FDA's New Stability Testing Mandate Sparks Concern Over Potential PET Drug Shortages

At a workshop held at the Food and Drug Administration (FDA) last fall, the agency stressed that the PET Good Manufacturing Practices (GMPs) require stability testing at each facility annually. SNMMI opposes that change, which could have a strong negative impact on the supply of PET drugs in the United States.

The workshop, titled “Positron Emission Tomography: Product Quality, Regulatory Submissions, Facility Inspections, and Benefit-Risk Considerations,” was held jointly by SNMMI, the Medical Imaging and Technology Alliance, the Coalition of PET Drug Manufacturers, and the FDA in November 2023; it was recorded and is available on the FDA’s website. One of the major topics discussed was the FDA’s recent policy changes on stability testing performed on PET drugs. After the workshop, the Coalition developed a paper on stability studies discussing the potential impact of the change.

Stability studies are part of the new drug application (NDA) or abbreviated new drug application (ANDA) for the product of interest. The protocol defines quality attributes and associated analytical methods that reflect the stability of the product. The NDA and ANDA submissions comprise various tests to assess stability, such as radiochemical purity and chemical purity. After FDA approval, product stability is tested periodically, in most cases annually, to demonstrate that the stability—and thus the shelf life—of the product has not changed since FDA approval.

Historically, stability studies were conducted at a single facility ("one stability, one facility" model), and the results were considered representative of other facilities using the same protocols and equipment. The FDA recognized this approach in a public meeting in 2011 when it stated, “We are not looking for site-specific stability. So long as your manufacturing process is the same, uses the same synthesizer, the data from that site should be okay. You don’t need to generate stability data at each site.”

In 2023, FDA inspections started requiring stability testing in each manufacturing facility annually. This was a departure from the previous “one stability, one factory” model. For many, this change was surprising and unclear.  The 2023 change was not explicitly stated in regulations or previous guidance documents. Consequently, it appears that the FDA’s position has changed since 2011 and, further, the agency’s new position appears to be a new interpretation of the regulations.

The FDA’s change may possibly stem from multiple factors including:

• The FDA’s experience with vertically integrated manufacturing models used in the traditional non-PET pharmaceutical industry may influence the agency’s perspective regarding facility-based stability.
• Based on discussions at the November 2023 workshop, the agency does not appear to be internally aligned on these policy changes and interpretations, perhaps reflecting the possibility that the changes have evolved out of FDA inspections (i.e., “regulation by inspection”).

The implications of the FDA’s policy change on stability testing for PET drugs will have tremendous impact on the supply of PET drugs in the United States. First, the additional requirement could increase the number of required stability batches by a very large percentage, raising costs by approximately 3 million per year across commercial manufacturing chains. Second, the change will impact the “just-in-time” supply chain for PET drugs. The negative impact will be felt in staffing, resources, workflows, and product availability. Most significantly, the policy will impact patients who rely on PET drugs. The execution of stability studies at each PET facility will require the complex coordination of resources, stakeholders, patient scheduling, and transfers of doses between PET facilities. In order to implement the “stability at every facility” model, the most likely scenario will result in the complete disruption of patient doses on days when stability studies are executed at a PET facility.

SNMMI opposes the FDA changes to the “one stability, one facility” model and calls on the agency to reaffirm their commitment to ensuring product quality without unnecessary increases in testing frequency and cost.