Pharmaceutical Technology - September 2019

Pharmaceutical Technology - Regulatory Sourcebook

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14 Pharmaceutical Technology REGULATORY SOURCEBOOK SEPTEMBER 2019 P h a r mTe c h . c o m ability of an analytical procedure in comparison to simpler studies, for example where only two sets of results generated by two analysts on different pieces of equipment are compared. Intermediate precision studies can be incorporated into more comprehensive reproducibility/ruggedness studies and should be considered, especially when analyti- cal procedures are being transferred across one or more geographical locations. This article provides three examples where a risk-based approach has been used to design bespoke studies that evaluate intermediate precision. Intermediate precision design requirements ICH Q2(R1) does not provide a definition for an IP condition of measurement; however, the Inter- national Vocabulary of Metrology does provide a useful definition as being from: "a set of conditions that includes the same measurement procedure, same location, and replicate measurements on the same or similar objects over an extended period of time, but may include other conditions involving changes" (17). In contrast, repeatability also has "the same operators, same measuring system, and same operating conditions … over a short period of time" (18). These definitions are aligned with those in ICH Q2, and for high-performance liquid chro- matography (HPLC) procedures, this differentiation is fairly well established. The short period of time is typically considered as one day (19) or one ana- lytical run (20). The University of Tartu provides two definitions of analytical run, one of which is taken from the clinical laboratory improvements amendment "as a set of samples analysed on one batch in a short time, or an interval during which accuracy and precision is expected to be stable and the interval between control samples defining the analytical run" (20). It also describes that interme- diate precision is the precision obtained within a single laboratory over a longer period of time—gen- erally at least several months—and takes into ac- count more changes than repeatability. In particu- lar, the following factors are mentioned: different analysts, calibrants, batches of reagents, columns, spray needles, etc. These factors are constant within a day (i.e., behave systematically within day tim- escale) but are not constant over a longer time pe- riod and thus behave as random in the context of intermediate precision. Kojima (4) provides the following clarifications when describing the design proposed by Japanese NIHS. To repeat the analysis independently means to repeat from the very beginning of the analyti- cal procedure so that the previous analysis result will not affect the next analysis result. Also, a test date does not have to be interpreted literally. If the procedure is followed as if the test date is changed, such as rebuilding the calibration curve, starting up the instrument from the off state and calibrat- ing according to the method, the experiment can be repeated at intervals of several hours. The decision on what is an independent analytical run and whether to allocate a factor to repeatability or IP may not always be clear, as is discussed in a cascade impactor method described in Example 2. IP is usually estimated through a designed experi- ment that enables estimation without requiring an extended period of time. Two important elements to designing such studies are knowledge of factors with their risk of causing variability within a labo- ratory over the longer term, and an experimental plan that changes their levels between "independent analytical runs," termed run-different intermediate precision by Boqué et al. (21). A simple assessment Analytical Procedure Validation

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