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18 Pharmaceutical Technology REGULATORY SOURCEBOOK SEPTEMBER 2019 P h a r mTe c h . c o m Analytical Procedure Validation ability can also be estimated with 17 degrees of freedom (from the two batches after allowing for a constant batch offset). An unmicronized batch and a micronized batch were selected as the two API batches to give further confidence of method performance (two preparations per batch per con- dition were used in the study) to incorporate the range of attributes likely to be encountered by the analytical method. Example 2: Cascade impaction method for an inhaled device A cascade impaction method—next-generation im- pactor (NGI) (24)—is used to measure aerodynamic particle size distribution (APSD) for an inhaled product. A dose of the inhalation powder from the inhaler flows through the impactor depositing par- ticles of different sizes at various stages (removable components such as throat, pre-separator or pre-sep, and a set of cups). The impactor configuration has removable cups with all the cups in one plane as illustrated in Figures 1 and 2, reproduced with per- mission from the European Pharmacopoeia (25,26). The factors selected were considered most likely to impact the method. The purpose of the study was to identify any particularly large sources of variation and to estimate repeatability and inter- mediate precision variances. This was important as typically the combined analytical and within- batch product variability for APSD (which mainly cannot be estimated separately) is relatively large compared to the product specifications. The risk assessment identified analyst and NGI equipment as important IP factors. It also identified cupset as a likely source of variation. Typically, approxi- mately six analyses can be performed on one NGI equipment in one day, either by the same ana- lyst or a pair of analysts. In routine use, different throat, pre-sep, and cupsets from a pool associ- ated with that piece of NGI equipment will be used to allow cleaning and drying to take place while the next analysis is underway. It is therefore not clear whether changes of throat, pre-sep, and cup- sets should be considered as the same measuring system (18) or not. However, as they are typically varied within a day they were not considered to be IP factors. The f lowrate is checked prior to each analysis while the NGI leak rate is checked daily. For a given NGI equipment an independent ana- lytical run could be considered to be: Figure 1: Impactor configuration illustrating pre-separator in place reproduced from the European Pharmacopoeia (Apparatus E). Figure 2: Impactor configuration illustrating component parts (including the removable cups) reproduced from the European Pharmacopoeia (Apparatus E). Figures courtesy of EDQM