Calculating Additional Safety Margins

There is no scientific rationale for setting safety margins. In other disciplines like the construction of buildings, bridges or cars, the safety margins regarded as necessary to cover unexpected extremes is set based on tradition and experience more than on experimental results. 

As far as pharmaceutical products are concerned, in exceptional cases where an additional margin of safety may be required, the real climatic conditions in the environment of the target market have to be considered compared to the test condition. Testing temperatures for tropical countries are normally moved up to 30°C, and relative humidities to 65, 70 or 75%. 

For temperatures the following equation (4.1) can be applied to calculate a safety margin  

The same principle can be applied to other parameters like partial water vapour pressure. 

The distributions of the loading and the resistance result in the probability of failure of a particular product in a particular market. 

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Reviewing the calculation methods as implemented in the various pressure vessel codes (see Table 4.3-1) shows that these are based on the scientific formulae as per Table 4.3-2 but partly appear in a different shape due to approximations, simplifications, additional safety margins and other factors taking care of manufacturing tolerances, weakening by corrosion and welding seams [3] [4] [5] involved. 

The tank overfill level is defined as the point at which either the tank will suffer mechanical damage or product will be lost from the tank. For fixed roof tanks without an internal roof, loss of containment is expected to occur from a fitting in the roof, typically a PV valve or a dip hatch (if open). For the purposes of setting alarms the overfill level for tanks of this type is considered to be the top of the shell. This gives additional safety margins and greatly simplifies the overfill calculation. Thus for this example the overfill level is defined as the top of the shell. This is 20 m above the base of the tank. 

This calculation method is also relatively simple and only requires information on a few, often well known, input parameters. An additional safety margin is obtained by ignoring cohesion. 

Essential modelling for scale-up relates to heat production (ref.4), and the universally applied calculation relates to the disaster calculation where the runaway instant temperature rise is always calculated for any one-shot exothermic reaction. In addition, the normal heat production rate is calculated to determine optimum feed rates, safety margins on cooling coil and condensers, etc. Increasingly, kinetic models are used as these become available. 

This method of design is only approximate and therefore, in a large tank, about 1 metre should be added to the calculated depth as a safety margin and to allow for the depth required for the suspension to reach the critical concentration. In addition, the bottom of the tanks may be slightly pitched to assist the flow of material towards the thickened liquor outlet. 

Generally, food laws state which substances may be used for which foods. Sometimes, the maximum amount permitted in a food and other conditions are also fixed. Both authorization and maximum amount are based on technological necessities, with calculation of a sensible safety margin. In contrast to other food additives, major differences exist in the food-coloring laws of the EU countries, the United States and Japan. 

These preliminary results indicate that with passive RVACS cooling and a coolant boiling temperature of 1430°C, there will be a considerable safety margin for an LOFC accident. An additional calculation performed by UCB for a 4000 MW(t) core yielded a peak core temperature of 1325°C, still more than 100°C below the salt boiling limit. These transient response calculations confirm early scaling analyses that predicted passive safety characteristics because of the very large thermal inertia of the AHTR. ... 

The criterion used here is the approach used in the ANSI B31.3 Petroleum Refinery Piping, that is, to limit the maximum calculated principal stress to the allowable stress range rather than using the shear theory of failure. The value 1.25(.S a + provides a safety margin against the possibility of fatigue due to localized stresses and other stress conditions (see Fig. 2.1). Obviously, stresses must be computed both with and without thermal expansion, since allowable stresses are much smaller for conditions without thermal expansion. As an additional safety precaution, the computed stresses are usually based on the modulus of elasticity E at room temperature [ 8 ]. 

An important outcome of the JECFA evaluation is the establishment of an ADI for a food additive. The ADI is based on the available toxicological data and the no adverse effect level in the relevant species. JECFA defines the ADI as an estimate of the amount of a food additive, expressed on a body weight basis, that can be ingested daily over a lifetime without appreciable health risk (8). JECFA utilizes animal data to determine the ADI based on the highest no-observed-adverse-effect level (NOAEL), and a safety factor is applied to the NOAEL to provide a margin of safety when extrapolating animal data to humans. JECFA typically uses safety factors of 50, 100, or 200 in the determination of an ADI. The NOAEL is divided by the safety factor to calculate the ADI. The food additive is considered safe for its intended use if the human exposure does not exceed the ADI on a chronic basis. This type of information may potentially be used to help assess the safety of a pharmaceutical excipient that is also used as a food additive, based on a comparison of the ADI to the estimated daily intake of the excipient. 

Comparison of results of dietary toxicity studies and estimated or calculated residues in avian food categories provide more than adequate margins of safety. As shown above, when a series of redundant worst-case assumptions arc made and the highest residue food item (short rangegrass) is used, the acute and chronic MOS values are 12.8 and 3.4, respectively (Tables 8.9 and 8.10). When actual residues (spinach) are used, the acute and chronic MOS values are 29 and 8.0, respectively. Further, when an additional conservative I Ox factor is applied to the exposure (i.e. 10 applications), the acute MOS values arc J-3 or greater. 

V.14. These are based on the calculated examples given in various references at the end of the appendix, see especially Refs [V.3, V.ll, V.17]. Friction between the package and the conveyance platform is to be ignored and can only be regarded as a bonns giving an additional but unquantifiable margin of safety. 

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