Establishment of acceptance criteria

The first step in the validation process involves the establishment of acceptance criteria, which are assay dependent, for the various validation parameters. Assays must meet these criteria in order to receive validation status. The most relevant validation parameters are specificity, accuracy, precision, sensitivity, and robustness. In this section we describe these parameters as they apply to the evaluation of immunoassays. 

Knowledge of precision and bias is important if acceptance criteria are to be established. Confidence in the values obtained is necessary when a test is used to separate acceptable and unacceptable material. Generally, the establishment of acceptance criteria requires extensive testing of the product forms of interest. 

As the stability data can be affected by many factors like formulation, manufacturing, storage conditions, in-process and GMP controls, analytical methods, and process validation, the biggest challenge is to figure out the source of the variability in the stability results. At least three batches of the drug substance or product are required to establish the acceptance criteria for future production batches as a measurement... 

Additionally, the process should be controlled by employment of a validation protocol, which defines the critical parameters and also establishes the acceptance criteria for the granulation or blend and which may include sieve analysis, flow, density, uniformity and compressibility, moisture content, etc. 

Concurrent validation is conducted under a protocol during the course of normal production. The first three production-scale batches must be monitored as comprehensively as possible. The evaluation of the results is used in establishing the acceptance criteria and specifications of subsequent in-process control and final product testing. Some form of concurrent validation, using statistical process control techniques (quality control charting), may be used throughout the product manufacturing life cycle. 

Validation in quality systems includes establishment of procedures on how to qualify the equipment and machinery, how to verify the design of products, how to verify the process designed, how to verify the achievement of production procedures, how to validate the process developed, and how to validate the methods for measurement and assay. Validation also requires verification of specifications or acceptance criteria of in-process parameters relating to both raw materials and intermediate (in-process product) and finished products, and verification of acceptance criteria for in-process parameters relating to operating conditions of machinery and equipment. Further, when the medical device is assembled at the user s site, validation includes establishing procedures of how to verify assembly. 

As emphasized in Section 1.1, the recommended approach to classifying waste does not provide a basis for establishing waste acceptance criteria at specific disposal sites. NCRP expects, however, that waste classified as exempt or low-hazard in accordance with its recommendations should be acceptable for disposal in the associated type of disposal facility at well-chosen sites. 

In most cases, evaluations of ecological impacts are site-specific and, as a consequence, are not considered when establishing a generally applicable waste classification system. These impacts normally are addressed in disposal site selection, design, and operation, and they may be used in establishing waste acceptance criteria for the site. To the extent that ecological impacts can be evaluated generi-cally, NCRP believes that the principles and framework for risk-based waste classification presented in this Report are sufficiently flexible to take them into account. 

NCRP reiterates that the risk-based waste classification system developed in this Report does not, and cannot, obviate the need to establish waste acceptance criteria at each hazardous waste disposal site based on the characteristics of the site, the particular disposal technology, and characteristics of the wastes that are intended for disposal at the site. NCRP expects that most waste that would be assigned to a particular class will be acceptable for disposal using the associated type of disposal technology indicated in Figure 6.1. However, the disposal capabilities of particular sites and engineered systems can vary substantially and can depend on the waste characteristics. The primary function of any waste classification system is to facilitate development of cost-effective approaches to waste management and disposal and effective communication on waste matters (see Section 2.1.2). 

In addition, the reliance on generic scenarios for inadvertent intrusion in classifying waste cannot, by definition, represent site-specific risks. However, this is not a serious shortcoming because such scenarios have been used in establishing subclasses of low-level radioactive waste for disposal in near-surface facilities (NRC, 1982a). Furthermore, as emphasized in this Report, establishment of a risk-based waste classification system using particular exposure scenarios does not obviate the need to perform site-specific risk assessments for the purpose of establishing waste acceptance criteria at each disposal site. 

Another credible assumption is that permanent access to the site could occur at the end of the 100 y period of institutional control. This assumption has been used in establishing waste acceptance criteria at all DOE low-level waste disposal sites (DOE, 1988c 1999c), including the Hanford site, based on an acceptable dose from chronic exposure of an inadvertent intruder of 1 mSv y Therefore, the waste acceptance criteria for the Hanford site already take into account an acceptable dose to an inadvertent intruder from permanent site occupancy, so the waste is acceptable for near-surface disposal as low-hazard waste according to this scenario without the need for further analysis. 

