Approved Stability Protocol

S.7.1 Stability Summary and Conclusions 3.2.S.7.2Post-approval Stability Protocol and Stability Commitment 3.2.S.7.3Stability Data... 

P.8.2 Post-approval Stability Protocol and Stability Commitment... 

Changes to an approved stability protocol or comparability protocol unless otherwise provided for in this guidance (e.g., Vlll.C, VIII.D, XLC.2). 

Any changes to an approved stability protocol should have a supplemental approval prior to initiation of the stability study. 

Marketed product stability studies are required to provide assurance that the drug product continues to exhibit reproducible quality over its shelf life and that accumulated minor changes over time have not adversely affected the product. These studies are initiated annually on one batch of each marketed product in each marketed container-closure system using the approved stability protocol. 

The FDA Draft Stability Guidance defines an approved stability protocol as a detailed plan described in an approved application that is used to generate and analyze stability data to support the retest period for a drug substance or the expiration dating period for a drug product. 

Approved stability protocols are important for the sponsor because they may be used in developing data to support an extension of an approved retest or expiration dating period via annual reports in accordance with 21CFR314.70(d)(5). To change an approved stability protocol or to define one in an application requires a prior approval supplement. 

Using the approved stability protocol and reporting data in annual reports. 

Formal studies are those undertaken to a pre-approval stability protocol that embraces the principles of these guidelines. 

Products without an Approved Stability Protocol Applicants who have previously performed stability studies on a drug product without an approved protocol are required to submit an appropriate protocol under a Prior Approval Supplement under 21 CFR 314.70(b) or (g) or 601.12(b) (see Section V regarding an Approved Stability Protocol). On approval of the protocol, applicants may initiate stability studies on all annual batches under the ICH long-term conditions. Data from the first three consecutive annual batches after the switch can be used to verify the current—or establish a new—expiration dating period. However, if the applicant wishes to verify product stability under the ICH conditions over a shorter time span, three production batches within 1 year, instead of three consecutive annual batches, may be studied... 

Products without an Approved Stability Protocol Applicants who have previously performed stability studies on a drug product without an approved protocol should submit an appropriate protocol as a Prior Approval Supplement. This protocol should contain 25°C/ambient humidity as the primary long-term storage testing conditions, and... 

Products with an Approved Stability Protocol Applicants who have an approved stability protocol may submit the alternate stability protocol in the annual report, reflecting the temperature and humidity as recommended by the ICH. Other changes to the stability protocol generally should be submitted in a Prior Approval Supplement, unless the changes are to comply with the current compendium. 

Products without an Approved Stability Protocol For applications that do not contain an approved stability protocol as defined above, a new or revised stability protocol may be submitted in a Prior Approval Supplement marked expedited review requested. This protocol should encompass 25°C/ambient humidity as the primary long-term storage conditions, and the ICH long-term conditions as the alternate, as well as accelerated stability storage conditions as defined by the ICH Guidance and above, in addition to other recommendations described in this guidance. On approval of the protocol, stability studies may be initiated on annual batches and on batches intended to support supplemental changes. 

Conduct or complete the necessary studies on the first three production batches and annual batches thereafter of each drug product, container, and closure according to the approved stability protocol through the expiration dating period... 

Annual reports should include new or updated stability data generated in accordance with the approved stability protocol. These data may include accelerated and long-term studies for each product to satisfy the standard stability commitment made in the original or supplemental application, including the annual batch or batches, and to support postapproval changes. The data should be presented in an organized, comprehensive, and cumulative format. 

Stability Profile — Physical, chemical, biological, and microbiological behavior of a drug substance or drug product as a function of time when stored under the conditions of the Approved Stability Protocol. 

P.8.2 Post Approval Stability Protocol and Stability commitment... 

Stability smdies are initiated based on approved stability protocols. Much discussion is provided in Chapters 3 and 4 regarding ICH and global requirements for stability protocols. 

In the course of developing pharmaceutical products, there are situations where a conscious decision to not follow written procedures occurs. This may happen in several instances such as the manufacture of the batch, the analytical testing, or other possible reasons. Just as an approved stability protocol has an amendment mechanism to document changes to the plan, the use of a formal deviation report mechanism allows work to be continued and any deviations to be... 

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