As a general rule, the use of overages of active substances in formulations is discouraged unless their use can be justified completely. The routine inclusion of overages by manufacturers of certain products without adequate justification is unlikely to be permitted. Similarly, the use of overages should not be an excuse for poor manufacturing, formulation, or analytical procedures. Where loss takes place during manufacture of the product, then the replacement might well be justified as a “manufacturing overage” because the amount present within the dose form at the time of release is likely to remain within the approved specification. However, large (for example 10%) overages used to compensate for poor product stability, in general, are not considered to be acceptable.
The presence in excess of inactive constituents in a formulation should also be explained and justified.作者: 大学习 时间: 2014-6-26 05:44
Manufacturers may want to use an overage of an excipient in the manufactured product. There is a general antipathy toward this practice and any overages will need to be justified. The approach will depend on whether the overage is proposed based on losses during manufacture or the need to meet a requirement for the level of the excipient during the shelf life. Large overages—usually taken as those in excess of 10%—are unlikely to be allowed. This is because such large overages could present unacceptable hazards to users. It would be better to reformulate the product if such large overages are needed. Other overages will need to be justified in terms of the technical need for the overage and the potential for adverse events arising from their presence or the presence of the degradation products arising from them.
Manufacturing Overage
If the statistical analysis of stability data for different batches is carried out, there is a consistenttrend for the intercept of the assay of the drug product being below 100%; this may indicateinstability during the manufacturing stages and during the initial storage before the releaseassay. For products with marginal stability (i.e., with a calculated shelf life of 18 months orless), it may be worthwhile considering adding a manufacturing overage. This would need tobe justified in the stability report. Where the data on individual batches, packaging, strengths,etc., can be pooled to give a common estimate of the intercept; this can be used to calculate theoverage.The manufacturing overage can be calculated as follows:
