Stability sampling considerations

The design of a stability study should take into consideration the variability of individual dosage units, of containers within a batch, and of batches, to ensure that the resulting data for each dosage unit or container are truly representative of the batch as a whole and to quantify the variability from batch to batch. The degree of variability affects the confidence that a future batch would remain within specifications until its expiration date. 

Batches selected for stability studies should optimally constitute a random sample from the population of production batches. In practice, the batches tested to establish the expiration dating period are often made at a pilot plant that may only simulate full-scale production. Future changes in the production process may thus render the initial stability study conclusions obsolete. 

Handbook of Pharmaceutical Manufacturing Formulations Semisolid Products 

Selection of containers, such as bottles, packages, and vials, from the batch chosen for inclusion in the stability study should ensure that the samples represent the batch as a whole. This can be accomplished by taking a random sample of containers from the finished batch, by using a stratification plan whereby at a random starting point every nth container is taken from the filling or packaging line (n is chosen such that the sample is spread over the whole batch), or by some other plan designed to ensure an unbiased selection. 

In general, samples to be assayed at a given sampling time should be taken from previously unopened containers. For this reason, at least as many containers should be sampled as the number of sampling times in the stability study. 

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More recendy, a number of tests of chemical stability of the latex concentrate have been developed. Chemical stability variance in the raw concentrate has considerable effect on the dipping characteristics of latex compounds, and can also affect mechanical stability of the compound. A broad rule is that, while latex MST can be increased or decreased without necessarily affecting its chemical stability, any change in the latter always is reflected in the MST. A new test, in which chemical stability is determined by measurement of the effect of weak zinc acetate solution added to a second mechanical stability sample and the result contrasted with the original MST, is available to numerically quantify chemical stability (56). 

The above considerations were a starting point in the formulation of the problems in the series of investigations discussed in this chapter.14-24 The motive for elucidating the mechanochemical aspect of the radiation cryochemistry of solids was the discovery14 of the effect of excitation of a reaction in the irradiated, low-temperature-stabilized samples of reactants in response to a local fracture. 

Delocalisation onto oxygen stabilizes radicals considerably. An important example is the ascorbate radical (Scheme 1.3) formed by electron-loss from the ascorbate anion, or electron-capture by dehydroascorbate. This is remarkably stable, and is characterized by an ESR doublet (1.7 G) which is quite distinctive. Because of the high sensitivity of ESR spectroscopy, and the fact that opaque samples can be used, ascorbate radical intermediates have been widely studied (Liu et al., 1988a). The most probable structure is shown in Scheme 1.3 but this is still a matter of some controversy (Liu et al., 1988a). A key factor in the formation of ascorbate radicals is that ascorbate anions... 

It is seen from Table 18 that coefficient y has different values depending on the extent of PAC conjugation, being introduced into cellulose acetate. So, initial CA and CA with BA additive after irradiation have the largest value of y. Coefficients y in CA with XXXV and XXXVI additives after irradiation do not change considerably in comparison with the value of initial CA. These results show that light resistance of CA stabilized samples essentially depends on the extent of PAC conjugation. 

The results obtained show that stabilizer injection causes a significant (over two times) deceleration of thermal oxidation in LCP. Of interest is the effect of additives on polymer morphology, determined during studying stabilized and non-stabilized samples (before and after thermal oxidation in air) by the X-ray difiraction analysis. It is found that crystalline reflex is preserved in stabilized polymers, whereas it disappears in non-stabilized samples. The stabilization effect on the physical structure of polymers was not studied well with respect to chemistry of degradation processes. Only complex consideration of the problem (chemistry + change of physical permolecular structure) may cause the increase of thermal stability of prepared product and extension of the material lifetime in articles. 

A considerable amount of time is necessary to reach the point at which sample analyses can commence, and it is essential that the stability and reliability of the mass spectrometer be high to ensure maximum sample throughput during the limited time available between calibration checta. 

In those cases where there are any doubts about the feasibility of producing a sufficiently homogeneous and stable reference material, a feasibility study might be needed. For this study, an extra amount of material is needed. Questions regarding the best way of preparing the sample, the stability of the material, or the fitness for purpose might justify the inclusion of a feasibility study in the project. In the BCR projects, it is common practice to have a feasibility study, which usually has as the sole purpose of assessing the performance of the laboratories in the collaborative study in relation to the certification of the reference material. The feasibility study allows the participants to fine-tune their equipment, their methods, and their procedures in view of the characterization measurements. In each of these cases, a considerable extra number of samples is needed. 

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