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CERTIFICATES OF ANALYSIS


The measurement of solvent’s density parameter is characterized by high accuracy, depending by gravimetric operations during solutions’ preparation. This evaluation is a further purity assay and proof of constancy of properties of solvent batch. Moreover, it allows reaching a high degree of accuracy in the determination of the equivalent mass of solvent for the subsequent operations. It also avoids the manipulations and volumetric measurements affected by greater variability and uncertainty than exclusive weight comparisons.
For each new batch of solvent , an analytic check confirms high purity and lack of organic pollutants. Then it is subjected to gravimetric analysis into the pycnometer, calibrated and certified at controlled temperature in the production department. The obtained density value and the uncertainty relating to the calculation contributes to the expanded production uncertainty.

Temporal validity of CRM solution is defined thanks to the temporal protocol of analytical monitoring. Solutions are subjected to this protocol in order to obtain data on the stability and homogeneity, in compliance with the ISO Guide 34, and according selection and statistical inference criteria described in ISO Guide 35. The quality assurance of CRM within the whole period of validity is represented either by the observation of the analytic solutions behavior in “stressed” and isochronous mode and by the substantial stability of the certified properties along the stated time.

The best conditions to preserve CRM properties are defined by storage temperature in primary intact packaging, and handling instructions. These parameters are determined considering the inherent nature of molecules, potential interactions with solvents and the results of stability and homogeneity tests. Silanized amber ampoules ensure protection against deactivation reactions due to electromagnetic radiations ranging in visible spectrum. Additional data about possible sonication of ampoule are available.

Gravimetric concentration is determined using metrological samples with mass at high metrological level (OIML Class E1 weights). This to ensure metrological traceability in the calibration of mass comparators used for preparation, weighing and dilution operations. Mass comparators are periodically calibrated according to DT-06-DT procedure (“Guidelines on the calibration of non-automatic weighing instruments”). A calibration control is carried out many times a day, to ensure that the accuracy of weighing is included in the upper and lower acceptance limits.

The “Primary reference CRM” is a data that ensures the “metrological chain” integrity. All molecular entities that are likely to become CRMs are directly related to the “primary NIST standard”, using the “absolute” technique of Nuclear Magnetic Resonance. The magnitude of the signal generated by the resonance of one or more protons of the highly pure NIST standard is directly compared with the signal generated by the “CRM candidate”. Since the NMR signal directly depends on the number of protons chemically and/or magnetically equivalent in resonance, this technique directly correlates the number of resonating entities to the quantity of molecules in solution. Therefore the integral of NIST signal allows a direct comparison with the signal from one or more selected protons. Ultimately, this technique directly transfers the metrological property, without the need of an intermediate standard, otherwise required in complementary analytical techniques.

I nuovi lotti di produzione di un materiale candidato CRM sono comparati col batch in esaurimento dello CRM in questione con l’ausilio di tecniche opportune, quali HPLC-DAD, GC-FID/ECD, LCMS, GCMS. Non meno di tre unità in confezionamento estratte in maniera casuale sono analizzate, ed la media aritmetica del segnale generato dalla soluzione non deve eccedere il 3% di variabilità intra-lotto rispetto al segnale generato dal batch precedente.

The numeric range defined as “Stated Uncertainty”, refers to the absolute expanded uncertainty. “Absolute” as it is expressed in units identical to the concentration and “expanded” as it results from the combined standard uncertainty multiplied by the coverage factor. This factor counts on a statistical confidence associated with the measurement of 95% (value 1.96). The expanded absolute uncertainty takes into account all the contributions related to solutions setting up, as shown in the Ishikawa diagram in the certificate of analysis. It is calculated according to the requirements of the EURACHEM CITAC and GUM guide (Guide to the Expression of Uncertainty in Measurement), applying the “metrological” approach (the most detailed and exhaustive). “Stressed uncertainty” means evaluation of the uncertainty on the material stored in drastic temperature conditions (CIPAC MT-46).

The substantial intra-batch homogeneity of the CRM solutions has to be verified. The sampling of the units to be tested is performed by dividing the lot into three subsets and randomly picking a unit from each subset. The adopted parameter defines the cut-off point of 0.5% in percentage variability among the three produced units.

Common name, molecular weight resulting from the sum of the atomic weights (weighted average of the isotopes), molecular and structural formula, CAS number and IUPAC nomenclature are useful data that allow unambiguous identification. In the analytical report the instrumental features are highlighted (diastereomers, geometric isomers, tautomers, enantiopurity).

The percentage of purity derives from instrumental evaluations in order to detect the impurities of organic nature (isomers, synthesis impurities, degradation products). This assessment is made by observing the NMR spectrum (that shows the presence of possible “spurious” signals) and by HPLC, DAD, GC FID/ECD analysis. To these possible impurities is to be added the adsorbed water on the powders, qualitatively detected by the FT-IR spectroscopy and quantitatively determined by means of Karl Fisher method. The declared purity takes into account the percentage of both detected and indeterminate impurities

The analytical report, included in the certificate of analysis, provides a comprehensive set of spectra and chromatograms of the CRM solution. NMR and IR spectra, and HPLC-DAD, GC-FID/ECD, LCMSMS, GCMS, LCHRMS chromatograms are provided with detailed information about the method of analysis, instrumentation, optimal conditions, MSMS transitions, experimental masses in high resolution so as to replicate methods and apply data collected and reported in the analytical laboratory routine.

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