Development of a comprehensive and risk-based hazardous waste classification system, in which waste classes are defined in relation to types of disposal systems that are expected to be generally acceptable in protecting public health, would not obviate the need to establish waste acceptance criteria at each disposal site based on the characteristics of the site and engineered disposal facility and the properties of wastes intended for disposal therein. The primary purposes of a hazardous waste classification system are to facilitate cost-effective management and disposal of waste and effective communication on waste matters. 

To establish reasonable acceptance criteria for accuracy during planning, we should obtain statistical laboratory control limits from the laboratory that will perform analysis for the project samples. We should also be aware of matrix interferences in environmental samples that may reduce the accuracy of analysis. As part of QC procedures, to estimate the effects of matrix interference on accuracy, laboratories perform the accuracy determinations on environmental samples, known as matrix spike (MS) and matrix spike duplicate (MSD). These fortified samples enable the laboratory to detect the presence of interferences in the analyzed matrices and to estimate their effect on the accuracy of sample analysis. (In the absence of matrix interferences, an additional benefit from MS/MSD analysis is an extra measure of analytical precision calculated as the RPD between the two recoveries.)... 

Data validation is a systematic process for reviewing a body of data against a pre-established set of acceptance criteria defined in a project document (NFESC, 1999). If a systematic review establishes that the data meet the acceptance criteria specified in the SAP, then the data are considered to be valid hence the term... 

Perhaps the simplest means of establishing an acceptance criteria (and perhaps to define one s entire program) is to follow the pack, and develop a firm s entire aseptic processing validation program based... 

Retrospective analysis of historical data can be used to assess process reliability [88]. The initial process capability specifications are established based on a few runs (usually less than around 5-10) with acceptable results [30]. This number of runs often is too small to accurately define and characterize actual process variability [30,31]. It can be difficult to claim that the previously set process capability specifications were flawed after validation runs fail to meet them [30]. Thus, the selection of acceptance criteria must consider the benefits of broad versus narrow tolerance ranges. 

The goal of the development phase for immunoassays is to establish a method that can consistently produce a reliable result culminating in a validation plan with established target acceptance criteria for accuracy and precision. The following recommended parameters are assessed critically during early development, evaluated in late development, and finally, confirmed during validation. 

Justification of the recommended specifications—It is often helpful to present the rationale used for establishing the acceptance criteria proposed for the API in the marketing application. This will provide the reviewers with an understanding of the thought processes used to establish the controls (e.g., are impurity limits based on safety/toxicity studies. 

Food chain effects in pit lakes should be determined before stable biological habitats are artificially established. Additional investigations are recommended to establish water quality criteria on selected metals for protection of aquatic life and for establishment of acceptable metal burdens in aquatic prey of migratory birds this is of particular interest in pit lakes located in arid areas with increasing metals concentrations attributed to high evaporation rates. 

From the analyst s viewpoint, the more demanding the acceptance criteria, the higher the risk of run failure the severity of these problems increases with the number of compounds to be analyzed by a given method, since failure to meet the established run acceptance criteria for... 

Fresh stock solutions should be used immediately after preparation if possible and certainly within 24 hours (one day) of preparation when used for comparison to stored stock solutions that are kept at the anticipated storage conditions. The number of rephcate injections of the freshly prepared and stored stock solutions (or dilutions thereof) should he sufficient to achieve the precision required to make such comparisons statistically meaningful (see Section 8.2). The solutions should be analyzed at relevant intervals spanning the maximum anticipated storage duration in order to expose any trends in the stabihty with time. The storage stahUity of an analyte stock solution is defined hy the period over which the mean peak area or peak area ratio of the stored solution deviates from the mean peak area or peak area ratio of the fresh solution by no more than the acceptable limit established in advance (10 % is a value that is often chosen). If a stock solution falls outside of acceptance criteria, an additional comparison can be made to verify instabihty. If the verification indicates that the analyte in solution was in fact stable (e.g. indicating a prior preparation error rather than instability), then at... 

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