Testing for long-term stability

Tier 4 Comprehensive solid-state characterization Discriminating dissolution testing Satisfactory Comprehensive testing for long-term stability and dosage-form development... 

The first three production batches of drug substance manufactured after approval, if not a part of the original submission, should be selected for long-term stability testing using the same stability protocol submitted in the approved drug application. 

If the submission does not include stability data on any production batches, a commitment to select the first three production batches for long-term stability testing and to continue testing through the proposed re-test period must be made. 

The stability of the fish oils was tested at -18°C, +20 C and +37°C over a period of 14 months. There was no significant difference associated with stability in the concentrations of CBs or the total lipid content in either fish oil stored at the three temperatures. This stability was expected as it is well known that CBs are very stable. The matrix stability was assured by the measures taken such as use of dark glass ampoules and sealing under argon. Storage at a temperature at ca. +20°C is acceptable for long-term stability a higher temperature up to +37°C is unlikely to cause any measurable effect on the CB-content. 

For long-term stability, the SAPC must remain assembled. To test for this type of stability, it was investigated whether the components can self-assemble. The rhodium complex HRh(CO)(TPPTS)3, TPPTS and water were loaded into a reactor with cyclohexane and 1-heptene. The reactor was pressurized with approx. 70 bar H2 + CO (CO H2, 1 1) and heated with stirring to 100°C. A second experiment was carried out in a manner similar to the one previously described except that CPG-240 was added also. The components of the SAPC self-assemble to form an SAPC and carry out the hydroformylation reaction [13]. Upon termination of the reaction, the solid collected contained HRh(CO)(TPPTS)3 and TPPTS. This test indicates that, under the conditions of the experiment, the individual components of the SAPC are more stable assembled in an SAPC configuration than separated. Therefore, the reverse, i.e., the separation of the solution and complex from the support, is not likely to happen under reaction conditions. 

In practice, sensors with oxoanionic solid electrolytes are less successful till now, especially in tests of long-term stability. There are many reasons for this, a fundamental reason is given by the electrode processes taking place during unevitable current flows. Every direct current causes on one side a loss of solid electrolyte material in consequence of alkali ion migration and gas delivery. On the other side the discharge of alkali ions causes chemical reactions with gas components forming compounds like oxides, hydroxides, basic salts or hydrates which do not correspond to the solid electrolyte material. Every flow of direct current produces an asymmetry in the body of the oxoanionic solid electrolyte. At the cathode, besides the reactions (25-66) and (25-67), simultaneously electrode reactions are possible, for example. 

As a consequence, the adequate temperature for long-term stability testing of medicinal products to be marketed in Brazil would be 30°C. That value includes a safety margin of 4% added to the highest MKT calculated for Brazil. 

To calculate the adequate relative humidity for long-term stability testing, the mean partial water vapour pressure calculated for Sanya (27.16 hPa) is used at the standard testing temperature 30°C to get 64.0% RH. Testing at 30°C would include a safety margin of 14% added to the MKT, and testing at 65% RH would include a safety margin of 2% for Pd. Sanya, however, presents an extreme climate compared to the other parts of the country. 

In the following, the climates of countries in Northern and Eastern Africa, the Arabian Peninsula, the Middle East and Southern Asia are presented and analysed, and the most appropriate testing conditions for long-term stability studies are proposed. 

On the other hand, testing at lower humidities would be less challenging for most of the products, in particular for solid oral dosage forms like tablets, which are generally more stable in a dry environment. It is therefore adequate and justified to test the long-term stability of products for countries in Climatic Zone III at higher humidities, e.g., 30°C/65%. 

The hottest place in Southern African Development Community (SADC) identi-tied so far is Dar es Salaam Group Aw) in Tanzania (see Fig. 4.13). Mean maximum temperatures increase to 31.6°C in February, and never decrease below 21°C. The most appropriate temperature for long-term stability testing of medicinal products to be marketed in Tanzania and SADC is 30°C. That value includes a safety margin of 13% added to the highest MKT calculated for Dar es Salaam. 

Li et al. [199] tested for long-term periods up to 415 days MFl and MOR membranes in water acetic acid mixtures, and the highest stability was observed for the membranes prepared in fluoride media. 

Some of the [Au(N,0)Cl2] derivatives, namely 58a, 59a and 59b, which have been tested for cytotoxic activity against various human tumor cell lines, have shown significant effects [144]. Compound 57 is a potential alternative to dimethylgold (III) P diketonates and can be used as a starting material for gold coatings by the CVD method [140]. Recent studies have shown that the long-term stability of these... 

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