Bracketing design

Typical bracket designs are shown in Figures 13.32a and b. The loads which steel brackets with these proportions will support are given by the following formula ... 

Figure 13.32. Bracket designs (a) Single gusset plate (b) Double gusset plate...

Cyclic ligands Square brackets designate that the ligand is cyclic and the number within the brackets is the number of atoms in the macrocyclic ring. Saturated macrocycles are designated by ane , while, for unsaturated ligands, ene is used preceded by a prefix to identify the number of double bonds (e.g. diene or tetraene). The donor atoms are then identified. Substituents attached to the macrocycle are indicated by either a prefix or suffix. 

Note that bracketing was not applied to the batch factor because the FDA regulation requires testing at least three batches to determine a drug product shelf life. Even so, the sampling required for the bracketing design was reduced substantially. The sample size required per time period is 12, a small number when compared to... 

The use of a bracketing design would not be considered appropriate if it cannot be demonstrated that the strengths or container sizes and/or fills selected for testing are indeed the extremes. 

Before a bracketing design is applied, its effect on the shelf life estimation should be assessed. If the stability of the extremes is shown to be different, the intermediates should be considered no more stable than the least stable extreme (i.e the shelf life for the intermediates should not exceed that for the least stable extreme). 

An example of a bracketing design is given in Table 3. This example is based on a product available in three strengths and three container sizes. In this example, it should be demonstrated that the 15 and 500 mL HOPE container sizes truly represent the extremes. 

Many organometallic compounds of groups 1 and 2 exist in associated molecular form (as aggregates) or contain structural solvent, or both. However, their names are often based solely on the stoichiometric compositions of the compounds, unless it is specifically desired to draw attention to the extent of aggregation or the nature of any structural solvent, or both (see Example 3 below). In the examples below, note how the different types of name reflect the different structural content implied by the formulae shown. As usual, the formulae enclosed in square brackets designate coordination entities. 

Where a range of sizes of immediate containers are to be evaluated, bracketing designs may be applicable if the material of composition of the container and the type of closure are the same throughout the range. 

The factors that may be bracketed in a stability study are outlined in ICF1Q1A and described in further detail below. The types of drug products and the types of submissions to which bracketing design can be applied are also discussed. 

Bracketing design is applicable to most types of drug products, including immediate- and modified-release oral solids, liquids, semisolids, and injectables. Certain types of drug products, such as MDIs, DPIs, and transdermal delivery systems, may not be amenable to, or may need additional justification for, bracketing design. 

Because of the complexity in product formulation, applicants are advised to consult the appropriate chemistry review team in advance when questions arise in the above situations or where justification is needed for bracketing design. In the case in which the strength and the container or fill size of a drug product both vary, bracketing design may be applicable if justified. 

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