Drug substances retest periods

The purpose of stability testing is to assess the effects of temperature, humidity, light, and other environmental factors on the quality of a drug substance or product. The data produced are used to establish storage conditions, retest periods, shelf loss, and to justify overages included in products for stability reasons. The most useful equation relating temperature and reaction rate is the Arrhenius equation. This equation (27) may be integrated and rewritten as Eqs. (31) and (32). 

Long-term testing Stability studies under the recommended storage condition for the retest period or shelf life proposed (or approved) are performed with several drug substance batches in the stipulate packaging. In the general case, the storage condition is at a temperature of 25°C and 60% relative humidity. 

For drug substances, a retest date is generally determined. The period up to the retest date is a period during which the material is known to adhere to its specification, for example, for assay or degradants. The retest date may be assigned on the basis of real-time stability data obtained at the recommended storage conditions or on the basis of accelerated stability data obtained under more stressful conditions. 

Drug substances intended for storage below -20°C should be treated on a case-by-case basis. When available longterm stability data on primary batches do not cover the proposed retest period granted at the time of approval, a commitment should be made to continue the stability studies postapproval to firmly establish the retest period. 

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). 

Specification, Shelf Life — The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of a drug substance throughout its retest period, or that a drug product should meet throughout its shelf life. 

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. 

The application (or Type II DMF) should include a detailed description of the complete container closure system for the bulk drug substance as well as a description of the specific container, closure, all liners, inner seal, and desiccant (if any), and a description of the composition of each component. A reference to the appropriate indirect food additive regulation is typically considered sufficient to establish the safety of the materials of construction. The tests, methods, and criteria for the acceptance and release of each packaging component should be provided. Stability studies to establish a retest period for bulk drug substance in the proposed container closure system should be conducted with fillers or desiccant packs in place (if used). Smaller versions that simulate the actual container closure system may be used. 

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. 

The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors, such as temperature, humidity, and light, and to establish a retest period for the drug substance or a shelf life for the drug product and recommended storage conditions. 

Primary stability studies are intended to show that a drug substance will remain within specifications during the retest period if stored under recommended storage conditions. [ICH Q1A]... 

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