Method of planning and performing stability studies

The present invention relates to a method and system for planning a stability study of a pharmaceutical composition. According to the current invention a new statistical principle for designing studies is provided. It addresses directly that the aim of the stability study is to derive more precise and efficient specification limits. The method involves making estimates of the needs that might be encountered and in that way determine whether a given stability study model can provide the precision necessary to derive appropriate shelf-life specifications. The approach is based on utilizing normal distribution calculations of the obtainable specifications in Allen's formula. The terms that are estimated include the degradation rates such that in the estimated model, the specifications arrived at have at least a 90% chance of being better than projected by other methods. In addition the standard evaluation of the uncertainty of the slope is performed. Data at accelerated temperatures are other conditions may also be included to increase precision.

The present invention encompasses improved methods of planning pharmaceutical stability studies and carrying out more efficiently the preparation of pharmaceutical preparations based on those studies.

The method provides a standard approach for choosing the size of long-term drug product stability studies; particularly for NDA stability studies. The approach is aimed at setting specifications, and specifically at finding the difference between release and shelf-life limits by means of Allen's formula. To do so, it must account for the expected degradation and the intermediate precision as well as study specific parameters. The list of parameters includes: the number of batches of a target pharmaceutical prepared; the number of samples at the various time points, and the length of the study at the time of setting the specifications.

Specifically, the current invention provides for a method for planning a stability study of a pharmaceutical composition. The method is comprised of the following steps including: selecting a value for a release limit variable for a given specification test; selecting a desired length of the shelf-life of said pharmaceutical composition; selecting a time at which an analysis of the data for said stability study will be performed in order to set specfications; selecting time points at which one or more measurements of one or more predetermined pharmaceutical test variables can be performed; selecting a number of measurements of said predetermined test variables that will be performed at each of said time points; selecting a value for the expected degradation rate of said pharmaceutical composition over time; selecting a value for the intermediate precision of said measurements; and finally selecting a probability level regarding the level of certainty of the outcome of said stability study.

It should be noted that there is no particular order established with regard to the steps recited above in which a value is selected. According to the current invention, the values can be selected and input in any order into Allen's formula. This also allows a user to alter the values to evaluate the benefits of various parameters before the initiation of a stability study. Once the above steps are completed, the method of the instant invention will allow the shelf-life specification limits of a test or target pharmaceutical composition to be calculated based upon the variables selected in the steps mentioned above.

Moreover, the method of the current invention also provides for optimizing the variables selected in the steps mentioned above by changing one or more of the variables and recalculating the shelf-life specifications as necessary utilizing Allen's Formula. The specification test limits provided by the current invention may also be re-calculated by substituting in actual data obtained during a stability study for one or more of the variables mentioned above. It is desirable that the variables selected and the method of the current invention are followed such that the confidence levels regarding the level of certainty of the shelf-life specifications arrived at are at least 90%, and preferably at 95%.

It is also important to point out that the value selected for the expected degradation rate may be based on previous long-term stability studies. The computed degradation rate may also be based on previous long-term stability studies of a target pharmaceutical composition in an alternate formulation or in a study accelerated by increased temperature. Accelerated stability results reached in this way may be corrected by the Arrhenius formula.

In an additional embodiment of the current invention the value selected for the intermediate precision of the analysis of the target pharmaceutical composition may be determined from previous long-term stability studies of the same or similar pharmaceutical compositions.

Also according to the instant invention the time points for measurement of the variables mentioned above may be at any time, preferably however these time points are at 0, 3, 6, 9, and 12 months after start of the stability study of a target pharmaceutical composition.

Other features and advantages of this invention will become apparent in the following detailed description of preferred embodiments of this invention, taken with reference to the accompanying drawings.