Impurity testing trends

Sample preparation (SP) is generally not given adequate attention in discussions of pharmaceutical analysis even though its proper execution is of paramount importance in achieving fast and accurate quantification (see Chapter 5). Non-robust SP procedures, poor techniques, or incomplete extraction are the major causes of out-of-trend and out-of-specification results. The common SP techniques have been reviewed with a strong focus on tablets or capsules, as they are the primary products of the pharmaceutical industry. Detailed descriptions of SP methods for assays and impurity testing are provided with selected case studies of single- and multi-component products. 

Impurity testing of pharmaceuticals is one of the most difficult HPLC method development tasks because of their requirements for both high-resolution and trace analysis in additional to stringent regulatory and reporting guidelines.20,21 There are several recent trends for these methods 22,23... 

This chapter provides an overview of modern HPLC method development and discusses approaches for initial method development (column, detector, and mobile phase selection), method optimization to improve resolution, and emerging method development trends. The focus is on reversed-phase methods for quantitative analysis of small organic molecules since RPLC accounts for 60-80% of these applications. Several case studies on pharmaceutical impurity testing are presented to illustrate the method development process. For a detailed treatment of this subject and examples of other sample types, the reader is referred to the classic book on general HPLC method development by L. Snyder et al.1 and book chapters2,3 on pharmaceutical method development by H. Rasmussen et al. Other resources include computer-based training4 and training courses.5... 

Trends toward MS-compatible, gradient methods for impurity testing... 

The Limit of Quantitation (LOQ) and the reportable limit for impurities also impact impurity test OOT procedures. It is common practice to report impurity peaks below the Limit of Quantitation as < LOQ, which is set to the reporting limit for that impurity per ICH Q3A(R2). Therefore, the purity result for peaks just below the LOQ cannot be used for trending although the analytical method variance may be satisfactory at that level. This reporting practice again decreases the information presented in the stability data tables, limits the QQT tools for impurities close to the... 

Figure 13. Changes in 6 Fe values of HPS Fe standard as a function of contaminate elements Al, Mg, or La (12.5 to 75 ppb). All solutions were 400 2 ppb Fe. The Fe isotope compositions of the solutions are shifted from those in the pure Fe standard (6 Fe = +0.49 0.05%o) as a function of the impurity concentration. The magnitude of the this shift with impurity concentration is variable, as shown by data collected during three analytical sessions (parts A, B, and C). These impurity matrix elements do not produce molecular isobars, as evidenced by the fact that 5 Fe and 5 Fe values plot along a mass-dependent array (part D). Note that an important conclusion of these tests is that accuracy of Fe isotope measurements cannot be demonstrated by preservation of mass-dependent trends in Fe/ Fe and Fe/ Fe. Data were collected using the Univ. of Wisconsin-Madison Micromass IsoProbe.

Rat. In a study previously reported in an abstract, four groups of 86 male and 86 female Sprague-Dawley rats, five weeks of age, were administered -butyl acrylate (purity, > 99.5% main impurities, butyl propionate and isobutyl acrylate) by whole-body inhalation at concentrations of 0, 15, 45 and 135 ppm (0, 86, 258 and 773 mg/m ) in air for 6 h per day on five days a week for 24 months. Interim kills were performed after 12 months (10 males and 10 females), 18 months (15 males and 15 females) and 24 months (10 males and 10 females). After a further six months, the study was terminated. No dose-related trend in mortality was observed. After 24 months of exposure, the mean cmnulative mortality w as approximately 20%. During the six-month post-exposure period, the cumulative mortality increased to approximately 45%. Exposure to -butyl acrylate vapour did not lead to an increased frequency of any tumour type in any organ that could be related to the test substance (Reininghaus et al., 1991). 

Qualification and maintenance Temperature and humidity records Investigation and reporting of excursions Stability reports Impurities profiles Test points used for data evaluation Selective reporting of data Data trends... 

The unused bed is quite homogenous, as seen in Fig. 4 for test I. As the test proceeds, two main trends in the compositional distributions are apparent. The distribution spreads out towards the Al+Si/ Na+P+S+K-edge on one hand, and to the Mg+Ca+Ti+Fe-comer on the other. The first trend is cormected to the formation of sodium-rich adhesive material in small agglomerates fomied around quartz impurities... 

The trending of potency and impurities over time can be challenging for biologies and several methods may be necessary to profile each of these attributes. First, as discussed earlier, there is not necessarily a direct link between concentration (quantity) and potency, since the concentration test, usually UV spectrophotometry, does not give information on biological activity, it simply gives protein concentrations... 

The common tests for stability testing are appearance, strength (content), and degradation impurities. In order to monitor stability, a quantitative test is best as it will demonstrate a trend. Thus, a description of color, for instance, may be best made by an instrumental approach. Pharmacopeial requirements... 

PIT behavior can be readily observed in test-tube experiments. Close to the balanced state, the samples of macroemulsions can be readily pr ared by hand because of the low interfacial tension between oil and water. Moreover, the surfactant purity is not very important. Impurities just shift the position of the macroemulsion inversion point, leaving the general inversion trend unchanged. In fact, the PIT trend itself was established not with pure surfactants but with a polydisperse surfactant product. On the other hand, good temperature control is necessary, in particular close to the balanced point. 

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