Changes Prior Approval Supplement

The following are examples of changes that are considered to have substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a product as these factors may relate to the safety or effectiveness of the product. 

A move to a different manufacturing site, except one used to manufacture or process a drug substance intermediate, when the new manufacturing site has never been inspected by the FDA for the type of operation that is being moved, or the move results in a restart at the new manufacturing site of a type of operation that has been discontinued for more than 2 years 

Transfer of the manufacture of a finished product sterilized by terminal processes to a newly constructed facility at a different manufacturing site Once this change has been approved, subsequent site changes to the facility for similar product types and processes may be filed as a Supplement—Changes Being Effected in 30 Days 

---

New method, no limit change Prior approval supplement Implement upon approval or run both methods... 

Prior Approval (PA) "Prior Approval Supplements" supplement submission fora major change for which distribution of the product made using the change cannot occur prior to FDA approval as provided in 21 CFR 314.70 and 21 CFR 601.12. 

A supplement [Changes Being Expected (CBE), Changes Being Expected in 30 Days (CBE-30), or Prior Approval Supplement (PAS)] can be submitted to the agency prior to implementation, and, if necessary, an inspection can be performed by a PAT team or PAT certified investigator before implementation. 

Filing documentation—A prior approval supplement with all data including the accelerated stability data is required. This change should also be documented in the annual report along with the long-term stability data. 

Filing documentation—Prior approval supplement with justification for change long-term stability data must be reported in the annual report. 

Filing documentation—A prior approval supplement must be filed with justification for the change. Long-term stability data should be submitted in the annual report. 

Prior Approval Supplement For a major change (substantial potential to have effect on quality and performance), a supplement has to be submitted to the FDA for approval before a product made with the change is distributed. There is also a provision for Prior Approval Supplement Expedite Review Requested for public health reasons and if the delay in approval may cause any substantial concerns for the applicant. 

Prior approval supplement (accelerated stability data) for MR and changes being effected supplement forIR... 

Processing changes affecting the Change in the type of process used Updated batch record Stability Updated batch record—stability Prior approval supplement... 

An f2 value less than 50 does not necessarily indicate lack of similarity. If the sponsor is of the opinion that the differences observed related to this calculation of f2 are typical for the drug product involved in this SUP AC situation, an appropriate j ustification can be submitted, but only as part of a prior approval supplement. This justification should include additional data to support the claim of similarity, as well as supporting statistical analysis (e.g. 90% confidence interval analysis). If this justification is not found acceptable, the potential effect of the proposed change on the differences in dissolution on bioavailability should be determined. 

An applicant can submit one or more protocols (i.e., comparability protocols) describing tests, validation studies, and acceptable limits to be achieved to demonstrate the absence of an adverse effect from specified types of changes. A comparability protocol can be used to reduce the reporting category for specified changes. A proposed comparability protocol should be submitted as a prior approval supplement, if not approved as part of the original application. FDA intends to issue separate guidance on comparability protocols. 

In some cases there may be a substantial potential for adverse effect, regardless of direct testing of the drug substance or drug product for conformance with the approved specification. When there is a substantial potential for adverse effects, a change should be filed in a prior approval supplement. 

---