Protocol validation

The design of the system must take into account possible variation of critical control parameters that could affect performance. The maximum performance of the process should be defined by a reasonable safety margin. In order to comply with cGMP guidelines, established validation protocols, and parameters should allow the process to achieve reproducible purity and yield under stressed conditions. This implies that the industrial SMB system must be stressed to simulate worst-case conditions for process validation. 

This system assures overall compliance with cGMPs and internal procedures and specifications. The system includes the quality control unit and all of its review and approval duties (e.g. change control, reprocessing, batch release, annual record review, validation protocols, and reports, etc.). It includes all product defect evaluations and evaluation of returned and salvaged drug products. 

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. 

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. 

C. Japanese guideline criteria for validation protocol of specific allergenic ingredient detection... 

The MHLW described the validation protocol criteria in the 2006 official guidelines to standardize the Japanese official method for specific allergenic ingredient detection. The outlines of the validation protocol criteria for the food allergenic ingredient quantitative and qualitative detection methods are shown in Tables 4.7 and 4.8, respectively. 

In September 2010, CAA annoimced the addition of ALLERGENEYE ELISA series of kits for egg, milk, wheat, buckwheat, and peanut as Japanese official methods based on their validation determined by the Japanese validation protocol. 

Since the MHLW designated shrimp/prawn and crab for mandatory labeling in June 2008 due to the almost unlimited use of crustacean in the processed foods in Japan and the status as a frequent cause of adverse food reactions in allergic patients, two ELISA methods for the determination of crustacean protein in processed foods have been developed (Seiki et al, 2007 Shibahara et al., 2007) EA test EIA-Crustacean [Nissui] produced by Nissui Pharmaceutical Co., Ltd. and Crustacean Kit [Maruha ] produced by Maruha Nichiro Eoods, Inc. Both kits have been validated according to the Japanese validation protocol (Sakai et al., 2008) and are commercially available. All the commercial ELISA kits are shown in Table 4.9. 

Both methods have been validated according to the Japanese validation protocol (Sakai et al., 2008), and both primers are commercially available. All the Western blotting and PCR kits are shown in Table 4.11. 

The method trial process for NADA methods is different to the process for non-NADA methods. However, the validation protocol followed by the participating laboratories and the requirements for acceptance of the method are the same. The trial process also differs for determinative procedures and confirmatory procedures. Determinative procedures are evaluated using the multiple laboratory process, whereas the confirmatory method needs to be evaluated only in a single government laboratory. 

Non-NADA methods may be designed to detect multiple residues and they may be designed for use in multiple species. In order to validate these multi-residue methods, modifications to the validation protocol relative to single analyte methods are made. Additional laboratories will participate in the method trial, but the number of samples... 

On the other hand, some sensible reduction may be acceptable. In the spiroxamine example, an appropriate reduced validation protocol may be as follows a full set of recovery experiments at both levels performed with the intact spiroxamine (which has the longest reaction pathway to the common moiety) and separately with one primary metabolite. Such two complete validations should be an acceptable test of the working range of the common moiety method. 

Different sample materials often need some adjustment of pesticide residue methods. The insufficient consideration of matrices in thcNKML method validation protocol may be a tribute to the wide scope of this standard. 

In contrast to many other validation protocols, the description of the NMKL validation process starts with the protocol of planned validation. This protocol should include, e.g., the needs of the client, available equipment, the chemical form in which the analyte occurs (i.e., in pesticide analysis the residue definition), matrix types, the availability of reference materials and the working range. Consequently, an extra paragraph is dedicated to the requirements for the documentation of validation results, which refers to the rules in Section 5.4.4 of EN 45001 (amended by ISO 17025). 

In summary, the procedure of the Nordic Committee describes a comprehensive validation protocol, but it is not specially designed for pesticide residue analysis and has no preferences with regard to single- or inter-laboratory validation. Therefore, if it is applied to pesticide residue methods, some specific validation requirements should be added. The procedure clearly lists all necessary steps of validation and adjusts its recommendations to the degree of previous external validation. 

The validation process is subject to the following design specifications, user and performance requirements, preparation of a master plan/validation protocol (installation qualification, operational qualification, and performance qualification), execution of the protocol, preparation of a summary report, and on-going validation (and revalidation if changes are made). 

McConnell, M., Canales, M., and Lawler, G., A validation protocol for analog-to-digital interfaces in chromatographic data systems, LC-GC, 9, 486, 1991. 

Validations fall into two types prospective and retrospective. In prospective validation (see flow chart in Figure 2) the validation is done in a sequential manner, involving installation qualification and operational qualification (IQ/OQ) of equipment (e.g., chromatography instrumentation or column hardware). Appropriate calibrations accompany the IQ/OQ. Process qualification, or PQ, involves formal review and approval of a PQ protocol, execution of this protocol, and issuance of a formal PQ report which includes data analysis and recommendations (i.e., approval/certification of the process). If the process is not approved, the report may recommend a redesign or redoing of the validation protocol and, in some cases, a return of the process to process development for further optimization. 

Industrial-scale manufacturing data may not be available at the time of submission of the application. In such cases a validation protocol (details of which are included in the draft guideline) should be included in the submission. 

Validation protocol Document describing the specific item to be validated, the specific validation protocol to be carried out and acceptable results, as per acceptance criteria... 

Partial or complete re-validation is another precedented approach to method transfer. Those variables described in method validation guidance documents (ICH Q2B, 1996 USP, 2012c) that are likely to be impacted by method transfer, should be assessed and documented (transfer or validation protocol). Agut et al. (2011) indicated that, in the changing industry model with the increased outsourcing of R and D activities (alliances, outsourcing, etc.), method re-validation may constitute, in some cases, an efficient approach when the transfer is performed from the Analytical Development Laboratory of an external partner who does not share exactly the same environment (validation standards, analytical culture or traditions , equipment, etc.). ... 

Transfer waivers should be assessed and documented (transfer or validation protocol). 

The accuracy of the method was evaluated by assaying six independently prepared solutions of IB-367 against two standard solutions of the same lot as external standards. The mean of 102.3% met the criteria set in validation protocol (97 to 103%). 

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 second approach is to prepare validation protocols for each method prior to the commencement of validation activities. This has the advantage of performing method-appropriate experiments while eliminating those portions of validation work that do not apply. It also allows the analysts to set more specific acceptance criteria based on the performance of the individual method instead. A drawback is that the protocol adds to the workload of the analyst since it must be prepared for each validation. This approach also allows for the possibility of greater variance in the approach to validation within the company. 

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