Sample Selection Strategies

The selection of the set of samples that best covers the impurity and degradation profiles of the API is critical to successful method development. For a given API there are several ways to design the method development sample set some of which are more advantageous, but incur more risk in terms of the ability to track peaks from column to column and condition to condition. This section will address method development sample set design strategies, experimental concerns, and trade-offs. 

The sample solvent can be the source of instability and rapid degradation of the relevant impurity can occur. In the case of one development compound, an imine process-related impurity was a primary degradation product. The imine was stable in acetonitrile, but would readily hydrolyze in aqueous media. In fact, on-column degradation was observed when screening 

Impurity enhancement techniques such as fraction collection and phase equilibrium purification can be used to provide enriched samples for use in the method development process.23 When using the fraction collection approach, one or more cuts (fractions) of the chromatographic separation of a bulk lot or mother liquor are isolated. The excess solvent in these fractions is then evaporated to achieve the desired concentration enhancement. These fractions typically contain extraneous peaks because of the presence of salts in the mobile phase or sample degradation during the concentration step. The salts can be removed by extraction and/or a LC cleanup step. To insure that these extraneous peaks/artifacts are not identified as key peaks for separation, the original bulk lot or mother liquor should be included in the method development sample set. The same holds true for phase-equilibrium-purification supernatants. 

For a given API, there can be numerous ways to mix and match the available samples to construct the method development sample set. During early stages of development, only a few isolated intermediates and purposeful degradation samples may be available, making sample set selection relatively easy. Later in development, more isolated samples of the major degradants 

Drug substance lots with different impurity profiles can be combined for peak-tracking purposes, provided the impurity profiles are relatively simple and that the abundance of each impurity in the final solution is sufficient to obtain accurate photodiode array UV data. 

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It is worth noting that these standards could be a subset of the same standards used to develop the calibration model for the property of interest. In this case, there are several sample selection strategies available for identifying the transfer standards from the complete set of calibration samples [107-111]. 

Another important issue that arises in the PDS method, as well as some other standardization methods, is the selection of the samples to use for standardization. It is critical that the standardization samples efficiently convey the magnitude and nature of instrument-to-instrument variability artifacts that are expected to be present in the analyzers while they are operating in the field. Note that this criterion is different than the criterion used for sample selection for calibration, which is to sufficiently cover the compositions of the process samples that the analyzer is expected to see during its operation. Sample selection strategies for instrument standardization have been given by many.73,77-79... 

M. M. Said, S. Gibbons, A. C. Moffat, and M. Zloh, A Novel Sample Selection Strategy by Near-Infrared Spectroscopy-Based High Throughput Tablet Tester for Content Uniformity in Early-Phase Pharmaceutical Product Development. Note missing reference J Pharm Sci. 2012 Jul 101(7) 2502-ll. doi 10.1002/jps.23153. Int.. Pharm., 415,102 (2011). 

Principles and Characteristics A sample can contain a great number of compounds, but analysts are usually interested only in the qualitative presence (and the quantitative amount) of a small number of the total compounds. Selectivity is an important parameter in analytical separations. The total analytical process clearly benefits from selectivity enhancement arising from appropriate sample preparation strategies. Selective separation of groups or compound classes can simplify a mixture of analytes before analysis, which in turn enhances analytical precision and sensitivity. Selective fractionation, in some cases, allows easier resolution of the compounds of interest, so analysts can avoid the extreme conditions of high-resolution columns. 

A second variant detection strategy involves directed resequencing of selected genomic regions from different individuals, usually between 50 and 100 unrelated individuals. Many of these efforts have screened a subset of the DNA Polymorphism Discovery Resource collection, a set of 450 samples selected by the NIH to be a sample of the ethnic diversity of the U.S. popu-... 

Probabilistic sampling, which lies in the core of the DQO process, is based on a random sample location selection strategy. It produces data that can be statistically evaluated in terms of the population mean, variance, standard deviation, standard error, confidence interval, and other statistical parameters. The EPA provides detailed guidance on the DQO process application for the... 

Any use of novel responsive polymer components in space applications requires ground testing and ultimately space qualification to accommodate the complex LEO environment and better understand synergistic materials degradation. We have therefore participated in MISSE-6 (Materials International Space Station Experiment) with a combination of active and passive sample exposures that have been selected as a first flight experiment of piezoelectric polymers in LEO for space qualification. Two exposure conditions were available, the VUV backside and the VUV+AO ram direction of the MISSE assembly. Our experimental strategies for sample selection, exposure conditions and in-situ performance measurements are presented here. 

Obviously, potential hazardous effects are not only related to pesticides, but possibly also to their metabolites in living systems and/or degradation products in the environment. Considerable attention has been paid in recent years to the characterization of degradation products of pesticides and to the monitoring and quantitative analysis of such compounds in environmental samples. Selected results and strategies are reviewed in this section. 

The group of Bakhtiar [57-59] described the chiral bioanalysis of MPH in various matrices, utilizing a number of sample pretreatment strategies, separation on a Chirobiotic V columns, and the use of positive-ion APCI-MS in SRM mode. The chiral selectivity of the Chirobiotic V column is based on the use of the macrocyclic glycopeptide antibiotic vancomycin. The column can be used in both aqueous and organic mobile phase. 

Zone sampling. This strategy (and related strategies) selects different titrant aliquots with known concentrations to be added to the sample zone [335] which expands the potential of flow titrations. 

The selection strategy applied was the stochastic universal sampling, which uses a single random value to sample all of the solutions by choosing them at evenly spaced intervals. 

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