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.