Error, analytical manufacturing

Following the completion of the Source Code Review, a review report or a number of review reports will be produced to summarize the review findings. These reports may identify actions to be taken by the LIMS supplier, the analytical manufacturer, or the personnel responsible for performing the validation of the LIMS. These actions may range from identifying specific testing that will need to be included in the testing process to revisions of the source code due to deviations from GPP or to correct errors. 

Of all the requirements that have to be fulfilled by a manufacturer, starting with responsibilities and reporting relationships, warehousing practices, service contract policies, airhandUng equipment, etc., only a few of those will be touched upon here that directly relate to the analytical laboratory. Key phrases are underlined or are in italics Acceptance Criteria, Accuracy, Baseline, Calibration, Concentration range. Control samples. Data Clean-Up, Deviation, Error propagation. Error recovery. Interference, Linearity, Noise, Numerical artifact. Precision, Recovery, Reliability, Repeatability, Reproducibility, Ruggedness, Selectivity, Specifications, System Suitability, Validation. 

ASSAY2.dat As part of a large validation program, 40 samples were pulled from a production batch. One measurement points to either a gross inhomogeneity or an analytical error the trend of the others could indicate variations in the manufacturing process. 

If an analytical test results in a lower value x, < x0, then the customer may reject the product as to be defective. Due to the variation in the results of analyses and their evaluation by means of statistical tests, however, a product of good quality may be rejected or a defective product may be approved according to the facts shown in Table 4.2 (see Sect. 4.3.1). Therefore, manufacturer and customer have to agree upon statistical limits (critical values) which minimize false-negative decisions (errors of the first kind which characterize the manufacturer risk) and false-positive decisions (errors of the second kind which represent the customer risk) as well as test expenditure. In principle, analytical precision and statistical security can be increased almost to an unlimited extent but this would be reflected by high costs for both manufacturers and customers. 

Methods intended for regulatory residue condol should be designed with as much simplicity as possible to limit the variety, size, and type of glassware and equipment needed to minimize the potential for analytical error and to reduce costs. Reagents and standards must be readily available while specific instrumentation should be based on performance characteristics rather than a particular manufacturer. 

A second example would be a group of 26 sherds assumed to be of local Hesi manufacture. The corresponding figures were iron 4.17 to 7.34% mean 5.55 16.5%, scandium 15.6 to 27.5 ppm mean 20.52 16.3%. The calculated ratio would be 3.697 23%. The standard deviation of 26 calculated Sc/Fe ratios was however only 2.1%. The small standard deviations (3.3 and 2.1% in the Sc/Fe ratio) remaining are close to that predicted for compounding errors caused by analytical technique. 

Another major source of aberrant results is improper or inadequate training of the personnel directly involved in the execution of the manufacturing process or analytical testing. There is a simple cause and effect relationship between inadequate training and frequency of errors made in the performance of any complex task. The more complex the task, the stronger and more direct the relationship. According to the GMPs (21 CFR 211.22)... 

Allowance must be made for variation from the true content of active ingredient because analytical methods are subject to error and variations in conditions during manufacture may also cause heterogenities of product composition. The allowance is known as a tolerance and represents the permissible departure from the declared figure. It is influenced by ... 

A useful application of the CoV is to compare different analytical methods or procedures, so that you can decide which involves the least proportional error - create a standard stock solution, then compare the results from several sub-samples analysed by each method. You may find it useful to use the CoV to compare the precision of your own results with those of a manufacturer, e.g. for an autopipettor (p. 11). The smaller the CoV, the more precise (repeatable) is the apparatus or technique (note this does not mean that it is necessarily more accurate, see p. 65). 

From the studies conducted by this committee in the past several years, it can be concluded that the quality of peptides produced by ABRF member laboratories is high, as judged by modem analytical techniques. However, there have always been a few less than satisfactory samples for which the source of synthetic problems could only be attributed to human error. In the present study, errors of this type originated not only from some member laboratories, but from manufacturers, as illustrated in some of the examples described below. 

The validation process determines the amount of error owing to variation among the values in the population. It is used to check for the existence of a relationship between the calibration set and the validation set. Manufacturers of NIRS instrumentation include software packages that allow the operator to predict analytical results on data files that have been stored, thus allowing for validation of the calibration equation and testing for errors in the developed calibration. This enables calibration equation performance testing in terms of precision. The validity of these models depends on the ability of the calibration set to accurately represent the samples in the prediction set. 

The elution method involves scraping off the separated zones of samples and standards and elution of the substances from the layer material with a strong, volatile solvent. The eluates are concentrated and analyzed by use of a sensitive spectrometric method, gas or liquid column chromatography, or electroanalysis. Scraping and elution must be performed manually because the only commercial automatic micropreparative elution instrument has been discontinued by its manufacturer. The elution method is tedious and time-consuming and prone to errors caused by the incorrect choice of the sizes of the areas to scrape, incomplete collection of sorbent, and incomplete or inconsistent elution recovery of the analyte from the sorbent. However, the elution method is being rather widely used (e.g., some assay methods for pharmaceuticals and drugs in the USP Pharmacopoeia). 

Evaporation of specimen from cups or tubes in the loading zone has caused analytical errors as great as 50% over 4 hours.Operationally, all cups or tubes containing solution for analysis should be covered until the time the specimen is to be analyzed. Many manufacturers of automated analyzers provide covers for individual cups or for part or the whole of the loading zone to reduce losses caused by evaporation. Cups may be covered by Parafilm or by caps that are placed over the cups and that have crosscuts to permit ready entry of a specimen probe. A type of antievap-orative cover that reduces evaporative losses to less than 0.1%/hr has been described. ... 

In practice, clinical laboratories are able to purchase materials from one of several companies that manufacture control sera or control products. These are generally sup-phed as liquid or lyophilized materials that are reconstituted by adding water or a specific diluent solution. Also available are materials having matrices representing urine, spinal fluid, and whole blood. Liquid control materials are also available and have the potential advantage of eliminating errors caused by reconstitution. However, the matrices of these liquid materials contain other materials that may be a potential source of error with some analytical methods and instruments. 

Another major change in the final rule was the elimination of an earlier provision that would have required the FDA to review a manufacturer s QC instructions. That was a key provision for allowing laboratories to simply follow a manufacturer s directions. However, with elimination of that provision, laboratories now have more responsibility for establishing effective QC systems that will monitor the complete analytical process, take into account the performance specifications of the method, detect immediate errors, and monitor long-term precision and accuracy. 

A proper model validation procedure consists of a model verification part and a part where the model predictions are compared to experimental data [61]. The model verification may be performed by the method of manufactured solutions[14 7, 163]. The method of manufactured solutions consists in proposing an analytical solution, preferably one that is infinitely differentiable and not trivially reproduced by the numerical approximation, and the produced residuals are simply treated as source terms that produce the desired or prescribed solution. These source terms or residuals are referred to as the consistent forcing functions. This method can be used to confirm that there are no programming errors in the code and to monitor the truncation error behavior during the iteration process. 

---