Stability studies marketed products

There are generally two types of stability studies conducted 1) regular and 2) accelerated. In the case of accelerated stability study, the product is stored under elevated temperature and relative humidity (RH) conditions to force or expedite its degradation pathway and assess the changes. The stability testing conditions depend on the anticipated market environment. An example of a recommended protocol is provided in Table 1. 

An Investigational Medicinal Product Dossier (IMPD) is intended to be more comprehensive than an IB, in that it should contain summaries of available quality data in addition to the safety and efficacy information that constitutes the main part of the IB. In total, it should provide information on the chemistry, manufacture, control and stability ofthe medicinal product, together with the results of non-clinical and clinical studies. In order to avoid repetition, the IB can be cross-referenced for non-clinical and clinical results. Ideally, the IMPD should follow the same structure as that which will be used later for the marketing authorisation application. For products with existing marketing authorisations, the Summary of Product Characteristics may replace the IMPD to varying extents (see Chapter 6). 

Bioavailability, dissolution and stability study data Regulatory status in other countries Marketing information Proposed product monograph... 

Supporting Data — Data, other than those from formal stability studies, that support the analytical procedures, the proposed retest period or shelf life, and the label storage statements. Such data include (1) stability data on early synthetic route batches of drug substance, small-scale batches of materials, investigational formulations not proposed for marketing, related formulations, and product presented in containers and closures other than those proposed for marketing (2) information regarding test results on containers and (3) other scientific rationales. 

For pharmaceutical scientists, the value in cocrystals would be if such materials would be superior active pharmaceutical ingredients relative to the drug substance itself. This possibility has been studied for the carbamazepine-saccharin cocrystal, where its performance characteristics were compared with the marketed form of carbamazepine [46]. It was learned that the physical and chemical stability of formulations containing the carbamazepine-saccharin cocrystal product were similar to those of carbamazepine in the marketed product, and comparative bioavailability studies demonstrated that the cocrystal was a viable alternative drug substance to the anhydrous drug form used in the conventional solid dose forms. 

The goal of this chapter is to provide an understanding of the overall stability study process and its corresponding compliance challenges. It is hoped that such an understanding will result in stability studies that not only meet all regulatory and compliance requirements, but also improve and increase the assurance of the quality of the marketed product. 

To Support Product Development. In addition to supporting the use of clinical trial materials, stability studies are carried out on both the API and different formulations in different container-closure systems to guide the development of the final formulation and container-closures. Stability studies may be carried out on either the formulation to be marketed or a representative formulation to evaluate different API suppliers, drug product manufacturing processes and sites, and drug product container-closures. 

Perhaps the most important criterion for registration stability studies (i.e., the studies used to determine the retest date for an API and the expirationdating period for a drug product) is the selection of batches, which must be representative of the material to be marketed. 

If the drug product in the registration stability study is not the same as the product used in the clinical trials, the differences must be assessed. Likewise, any differences between the drug product in the registration stability study and the product to be marketed must be assessed. All differences should be explained and justified. Release data comparisons and/or a bioequivalence study may be required, depending on the significance of the differences. 

Sometimes container-closure development is not complete when the registration stability studies are initiated. Firms may then include multiple container-closure systems in the registration stability study and choose the one(s) to be used for the marketed product based on the results of the stability study. Although this means additional work, it is usually preferable to a delay in the start of the stability study. 

Extrapolation of an expiration-dating period beyond real-time data may be justified if supported by data from accelerated and supportive stability studies. The extrapolated expiration-dating period must be confirmed by real-time stability studies on the marketed product. Although a long expiration-dating period is most desirable, caution should be exercised in extrapolating beyond real-time data, as this could put marketed product at risk. Batches that fail to maintain the required quality parameters throughout the extrapolated period could be subject to a recall. 

In addition to stability studies on the product as it will be marketed, the product s conditions-of-use should be examined to determine if special studies are necessary. Such studies only need to be as long as the duration of expected conditions-of-use, or to be conservative, some multiple of the duration of the expected conditions-of-use. 

It appears that stability studies never really end. Indeed, development and registration stability studies that culminate in approval to market a drug may be considered just the start of stability studies for that product. Example 6 shows the various types of postapproval stability studies. 

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. 

All stability studies on a marketed product must of course be carried out in full compliance with cGMPs. Example 8 presents stability areas often cited as deficient during regulatory inspections. 

Failure to complete registration stability studies Failure to include each marketed product in the stability program Stability data not evaluated as part of the annual product review Stability results do not support expiration dating period Batches evaluated under QA requested studies released before sufficient data were available Stability data do not support proposed changes... 

State the proposed expiration dating period and storage conditions. Summarize the stability studies justifying the expiration dating period. Stability data should be submitted for the drug product in the container in which it will be marketed. 

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