Stability formal studies

Stability Assessment In general there is no formal stability study prior to the certification of a natural matrix S RM. H owever, the stability of the certified analytes is monitored on a regular basis, typically every 1-3 years depending on the analytes, as the SRMs are analyzed as control samples during the analyses of similar matrix samples. A recent study of PAHs in frozen mussel tissue over nearly 10 years found no significant changes in the concentrations of the measured PAHs (Schantz et al. 2000). 

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). 

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. 

Figure 1 Cartoon illustration of hypothetical chromatograms from stress testing (upper) and accelerated or long-term stability studies. Peaks A-I represent all the degradation products from stress-testing studies under various stress conditions and are therefore classified as potential degradation products. Peaks B-E and G represent the products that form at significant levels during formal stability studies and are therefore classified as the actual or relevant degradation products.

Another example of an amine reacting with a formulation component is found in the case of duloxetine hydrochloride (84). This example, which is also discussed in Chapter 2, is summarized in Figures 49 and 50. In this example, the secondary amine of duloxetine hydrochloride reacted with the enteric coating polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS) to form a succinamide degradation product. This reaction occurred under both stress conditions (60°C for 14 days) and during formal stability studies (30°C/60% relative humidity and 40°C/75% relative... 

Confirmatory studies should be conducted on both the drug substance and the final formulation as part of the formal stability studies for registration, and may be regarded as an accelerated stability test (2). It is very important that the physical state of the sample be in its manufactured and / or marketed form (i.e., final crystal form, particle size, and hydration state) during exposure. Techniques used to alter the physical state of the sample (e.g., such as grinding to reduce particle size) as recommended in some publications (7) should be avoided. 

The design of the formal stability studies for the drug product should be based on knowledge of the behavior and properties of the active ingredient, results from stability studies on the active ingredient, and experience gained from clinical formulation... 

Formal stability studies must be performed to determine key parameters to support an acceptable and successful marketed product. The following are some of the parameters required ... 

NONE or N/A (not applicable) on the label for expiration date. The laboratory must, however, be prepared to justify this designation. For other materials an expiration date should always be indicated on the label. The FDA has indicated that formal stability studies are not required to justify assigned expiration dates it is sufficient to assign expiration dates based on literature references and/or laboratory experience. 

A stability report is written to document expiration dates and a storage statement for the registration batches for the formal stability studies. It is also used to document the expiration date for formulations that are being used in the clinic. In this case, the expiration date is generally a date when the product should be discontinued or that additional data are required to extend the expiration date. A more detailed discussion of the information included in the stability report is given in Section lI.E. 

Data from formal stability studies should be provided on at least three primary batches of the drug substance. The batches should be manufactured to a minimum of pilot scale by the same synthetic route as production batches and using a method of manufacture and procedure that simulates the final process to be used for production batches. The overall quality of the batches of drug substance placed on formal stability studies should be representative of the quality of the material to be made on a production scale. Other supporting data can be provided. 

Provisional specifications have been created for all packaging components, and these are subsequently used to clear all materials through a QC plus type operation prior to use in any tests, irrespective of whether these are feasibility or formal stability studies. Procedures should include (for plastics) material identification (by IR, UV, differential scanning calorimetry (DSC), etc.), physical assessment including dimensions and functional tests, and should be of greater technical and scientific depth than the QC procedures used for subsequent regular incoming production materials (hence the use of the phrase QC plus ). 

The design and execution of formal stability studies should follow the principles outlined in the parent guideline. The purpose of a stability study is to establish, based on testing a minimum of three batches of the drag substance or product, a retest period or shelf life and label storage instmctions applicable to all future batches manufactured and packaged under similar circumstances. 

The basic concepts of stability data evaluation are the same for single- vs. multifactor studies and for full- vs. reduced-design studies. Data evaluation from the formal stability studies and, as appropriate, supporting data should be used to determine the critical quality attributes likely to influence the quality and performance of the drug substance or product. Each attribute should be assessed separately and an overall assessment made of the findings for the purpose of proposing a retest period or shelf life. The retest period or shelf life proposed should not exceed that predicted for any single attribute. 

A systematic evaluation of the data from formal stability studies should be performed as illustrated in this section. In general, stability data for each attribute should be... 

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