21 U.S.C. § 356a — Manufacturing changes

(a) In general. For a drug with an approved application or license in effect, the holder of that application or license may change the approved manufacturing process, and distribute the drug made with the change, if: (1) the holder has validated the effects of the change under subsection (b); and (2) either (A) for a major manufacturing change, the holder has met subsection (c)'s requirements, or (B) for a change that isn't major, the holder complies with the applicable requirements of subsection (d). (b) Validation of effects of changes. Before distributing a drug made with any manufacturing change — major or not — the holder must validate how the change affects the drug's identity, strength, quality, purity, and potency, to the extent those relate to the drug's safety or effectiveness. Only after validating this may the drug be distributed. (c) Major manufacturing changes. A drug made with a major manufacturing change may be distributed only if, before distribution, the holder submits a supplemental application to the Secretary and the Secretary approves it. The application must contain whatever information the Secretary determines appropriate, including the subsection (b) validation information. A "major manufacturing change" is one the Secretary determines has substantial potential to adversely affect the drug's identity, strength, quality, purity, or potency as they relate to safety or effectiveness. This includes a change that: (A) alters the drug's qualitative or quantitative formulation, or the specifications in the approved application or license (unless the Secretary exempts it by regulation or guidance); (B) the Secretary determines by regulation or guidance requires a clinical study showing the changed drug is equivalent to the drug made without the change; or (C) is another type of change the Secretary determines by regulation or guidance has substantial potential to adversely affect the drug's safety or effectiveness. (d) Other manufacturing changes. For changes that aren't major, the Secretary may: (A) authorize holders to distribute the drug without submitting a supplemental application; (B) require holders to submit a supplemental application before distributing; and (C) establish categories of changes and assign each category to (A) or (B) treatment. For changes to which (A) applies, the holder must submit a report on the change — containing appropriate information and the subsection (b) validation data — by whatever date the Secretary specifies; if a holder makes more than one such change in a single year, the Secretary may let the holder file one combined annual report covering all of them. For changes to which (B) applies, the required supplemental application must contain appropriate information, including the validation data. The holder may begin distributing the drug 30 days after the Secretary receives that supplemental application, unless the Secretary notifies the holder within those 30 days that prior approval is required before distribution. The Secretary may also designate a category of such changes where the holder may begin distributing as soon as the Secretary receives the supplemental application. If the Secretary disapproves a supplemental application, the Secretary may order the manufacturer to stop distributing drugs made with that manufacturing change.