Validation methods

The methods used for testing at various stages in the manufacturing process must be validated to show that they are fit for their intended application. For example, a method may be capable of measuring an analyte to a high of degree of accuracy and 

Business Critical - affects areas other than GMP, 1 

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C. C. Andeison and E. C. Gundeison, Methods Validation Study of High Peformance Uquid Chromatographic Technique for Determining the MPDA and... 

This approach enables also to substantiate acceptance criteria for detection and qualification limits in impurity control method validation. 

In general, the publications cited here pertain to methods valid for several sulphoxides, even though some other compound classes may have been studied at the same time. However, many methods for dimethyl sulphoxide alone are also given on account of the considerable current importance of this compound. 

Control All control points starting with the basic raw materials right through to the finished product must be identified. Descriptions of the specifications, test methods, reference standards, and methods validation data should be included. 

In general terms, electrospray ionization is considered to be concentration-sensitive at Tow flow rates and mass-flow-sensitive at high flow rates, while APCI is considered to be mass-flow-sensitive. Low and high are both subjective terms and require investigation as part of method validation. 

The simplified theory allows the time-dependent wave function to be calculated rapidly for any specified laser field. However, controlling the dynamics of the charge carriers requires the answer to an inverse question [18-22]. That is, given a specific target or objective, what is the laser field that best drives the system to that objective Several methods have been developed to address this question. This section sketches one method, valid in the weak response (perturbative) regime in which most experiments on semiconductors are performed. 

Reproducibility of experiments indicates whether measurements are reliable or not under GMP regulations this is used in the systems suitability and the method validation settings. 

Demonstrating that an analytical procedure performs as intended is a GMP concem. 9.35-37,128-132 Jo this end, the employed equipment and the design of the method should be such that the intended goals can be met. The method validation delivers the formal proof that the outcome meets the expectations. 

Method Validation The signal path from detector up to the hard copy output of the final results must be perceived as a chain of error-prone components there are errors due to conception, construction, installation, calibration, and (mis-)use. Method validation checks into these aspects. 

During the method validation phase, the calibration, using the CS solutions, is repeated each day over at least one week to establish both the within-day and the day-to-day components of the variability. To this end, at least 6 CS, evenly spread over the concentration range, must be repeatedly run (m = 8-10 is usual), to yield n 50 measurements per day. If there are no problems with linearity and heteroscedacity, and if the precision is high (say, CV < 2-5%, depending on the context), the number of repeats m per concentration may be reduced from the second day onwards (m = 2 - 3 is reasonable). The reasoning behind... 

The trend logio(CV) vs logjo(c) appears reasonably linear (compare this with Ref. 177 some points are from the method validation phase where various impurities were purposely increased in level). A linear regression line B) is used to represent Ae average trend (slope = -0.743). The target level for any given impurity is estimated by a simple model. Because the author-... 

Table 4.42. Raw Data from Method Validation Tests...

Research reports—Research reports such as stability reports, method validation and transfer reports, and pharmaceutical development reports are key documents used for NDA/MAA filings. These documents are strictly version controlled. 

Chandra, A., Rana, J., and Li, Y., Separation, identification, quantification, and method validation of anthocyanins in botanical supplement raw materials by HPLC and HPLC-MS, J. Agric. Food Chem., 49, 3515, 2001. 

P. Van Keerbergen, J. Smeyers-Verbeke and D.L. Massart, Decision support system for run suitability checking and explorative method validation in electrothermal atomic absorption spectrometry. J. Anal. Atomic Spectrom. inch Atomic Spectrom. Updates, 11 (2) (1996) 149-158. 

As laboratory accreditation becomes more established, the requirements to demonstrate traceability and to determine uncertainty will inevitably feature as part of method validation (Christensen 1996). The fundamental role which reference materials play in these steps has already been alluded to in the Introduction. 

Christensen JM (1996) Correcting measurement errors using reference materials in method validation. Mikrochim Acta 123 231-240. 

A pharmacopoeial reference substance is intended for the determination of the main component of a substance or for the active ingredient of a pharmaceutical formulation which is usually present at a high proportion of the total. The reference substance is to be used as a primary standard in a specific method validated as prescribed in the ICH Guideline Validation of Analytical Procedure Methodology" (Technical Guide for the Elaboration of Monographs 1996 ICH Guideline 1997). the reproducibility of which is known. This is taken into account when the limits of acceptance (tolerance) for the substance or product are fixed (Daas and Miller 1997,1998). 

The use of reference samples for method calibration and development/validation occurred hand-in-hand with the development of all modern instrumental methods of analysis. In fact, the two developments are intimately linked with one another. As already noted, G-i and W-i (Fairbaim et al. 1951 Stevens i960) illustrate first instance of reference samples specifically developed for calibration purposes. Following that, the use of BCR-i as a reference sample throughout the lunar program (Science 1970) is a prime illustration of the quality assurance and method validation applications in large-scale inter-laboratory measurement programs. 

Identification of sources of analytical bias in method development and method validation is another very important application of reference materials in geochemical laboratories. USGS applied simplex optimization in establishing the best measurement conditions when the ICP-AES method was introduced as a substitute for AAS in the rapid rock procedure for major oxide determinations (Leary et al. 1982). The optimized measurement parameters were then validated by analyzing a number of USGS rock reference samples for which reference values had been established first by classical analyses. Similar optimization of an ICP-AES procedure for a number of trace elements was validated by the analysis of U S G S manganese nodule P-i (Montaser et al. 1984). 

LGC - VAM Publications (i) The Fitness for Purpose of Analytical Methods, A Laboratory Guide to Method Validation and Related Topics, (2) Practical Statistics for the Analytical Scientist A Bench Guide By TJ Farrant, (3) Trace Analysis A structured Approach to Obtaining Reliable Results By E Pritchard, (4) Quantifying Uncertainty in Analytical Measurement, and (5) Quality in the Analytical Chemistry Laboratory. LGC/RSC Publications, London, England. 

Established in 1894, AOAC International is an independent association of scientists and organizations in the public and private sectors devoted to promoting methods validation and quality measurements in the analytical sciences. AOAC has a mission to ensure the development, testing, validation, and publication of reliable chemical and biological methods of analysis for foods, drugs, feed-stuffs, fertilizers, pesticides, water, forensic materials and other substances affecting public health and safety and the environment. 

Interest in promoting the use of reference materials in method validation studies led in March 1993 to the formation of a Technical Division on Reference Materials, TDRM (Heavner 1995). The stated purpose of the TDRM is to improve the quality of... 

BERM-5 presented the changing outlook of the AOAC International in recognizing the usefulness of incorporating RMs for use in conjunction with their methods validation protocol. 

The general sample set for method validation parameters is the same for all matrices under consideration (except body fluids and tissues, see Section 4.2.5) ... 

For each group, one representative sample matrix has to be used for method validation. If the intended use is restricted to one of the crop groups, the method must be validated only for this group. On the other hand, the method has to be validated for all groups if the use is intended for a variety of crops that belong to two or more different groups. In addition, specific crops which are difficult to analyze due to matrix interference require individual method validation (e.g., hops, brassica varieties, bulb vegetables, herbs, tea). 

In contrast to the requirements for enforcement methods, validation of a previously collaboratively tested method, which is used to generate data, should be validated for new laboratory conditions. Also, where published methods are submitted, validation is required, when applied to the relevant sample matrix and laboratory conditions. 

Other considerations could include availability of reagent(s) or equipment, method for routine analyses vs limited samples, and confirmatory method vs multi-residues. Plan for method validation and/or analytical quality control. 

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