Stability protocols

Methods of assessing the stereochemical integrity of enantiomeric drug substances and drug products should be included in the stability protocols for both, but stereoselective tests may not be required once it has been shown that racemization does not occur. 

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... 

Stability Stability protocols and data should be submitted, along with the commitment and protocols to continue stability testing post-approval. 

The inclusion of the a routine microbial limit test in a marketed product stability protocol depends on the pharmaceutical dosage form. Typically, the test would be used only for nonsterile products, especially oral liquids, nasal sprays, and topical liquids, lotions, and creams that have sufficient water activity to support the growth of microorganisms. In contrast, tablets, powder- and liquid-filled capsules, topical ointments, vaginal and rectal suppositories, nonaqueous liquids and inhalation aerosols with a water activity too low to allow for the product to support the growth of microorganisms would not be routinely tested. 

Since, in the absence of bacterial growth in the produet, the endotoxin level does not increase on storage during the shelf life, baeterial endotoxin testing is not indicated in stability protocol. If there is a eontinued need to inelude endotoxin testing in a protocol, testing at release and at expiry is reeommended. 

Additional container/closure integrity testing is to be performed on the first commercial batch at the end of the expiration date as indicated in the stability protocol. 

Container closure integrity. Test methodology is per ABC Pharmaceutical Industries. The dye ingress challenge test is performed as described in the manufacturing site stability protocol. 

Endotoxin testing. Endotoxin analysis, whenever applicable, is conducted as described in the stability protocol in (provide section number specihed in ANDA hie). 

Formal Stability Studies — Long-term and accelerated (and intermediate) studies undertaken on primary or commitment batches according to a prescribed stability protocol to establish or confirm the retest period of a drug substance or the shelf life of a drug product. Impermeable Containers — Containers that provide a permanent barrier to the passage of gases or solvents (e.g., sealed aluminum tubes for semisolids, sealed glass ampoules for solutions). 

Product stability Inspection of the establishment to determine compliance with cGMP requirements and to conduct an audit of the data furnished to CDER in the application is a Field responsibility. This requirement applies to both the relevant preapproval batches, as discussed above, and the proposed commercial batches. CDER application review chemists are responsible for review of the proposed drug product stability protocol, specifications, and evaluation of the data submitted in support of the expira-... 

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

Addition of time points to the stability protocol or deletion of time points beyond the approved expiration dating period. 

The scope section describes what the process validation protocol covers, the number of batches, and what it does not cover. In this part, usually packaging validation or mouthpiece testing is included or excluded. Any worst-case tests may be briefly described. Stability commitments and stability protocols should be mentioned. 

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

Site change (maintaining same specifications) New validation protocol Stability protocol revisions for expanded accelerated and longterm stability Update methods validation Master and batch record revisions Equipment comparability study... 

Stability protocol for accelerated and long-term studies, including all the information in the phase 2 stability protocol (tests, analytical procedures, time points for each of the tests, and duration of the study) plus temperature and humidity conditions and a detailed description of the material under investigation, including packaging... 

Clearly specified stability protocol for the first three production batches and annual batches thereafter... 

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. 

Awell-designed stability program has many aspects. Some aspects are general and best addressed in a stability program SOP. Other aspects are specific and best described in product-specific stability protocols. 

A stability program SOP should define all general aspects of stability studies and serve as the basis for preparation of specific protocols. The SOP should include sections on (or reference other SOPs for) the procedures for the stability protocol, samples, testing, chambers or rooms, and final report. Items to be included in each section of a stability program SOP are outlined in Examples 9-15. 

A product-specific stability protocol supplements the information provided in the stability program SOP. In some instances, the requirements in a product-specific stability protocol may differ from those specified in the stability program SOP for scientific, regulatory, or business reasons. In all cases, aproduct-specific stability protocol takes precedence over the general stability program SOP. The product-specific stability protocol should clearly define and justify both the conditions to be used and any deviations from the stability program SOP, including reason and justification. 

A product-specific stability protocol should include the items outlined in Example 14. 

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