Validation test establishment

There are several reasons for careful placement of the ruggedness test in a program of method validation tests. Firstly the ruggedness test itself can be a complex and time consuming task and thus should be carried out as late in the method validation as possible, (i.e. when most other performance characteristics have been established and are acceptable). This reduces the chance of a failed ruggedness test and for this reason it is recommended that the precision study be one of the last experiments in a validation study. 

Some validation tests can provide valuable information that helps to design a more efficient ruggedness test. For instance, if the repeatability of the various stages in the method is already established then the order of an experimental design is not so critical and it is usually sufficient to perform duplicates for each experiment. These features will be discussed in more detail in the section on experimental designs. 

The basic criterion for successful validation was that a method should come within 25% of the "true value" at the 95% confidence level. To meet this criterion, the protocol for experimental testing and method validation was established with a firm statistical basis. A statistical protocol provided methods of data analysis that allowed the accuracy criterion to be evaluated with statistical parameters estimated from the laboratory test data. It also gave a means to evaluate precision and bias, independently and in combination, to determine the accuracy of sampling and analytical methods. The substances studied in the second phase of the study are summarized in Table I. 

Development and standardization of the protocols will be dynamic processes that involve establishing interim procedures that are to be optimized and modified as a result of validation testing. 

Interpretation. Whereas statistical tests establish whether results are or are not different from (over) an exposure criteria, the generality of this outcome must be judged. What did the samples represent May the outcome, which is inferred to cover both sampled and unsampled periods, be legitimately extrapolated into the future In other words, is the usual assumption of a stationary mean valid All of these questions are answered by judgment and experience applied to the observations made at the time of sampling, and the answers are used to interpret the quantitative results. 

Sterilization validation involves establishing that a system sterilizes, whether or not testing is performed on the end product. The need for such evidence stems from the fact that sterility is not an absolute product attribute that can be determined by end-product testing alone. 

Computer systems validation, as established in 21 CFR Part 211.68, Automatic, Mechanical, and Electronic Equipment, is one of the most important requirements in FDA-regulated operations and an element of the system life cycle (SLC). In addition to the testing of the computer technology, other verifications and inspection activities include code walkthroughs, dynamic analysis and trace analysis. These activities may require 40% of overall project efforts. 

The FDA also has proposed adding a new subpart L to part 211 entitled Validation, which would consist of two regulations section 211.220 for process validation, and section 211.222 for methods validation. Proposed section 211.222 (methods validation) would require the manufacturer to establish and document the accuracy, sensitivity, specificity, reproducibility, and any other attribute necessary to validate test methods. Validation would be necessary to meet existing requirements for laboratory records provided in section 211.194(a)(2). 

Similar information is required for the metal canister and actuator/mouthpiece. The guidance further requires that the drug product be evaluated for leachables with appropriately validated test methods, and that appropriate acceptance criteria for the levels of leached compounds in the formulation should be established. 

Proper validation tests of a data acquisition system should include calculation of an overall system error when the input is known and controlled (e.g., an NIST traceable signal generator providing a sinusoidal signal with a known amplitude and frequency, to simulate compression events on a press). Comparing the output (for example, peak heights as reported by the software) to the known input, the overall system error can be reliably established. 

So, the methods characteristic of each test, comprising taken together a type of tests, must undergo validation testing of their results. This is the implementation of the method, and the establishment of a standard for its performance. For the standardization of quantitative methods, this consists at a minimum of a determination of trueness when blank utilization, certified reference materials (or reference materials, or spiking materials) or collaborative trials are used, repeatability (r) with repetition,... 

Alert and action levels for each parameter in each area or critical utility will be established based on the results from validation testing, compendia requirements, and cGMPs. Area or room limits will be based on the environmental data collected during the validation of the aseptic filling process validation. Specific action plans will be developed for addressing excursions beyond alert and action limits for each area or utility. 

Phase II demonstration/validation testing was conducted at Porton Down in 2004 (Bixler, 2005). The tests included detonation of two munitions per shot, a key point in establishing the potential throughput of the CDC. Extensive computer control and safety interlocks were added to regulate contact of any agent vapors with the treatment system and to remove any opportunity for a detonation to occur before the complete system is ready for operations. 

The quality control unit should provide assistance or take part in the periodic validation tests carried out by the other units, especially the production unit, of the company to ensure that each manufactured product consistently meets the established specifications. 

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