Validation rationale

Defining and adhering to a validation plan to control the application and system operation, including GMP risk and validation rationale Documenting the validation life-cycle steps to provide evidence of system accuracy, reliability, repeatability, and data integrity... 

Software and hardware types can influence the system validation rationale, and a strategy for the software and hardware types that may be used should be addressed during validation planning. 

It is opportune at this point to document the GMP electronic raw data that need to be collected by or through the computer system. This will be used to support the validation rationale and influence the extent of qualification testing. It will also identify candidate data for electronic records and electronic signature compliance and help distinguish between electronic raw data and transient electronic data. 

Description of process/environment Quality-related critical parameters Purpose and objectives of the system Major benefits of the system Special requirements Specific training needs System operating strategy Related GMP compliance/regulations Physical and logical boundaries System GMP risk assessment System validation rationale Life-cycle documentation Assumptions and prerequisites Limitations and exclusions Quality-related critical parameters/data Standard operating procedures System requirement specification Supplier and system history... 

Validation Policy Plans Training Plans GMP Risk Assessments) Validation Rationale Organisation Chart Validation Procedures Quality Procedures... 

Change control during operation and maintenanee must assess and verify that the rationale for validation is not affected by modihcations to individual systems. The use of individual systems often ehanges over time, and at some point it is possible that a non-GxP system may be used in a GxP eontext. It is important not to inadvertently imdermine the validation rationale for the overall integrated system. 

Research is needed on low-level, long-term cyanide intoxication in mammals by oral and inhalation routes in the vicinities of high cyanide concentrations, especially on the incidence of skin dermatitis, nasal lesions, and thyroid dysfunction, and on urinary thiocyanate concentrations. These types of studies may provide a more valid rationale in establishing standards and threshold limit values for HCN and inorganic cyanide. Data are scarce on the carcinogenic, teratogenic, and mutagenic properties of cyanide, and on the distribution and transformation of cyanides in air, land, or water. Additional analysis of available information and more research in these areas is recommended. Finally, more research is needed... 

The rationale for these simple approaches to water treatment is the argument that these kinds of systems have minimal requirements for MU water and are therefore subject to a reduced level of risk. In practice, the validity of this argument is suspect but is difficult to prove because totalizing water meters are seldom installed on the MU water line. 

Ciraulo DA, Jaffe JH Tricyclic antidepressants in the treatment of depression associated with alcoholism. Clin Psychopharmacol 1 146—150, 1981 Ciraulo DA, Nace E Benzodiazepine treatment of anxiety or insomnia in substance abuse patients. Am J Addict 9 276—284, 2000 Ciraulo DA, Barnhill JG, Jaffe JH, et al Intravenous pharmacokinetics of 2-hydroxy-imipramine in alcoholics and normal controls. J StudAlcohol 51 366-372, 1990 Ciraulo DA, Knapp CM, LoCastro J, et al A benzodiazepine mood effect scale reliability and validity determined for alcohol-dependent subjects and adults with a parental history of alcoholism. Am J Drug Alcohol Abuse 27 339—347, 2001 Collins MA Tetrahydropapaveroline in Parkinson s disease and alcoholism a look back in honor of Merton Sandler. Neurotoxicology 25 117-120, 2004 COMBINE Study Research Group Testing combined pharmacotherapies and behavioral interventions in alcohol dependence rationale and methods. Alcohol Clin Exp Res 27 1107-1122, 2003a... 

Example 62 If a manufacturing process involves two raw materials, each defined by three sets of specification limits, and four pieces of equipment with one control knob, then a complete validation protocol would ask for (Three settings Lo, Target, Hi) (2 materials 3 specs + 4 machines 1 control) = 3 = 59 000 experiments, even without repetitions. This product would never reach the market if one did not employ experience and scientific rationale to simplify development by testing only the presumed critical issues, say a total of three specification points for 3 = 27 experiments. 

The rationale of validation experiments with fatty matrices is the high amount of fat extracted with many organic solvents. If analytes are not fat soluble and extraction is performed with water or aqueous buffer solutions, the troublesome fat is not extracted together with the analyte. Such extractions are typical for, e.g., the class of sulfonylurea herbicides. Examples exist where in such cases the applicability of an analytical method to fatty matrices was accepted by the authority without particular validation. 

NSAIDs are a reasonable alternative when acetaminophen fails to provide an acceptable analgesic response. Some authorities recommend NSAIDs over acetaminophen for patients presenting with severe pain or signs and symptoms of inflammation, but this is a matter of much contention. The rationale for this recommendation is that acetaminophen s central mechanism of action renders it ineffective against peripheral joint inflammation, and therefore, less effective.18 Consensus guidelines support the use of NSAIDs as an alternative to acetaminophen if clinical features of peripheral inflammation or severe pain are detected.11,12 Unfortunately there is no validated mechanism to identify patients who are more likely to respond to NSAIDs than acetaminophen. 

Microbiological aspects will need to be discussed, but the amount of information will depend on the type of product. For nonsterile products there will need to be a description of the microbiological attributes of the product and, if appropriate, a rationale for not performing microbial limit tests. For preserved products the selection of the antimicrobial preservatives will need to be discussed and the effectiveness of the selected system demonstrated. For sterile products there will need to be appropriate process validation data and information on the integrity of the container-closure system. 

The application should state the rationale for the design of the in-use stability tests performed. The procedures used should be fully validated. One key factor is that the test should simulate the use of the product as far as practicable. This should include any reconstitution or dilution prior to use. Aliquots should be removed in an appropriate manner following, as far as possible, the usage pattern that will be encountered in practice. Physical (color, clarity, closure integrity, particulate matter, and particulates/particle size), chemical (assays for active ingredient, antioxidants and... 

Minimal bounds on the production quantity are most often process dependent. Typically, a minimal campaign length is required if for example a critical mass is necessary to initiate a chemical reaction. The same is valid for maximal bounds on the production quantity. The rationale here is that a cleaning operation may be required every time a certain amount has been produced. Finally, batch size restrictions often arise in the chemical industry, if for example the batch size is determined by a reactor load or, as discussed above, the processing time for a certain production step is independent of the amount of material processed. In these scenarios, when working with model formulations using a discrete time scale, it is important that the model formulation takes into account that lot sizes may comprise of production in several adjacent periods. 

For many chemical reactions with high sharp barriers, the required time dependent friction on the reactive coordinate can be usefully approximated as the tcf of the force with the reacting solute fixed at the transition state. That is to say, no motion of the reactive solute is permitted in the evaluation of (2.3). This restriction has its rationale in the physical idea [1,2] that recrossing trajectories which influence the rate and the transmission coefficient occur on a quite short time scale. The results of many MD simulations for a very wide variety of different reaction types [3-12] show that this condition is satisfied it can be valid even where it is most suspect, i.e., for low barrier reactions of the ion pair interconversion class [6],... 

A rationale should be generated to explain and support the reasoning for validating the selected parameters. The use of reference standards during validation helps to reinforce the reliability of the analytical method developed. The conditions of how a test is performed may have a strong influence on the results. These conditions have to be recorded and followed. 

Documentation should be provided in each case to outline the rationale for location and design of monitoring stations and the rationale for data validation for photochemical oxidants. 

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