from manufacturers to the Agency regarding supply interruptions play a significant role in decreasing the incidence, impact, and duration of supply disruptions and product shortages,” they wrote.

While acknowledging the agency’s authority is limited, LLS noted increased transparency in the drug supply chain could help prevent and reduce drug shortages. One example would be allowing FDA to track manufacturer overreliance on single facilities or countries for APIs, or requiring manufacturers to disclose demand and inventory levels, they said.

“These are key pieces of information that the Agency must rely on manufacturers to provide in good faith and with little guidance as to when notification is necessary,” LLS noted.

Association for Clinical Oncology

The Association for Clinical Oncology (ASCO) agreed with FDA that the 6-month notification requirement is appropriate in the draft guidance, but disagreed with the idea of allowing alternate timeframes.

“The current draft guidance suggests the alternative of ‘as soon as practicable’ and ‘no later than 5 business days after the discontinuance or interruption in manufacturing occurs,’” ASCO wrote in their comment. “Instead, we recommend the final guidance language require the manufacturers to contact the FDA with reasoning as to why a 6-month notification is not possible, with weekly updates versus every 2 weeks, until resolved.”

ASCO also “strongly” agreed with FDA’s decision to not have manufacturers consider other manufacturers or competitors in their assessment of what constitutes a “meaningful disruption.” Manufacturers should “notify the agency when an unexpected spike in demand is the cause of their inability to meet demand, in the absence of an interruption in manufacturing, to allow the FDA to take appropriate steps to address the potential shortage,” they said.

Bulk Pharmaceuticals Task Force

The Bulk Pharmaceuticals Task Force (BPTF) provided FDA with a few examples of how API manufacturers identify and act on discontinuations. They asked the agency for more information on what constitutes a discontinuation since many manufacturers of APIs “produce APIs on a basis of intermittent campaigns, responding to market opportunities and sales orders.”

“In many instances an API might not be manufactured for more than 10 years, because of market conditions and a manufacturer’s costs, which are based on its raw materials, plant utilization, and technology,” they explained.

While drug product manufacturers are responsible for notifying the agency of discontinuations in manufacturing, BPTF noted, “API manufacturers do not know the use or market share of the APIs they produce, and an assessment of the market implication for discontinuing API production is not feasible.”

“The drug product manufacturer is the appropriate entity to make the market assessment, and we agree with the direction of this draft guidance,” they said.

BPTF expressed concern, however, that this guidance contradicts another draft guidance released by the agency in May 2022 on risk management plans (RMP) to mitigate drug shortages, which contained an “expectation that API manufacturers prepare a supply risk assessment for products under 506C.”

“For the same reason that the current guidance excludes API manufacturers from reporting an API manufacturing discontinuance, BPTF recommends that API manufacturers should not have to assess the market application of their API products, and therefore, not be responsible for a supply chain RMP assessment for section 506C products,” they wrote.

Bristol Myers Squibb

Bristol Myers Squibb (BMS) also had concerns about notification requirements for APIs.

In their comment, BMS said they wanted more information from the agency about cases where a drug product has more than one API supplier.

“[I]s a notification required in the event a disruption in manufacturing occurs at one of the applicant’s API suppliers, but the applicant’s alternate approved (and active) API supplier is able to cover the supply demand, eliminating any impact to API safety stock or Finished Goods inventory?” they asked.

Boehringer Ingelheim

Boehringer Ingelheim sought more clarity from the agency in their comment on situations where a product is discontinued but then resumed by a different manufacturer.

“It would be useful to clarify whether this guidance is applicable to the divesture of a product from one manufacturer (i.e. discontinuation of production) to another manufacturer assuming there will be a continued, uninterrupted supply via the new manufacturer,” they wrote.

Concerning APIs, Boehringer Ingelheim also wanted to know more about FDA’s definition of a meaningful disruption in the supply chain.

“From the finished drug manufacturer’s perspective, a ‘meaningful disruption in the supply of the API’ is constituted by an impact on the supply of the finished product,” they said. “Given the fact that Safety Stocks of API with coverage of several months may be available, a short-to mid-term disruption of API supply will not necessarily lead to a shortage on the drug product level. It would be helpful to include this aspect in the definition.”

Pharmaceutical Research and Manufacturers of America

The Pharmaceutical Research and Manufacturers of America (PhRMA) largely agreed with FDA’s draft guidance, but said 506C notifications are “are only one piece of the efforts” to prevent and reduce drug shortages, such as voluntary outreach efforts.

PhRMA also took the opportunity to highlight the individualized nature of the drug and biologic supply chain.

“As we have noted in prior comments to the Agency, the approach to mitigating supply chain risk necessarily differs from product to product. Every product has its own unique supply chain and corresponding risk factors, so the approach to mitigating risk may differ between products while maintaining the overarching goal of preventing drug shortages,” they wrote.

Draft guidance, Federal Register notice

Manufacturers seek clarity on FDA’s drug shortage notification guidance

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