Compliance calibration method

This chapter discusses regulatory issues in HPLC laboratories with a focus on procedures and requirements for system qualification, calibration, method validation, and system suitability testing. Examples in a cGMP pharmaceutical environment are used to illustrate the various tools and systems used to ensure the degree of HPLC data accuracy necessary to achieve the delicate balance of regulatory compliance and laboratory productivity. 

Dynamic mechanical analysis (DMA) was performed to determine the influence of the polymer constitution on tensile modulus and mechanical relaxation behavior. For this purpose, a Perkin Elmer DMA-7 was run in tensile mode at an oscillation frequency of 1 Hz with a static stress level of 5 x lO Pa and a superposed oscillatory stress of 4 x 10 Pa. With this stress controlled instrument, the strain and phase difference between stress and strain are the measured outputs. Typically, the resulting strain levels ranged from 0.05% to 0.2% when the sample dimensions were 8 mm x 2 mm x 0.1 mm. A gaseous helium purge and a heating rate of 3°C min" were employed. The temperature scale was calibrated with indium, and the force and compliance calibrations were performed according to conventional methods. 

In NIR, a series of samples are scanned and then analyzed by a referee method. An equation is generated and used for future unknowns. This equation is used after the instrument is checked for compliance with initial performance criteria (at the time of the equation calibration). No standard is available for process or natural samples. The value(s) is gleaned from chemometric principles. This is defined as a prediction. 

EXPERIMENTAL The sampling and analytical method employed in determining the various solvent vapor concentrations in air are described in detail by White etal (A)and NIOSH (2), Four Bendix National Environmental Instruments Model BDX 30 Personal Samplers were used daily (one in each laboratory) with large size charcoal tubes (SKC cat no. 226-09-100) which contained two sections of activated charcoal per tube (a 400 milligram section followed by a 200 mg backup section to indicate when "breakthrough" of the main section has occurred). The sampling pumps were operated at a rate of one liter per minute and were calibrated by means of an Environmental Compliance Corporation Model 302 Universal Pump Calibrator (a device that generates a thin film of soap which is carefully timed as it traverses a very... 

Method development of TLC has been thoroughly discussed in the recent books by Elke Hahn-Deinstrop, and Bernard Fried and Joseph Sherma.30,31 The most recent review article by Colin Poole and Neil Dias also provided certain guidance on method development in TLC.32 While the focus of this chapter is not on TLC method development, there are a few points that need to be stressed regarding method development from a regulatory perspective. First and foremost, use of qualified/calibrated equipment is part of the GMP compliance. In other words, all instruments must have updated Instrument Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ) according to the company s SOP (Standard Operation... 

Kenna and Sheiner (41) used a simulation study to show that the MPML method— which uses an aU compliance data-dosage history questionnaire, Cq, available from all subjects and combines that with dosing history obtained with MEMS, C, from a random fraction of subjects, effectively calibrating Cq to C—is superior to other methods that use only one compliance measure, or both, or neither where neither was intention-to-treat. The authors showed that the MPML approach yielded efficient dose-response estimates over a wide range of clinical trial designs, effect sizes, and varying quality and quantity of compliance information. The method was shown to maintain good performance even when its key assumptions were violated and compliance data were sparse. 

The U.S. EPA has developed a series of performance specifications (PS) for continuous emissions monitoring systems (see Figure 7.55) for measuring a wide range of pollutant emissions [43]. These specifications are listed in Table 7.3. Note that two of the specifications (4 and 4A) have identical titles. PS-4 is for the general measurement of CO emissions while PS-4A is for measuring lower concentrations (< 200 ppmv) of CO emissions. These are to be used in conjunction with the EPA methods discussed above. The performance specifications include discussions of calibration procedures and relative accuracy requirements. The EPA has also developed quality assurance procedures to be used for compliance determination [44]. 

However, when the LOQ of a method is significantly lower than the actual concentrations monitored for compliance with a MRL, it may be more appropriate to carry out the validation experiments based on a lowest calibrated level (LCL), typically 0.5 x the MRL. For use in a regulatory program, the limits of detection and quantification are important parameters when the method will be applied to estimate exposure to residues, where there may be an interest in monitoring residues at concentrations below the MRL, or when conducting residue analyses for substances that do not have ADIs or MRLs. For monitoring compliance with a MRL, it is important that an LCL be included in the analysis that adequately demonstrates that the MRL concentration may be reliably determined. The LCL of a method used to support a MRL should not be less than the LOQ. 

Erom this method calibration, simple extrapolation of a measurement unknown will produce a concentration estimate. However, from a QA perspective, day-to-day comparisons of these simple calibration measurements, and the associated statistics, can often highlight aspects of reagent quality, apparatus (balance, volumetric glassware, etc.), and operator competence when compared. These data can be invaluable in assisting regulatory compliance, and ensuring that the complete measurement system is under control. 

The requirement that equipment should be tested and proven to be fit for purpose is effectively fulfilled by an approach known as equipment qualification (EQ), which is well established and proven in the highly regulated pharmaceutical industry. EQ is complementary to method validation for the spectrophotometer and is built on effective instrumental calibration validation (see below). EQ is a systematic procedure, which ensmes that suitable equipment is purchased and that it remains fit for its chosen purpose throughout its operating life. The same requirement is present in ISO/IEC 17025, where section 5.5.5 Records of Equipment requires checks to ensure compliance with the specification, maintenance plans, etc. 

Retention-time locking provides the immediate benefits of increased sample throughput, greater confidence in results, easier analysis for compliance, and lower costs of sample analysis. All you need is a GC equipped with the RTL software, EPC, and a GC ChemStation. With RTL, all peaks match and elution order is constant. Retention-time locking eliminates the need to update calibration tables, timed events tables, and integration events tables when a method is transferred, a new column is installed, or routine maintenance is performed. 

The compliance method measures the compliance of the specimen by unloading it during the experiment. Comparing the measured value with a calibration curve determined on specimens with known crack length, the crack length can be determined. 

A speed limit decrease generally induces a decrease in the road injury and fatality accident count. This chapter presents a method for the ex-ante assessment of such a decrease and its application on a French motorway network. Some results on the calibration and the use of relationships linking traffic density or speed to accident counts are given. The envisaged decrease in the speed limit by 20 km/h should lead to a 1.9% decrease in the accident count with the current compliance and to a 3% decrease with full compliance. These figures are a trade-off between a null trend for certain accidents (due to driver or vehicle failure), a decrease in accidents linked to speed and an increase in accidents linked to a high density. However, this prediction is very sensitive to the traffic and safety models, to their calibration and to the conditions of their use. 

The GC-MS/MS detection method described uses a timed-SRM (selected reaction monitoring) setup with three transitions for each analyte for a confirming ion ratio confirmation. The t-SRM window is typically set to 30—60s width for all compounds. The compliance with the calibrated compound ion ratios of standards is checked by the processing software for the peaks identified in the samples (Figure 4.35 and Table 4.9). 

The limit of detection calculated according to the lUPAC criterion as 3se/bi, where s is the square root of the residual variance of the calibration plot and bi is the slope, resulted in values of 1. ig H for As(III) and 2. ig H for total As. These limits of detection are adequate to assess the compliance of the method with the maximum tolerable levels for As in drinking water (WHO, 2004). 

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