Deviation protocol, testing

Accuracy is the term used to describe the degree of deviation (bias) between the (often unknown) true value and what is found by means of a given analytical method. Accuracy cannot be determined by statistical means the test protocol must be devised to include the necessary comparisons (blanks, other methods). 

Figure 3.3 Comparison of array CGH among DNA extracted from fresh tissue, FFPE tissue by heating protocol or nonheating protocol for two human tissue samples of metastatic carcinoma in lymph node (a-c), and undifferentiated non-small cell carcinoma (d-f). Array CGH hybridization genomic profiles show ratio values representing relative copy number of single BACs. A good result is scored as 1.0 that indicates a low standard deviation for gains (>0.2), normal (0.0), or losses (<-0.2). In these two cases, fresh samples show best score as 2, both FFPE tissue samples show identical score of 3. Each spot represents the average of three replicates. Clones are ordered by chromosomal position as numbers at the bottom (x axis) of each picture. The y axis is the log2 ratio of test reference intensity. Provided by Sandy DeVries from Dr. Frederic Waldman s Lab at UCSF.

It is important to appreciate that the statistical significance of the results is wholly dependent on the quality of the data obtained from the trial. Data that contain obvious gross errors should be removed prior to statistical analysis. It is essential that participants inform the trial co-ordinator of any gross error that they know has occurred during the analysis and also if any deviation from the method as written has taken place. The statistical parameters calculated and the outlier tests performed are those used in the internationally agreed Protocol for the Design, Conduct and Interpretation of Collaborative Studies.14... 

DQ is performed by the supplier of the equipment or system at the supplier s factory as part of the factory acceptance test (FAT). IQ (based on site acceptance test—SAT), OQ, and PQ are performed on-site at the GMP facility. For a GMP manufacturing facility, the validation activities include the facility design, FTVAC system, environment control, laboratory and production equipment, water system, gases and utilities, cleaning, and analytical methods. Validation protocols (IQ, QQ, and PQ) are prepared for each item, listing all critical steps and acceptance criteria. Deviations are reviewed and resolved before the validation activity proceeds to the next phase. 

A validation report is a written document that cross-references the validation protocol, summarizes the results obtained, describes any deviations observed, and draws the necessary conclusions, including recommending changes required to correct deficiencies for the qualification and validation performed [5]. In this report it is required to present both the results and conclusions and the secure approval of the study. The report should include a summary of the procedures used to clean, sample, and test as well as the physical and analytical test results or references for the same. The conclusions regarding the acceptability of the results should also be included. Other information would be the status of the procedures being validated, any recommendations based on the results, or any relevant information obtained during the study. These include, re validation practices (if applicable), the approved conclusions, and any deviations of the protocol that might have occurred. In cases where it is unlikely that further batches of the product will be manufactured for a period... 

The report must review the test results, draw conclusions, and make recommendations for future action (as applicable). This may take the form of corrective actions in the event of deviations or a test failure, or additional procedures if use of this part of the system is conditional. The qualification report and conclusions should be approved by the same signatories that approved the qualification protocol. 

It is important that the protocol has provisions for deviations and corrections, as well as cases in which an alternative test method would have to be used because of test equipment problems. This could prevent having to repeat the entire validation. 

Exceptional conditions must be documented and evaluated for their effect on the validity of the test data. Deviations must be approved in writing by all persons responsible for initial approval of the protocol, and this must be documented in an addendum. 

Deviations in the conduct of the study from the protocol must be properly documented. There must be a formal protocol amendment signed and dated by the study director Eor any prospective change in the conduct of the study. This includes changing such things as the location of the trial, the application rate, or the formulation of the test chemical. Unavoidable changes such as those caused by adverse weather, seasonal variations, or wildlife damage must be clearly documented in the raw data and a written opinion by the study director about the impact of each change on the study must be put in the study file. 

If nonconformances or deviations to the project plan or IQ protocol are encountered during the software IQ testing, these must be documented, analyzed, resolved, reviewed, and approved. The resolution process must indicate what additional actions must be taken to provide a conforming product (e.g., return the program to development for error analysis and correction, and re-execute the test script after correction the nonconformance was due to an inaccuracy in the test script, review and update the test script, etc.). After the successful resolution of the nonconformance has been obtained, the original test, the nonconformance information, and the retest must all be retained, approved, and reviewed by the appropriate personal. 

Once the protocols have been completed, the test results and data need to be formally evaluated. The written evaluation needs to be presented clearly, in a manner that can be readily understood. The report should also address any nonconformances or deviations to the validation plan encountered during the qualification and their resolutions. The format of the report should be similar to the structure of the associated protocols. The qualification testing should be linked with the acceptance criteria in the relevant specification deliverable, so that the PQ will link with the requirements specification deliverable the OQ will link with the company system specification deliverable and the IQ will link with the technical design specification deliverable. 

When a deviation takes place, the project manager and/or tester executing the protocol must complete a test incident (or similar) report. This report describes the nature of the event, the corrective action(s) necessary to resolve the event, an assessment of the impact of the event on the test case or any related documentation, software and any subsequent test cases and/ or protocols. 

Investigation and reporting of protocol deviations and timelines, i.e., the fact that it is timely of corrective actions Reasonable test parameters, testing frequency, and acceptance criteria... 

Once the retesting protocol is executed successfully (i.e., no analytical deviations), the results will either support the OOS result and confirm a material failure or render the OOS result invalid and provide ample justification to pass the test specifications. If the OOS result is confirmed, the batch is rejected and the quality assurance department should take appropriate steps for batch disposal. Since confirmation of the OOS result strongly suggests an operator-related or process-related error, the onus is now placed on the formal or phase II investigation participants to identify a cause. If an operator-related error is found and batch rework is possible and prescribed in an approved batch record and approved regulatory submission, this may be the desired course of action. If no rework or reprocessing is possible, the batch is rejected and disposed of in an acceptable manner. 

Safety analysis patient set was defined as all patients who received the Biod/VTs/o Batimastat OC stent, per-protocol analysis patient set was defined as all patients in the Safety analysis set who did not deviate from the protocol. Categorical variables were summarized using counts and percentages. Continuous variables were summarized using mean, standard deviation, minimum and maximum, and median for variable not showing a normal distribution. For comparison of subgroups, the unpaired two-tailed student s t-test was used. Results were considered statistically significant at P< 0.05. 

At the end of the equilibration protocol, a 3D-QSAR equation with a good correlation (r = 0.81) and a low root mean square deviation (rmsd 0.85) on the estimated interaction energies were derived. The predictive power of the model was evaluated with a test set of 11 taxanes and epothilones, obtaining a prediction coefficient of 0.78. 

The purpose of the qualification/audit is for the sponsor to investigate the standard practices of the contractor. Quality as well as technical capabilities should be evaluated. One should determine where the test article will actually be stored, the department that will conduct the in-life portion, make an assessment of procedures (SOPs) for dosing, identify differences between the sponsor s general practices and the facilities operating procedures (proto-col/study-specific procedures (SSPs), and assess the process of interim data exchange and the method of reporting of SOP and protocol deviations to the study director and the sponsor. 

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