Stability commitments

The use of alternative designs, such as bracketing and matrixing, may be appropriate (see Sections VII.G and FI). 

A stability commitment is acceptable when there are sufficient supporting data to predict a favorable outcome with a high degree of confidence, such as when an application is approved with stability data available from pilot-plant batches, when a supplement is approved with data that do not cover the full expiration dating period, or as a condition of approval. This commitment constitutes an agreement to 

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 

Submit stability study results at the time intervals and in the format specified by the FDA, including the annual batches 

Withdraw from the market any batches found to fall outside the approved specifications for the drug product. If the applicant has evidence that the deviation is a single occurrence that does not affect the safety and efficacy of the drug product, the applicant should immediately discuss it with the appropriate chemistry team and provide justification for the continued distribution of that batch the change or deterioration in the distributed drug or biological product must be reported under 21 CFR 314.81(b)(l)(ii) or 21 CFR 601.14, respectively 

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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... 

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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. 

Type Stability data at time of submission Stability commitments ... 

Registration stability commitment—first three production batches Annual batches—one batch of each product in each container-closure system or as approved in the application Multiple manufacturing sites... 

Specifications and Test Methods Storage Conditions Testing Frequency Stability Commitments Data Evaluation DRUG PRODUCT... 

The magnitude of the stability database included in the submission influences the stability commitment that must be made. 

The same stability protocol used for the primary batches must be used for the stability commitment unless scientifically justified otherwise. In this case prior agreement with the regulatory agencies is recommended. 

The stability protocol used for long-term studies for the stability commitment should be the same as that for the primary batches, unless otherwise scientifically justified. 

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. 

In general, site-specific drug product batches should be made with identifiable site-specific drug substance batches both for original applications, wherever possible, and for postapproval stability commitment. 

Summary and conclusions Postapproval stability commitments Stability data... 

Postapproval stability commitments— Agencies expect that companies will have in place a procedure for routine monitoring of the stability characteristics of API production material. Recently, several agencies have required that the... 

ICH Q1A(R2) recommends that a stability commitment be submitted in the registration application. It commits the applicant to perform stability testing on three commercial production batches according to the current protocol through the proposed shelf-life. 

The stability commitment section could include the protocol to be followed for future stability studies. These studies can be for either the first three production batches or for representative batches for annual product monitoring. Commitment should be clearly made and followed through. For a new submission, a commitment is made for the first three production batches, which follows a protocol similar to the submission batches, and also for the annual product monitoring, which generally contains only stability conditions at long-term storage. 

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

Similar to other pharmaceutical products, for combination products the FDA requires a stability commitment at time of filing. This commitment must include stability studies on the first three commercial batches and one annual product monitoring batch. It is usually in the form of a protocol detailing checkpoints and test methods and a commitment to communicate the results to the FDA. However, recently there appears to be a trend in expectations for inhaled products whereby 10% of commercial batches fall within the remit of such a stability commitment. 

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