SIDEBAR 8.1

FDA Approval Process

Technetium-99m, used in radiolabeled compounds intended for human use, is regulated by the FDA under the Food, Drug, and Cosmetic Act. The production of the Mo-99 precursor to Tc-99m is not regulated by the FDA if it is used only as a radiochemical. However, if the Mo-99 is to be used to make Tc-99m for radiolabeled compounds, its producer typically submits a Drug Master File (DMF) to the FDA; however, a DMF is not strictly required. The DMF describes the facility in which the Mo-99 is made; the production process itself, including any raw materials used in production; and product test methods, specifications, stability, and release criteria. The DMF is not approved by the FDA; instead, it is used as a source of information when FDA approval is sought to sell Tc-99m radiolabeled compounds made with that producer’s Mo-99.

A company seeking to sell a radiolabeled compound (e.g., a technetium generator producer) is required to submit an NDA to the FDA and pay a one-time application fee (in 2008, this fee was $1,178,000). The NDA is tied to one or more specific DMFs; the NDA for a radiolabeled compound, for example, would be tied to the DMFs for Mo-99 and any other raw materials used to make that compound. Like the DMF, the NDA describes the facilities, processes, test methods, and specifications for producing the radiolabeled compound. The FDA must review and approve the NDA before that radiolabeled compound can be sold for human use.

When a Mo-99 producer makes major changes to the process or raw materials it uses to make that isotope, it submits an updated DMF to the FDA. Any company (e.g., a technetium generator producer) that wants to use the Mo-99 produced under this updated DMF may find it necessary to submit an sNDA to obtain FDA approval to use that isotope. There is no fee for this submission, but there is a cost to the company for preparing the sNDA (described elsewhere in this chapter). To obtain FDA approval of the sNDA, the company must demonstrate that the Mo-99 precursor and Tc-99m product derived from it meet product specifications on three full production batches of Mo-99. A single production batch for a large-scale producer can contain hundreds to thousands of 6-day curies recovered from multiple targets.

An sNDA is required any time there are significant changes to the Mo-99 production process. However, if the changes to the Mo-99 production process are judged by the company to be minor, it could elect to submit a Change Being Effected (CBE) notification to the FDA instead of an sNDA. The CBE informs the FDA about the change but does not provide analytical testing data. The FDA would review the CBE and could approve it or direct the company to submit an sNDA.

Application (sNDA) to the FDA (see Sidebar 8.1). The committee was told by representatives of CORAR (see also Brown, 2005) and some Mo-99 producers that a great deal of time and effort would likely be required to develop and submit an sNDA, particularly to support the three required production runs to test the new product: Protocols must be developed for



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