Validation Plans

On basis of systematie use of the prineiple of insignifieanee, aeeeptanee eriteria system of validation eharaeteristies was developed and standardized validation plan of pharmaeeutieal analysis proeedures was proposed, the latter plan found an applieation in the establishing of NSRS and PPT establishing. Have been developed and issued two editions of the SPU, whieh is harmonized with European Pharmaeopoeia and now is a sole national pharmaeopoeia in CIS. 

The FDA mandates that of all the calibration concentrations included in the validation plan, the lowest jc for which CV < 15% is the LOD (extrapolation or interpolation is forbidden). This bureaucratic rule results in a waste of effort by making analysts run unnecessary repeat measurements at each of a series of concentrations in the vicinity of the expected LOD in order to not end up having to repeat the whole validation because the initial estimate was off by + or - 20% extrapolation followed by a confirmatory series of determinations would do. The consequences are particularly severe if validation means repeating calibration runs on several days in sequence, at a cost of, say, (6 concentrations) x (8 repeats) x (6 days) = 288 sample work-ups and determinations. 

Statistical and algebraic methods, too, can be classed as either rugged or not they are rugged when algorithms are chosen that on repetition of the experiment do not get derailed by the random analytical error inherent in every measurement,i° 433 is, when similar coefficients are found for the mathematical model, and equivalent conclusions are drawn. Obviously, the choice of the fitted model plays a pivotal role. If a model is to be fitted by means of an iterative algorithm, the initial guess for the coefficients should not be too critical. In a simple calculation a combination of numbers and truncation errors might lead to a division by zero and crash the computer. If the data evaluation scheme is such that errors of this type could occur, the validation plan must make provisions to test this aspect. 

Validation should always proceed according to a validation plan. A well-defined validation strategy saves time and effort on the part of the... 

Together, the defined/written series of tasks, test methods, requirements and docnmentation required to carry out the validation procedure for a system can be described as the validation protocol. The instrnc-tion mannal for all of this is the validation plan, developed by the validation team. 

If it has not been already completed, the first recommended task is to establish/designate a validation team within the company—perhaps one snch team at each of mnltiple sites. If one elects to have a separate team at mnltiple sites, these teams mnst make certain that they carry ont the validation processes consistently across all sites. In larger corporations, this is often accomplished via a central validation committee managing the individnal gronps at the varions sites. For smaller companies a team may consist of only one individual. The goal of the team(s)/committee is to draft comprehensive validation plans and protocols across all the instrnments, systems and processes that reqnire validation. They must then diligently execnte, document and verify each validation procedure. 

The change control SOP warrants particular attention. This procedure should clearly spell out how any deviations in instrument operation/per-formance, and hardware/firmware/software updates are to be handled and documented. It should also make clear what distinguishes routine maintenance, minor vs. major changes and what the procedural differences should be. The change control procedure may be a specific SOP, as part of an HPLC system s validation plan, or as part of the corporate validation master plan (VMP) that is established within each company. 

Consider the VMP as the corporate doctrine of a corporation s general validation, testing, recording and archival practices. Typically, the SOPs within the VPM are too general and, therefore, it is advised that one create specific SOPs for a particular system to be validated. These would be part of an HPLC system s validation plan. Note that the VMP should be thought out and drafted well in advance of developing a specific system Validation Plan. 

Following risk assessment, the next step is to draft a formal validation plan. This is a written plan that includes all the specific validation procedures, installation tasks, acceptance testing, documentation requirements, reviews and verification tasks that need to be followed for proper system validation. The plan should also define individual responsibilities for these tasks and include an expected timeline. The plan should be designed around the URS and take into account the risk assessment determinations performed earlier. 

Installation Qualification—The IQ is the protocol that verifies that the installation of the system has followed the guidelines established within the validation plan and is in accordance with the vendor s installation requirements. 

Haider SI (2002) Pharmaceutical Master Validation Plan The Ultimate Guide to FDA, GMP, and GLP Compliance. Informa Healthcare... 

Multitier validation plan The FDA has produced a long hst of systems subject to vahdation requirements, but it is possible and appropriate to limit the amount of investment and effort necessary to compliantly validate each of those systems. Companies are permitted and encouraged to develop a multitier validation plan, using the risk analysis procedures developed for the regulation of medical devices. Under this procedure a regulated laboratory or facility should... 

II. Regulatory (or expert) review of plan Once the multitier validation plan has been developed it is possible to develop a preuse level of confidence by conferring with FDA representatives or experienced industry experts. While most FDA divisions... 

Bronstein RJ. The concept of a validation plan. Drug Info J 20 37-42, 1986. 

Sometimes the blind review can throw up data issues that require further evaluation by the data management group with data queries being raised, and these perhaps may result in changes to the database. This sequence of events can cause major headaches and delays in the data analysis and reporting, and so it is important in the planning phase to get the data validation plan correct so that issues are identified and dealt with in an ongoing way. 

Steam sterilization validation. All autoclave operations conform to the Master Validation Plan employed at ABC Pharmaceutical Industries. The autoclave has undergone installation qualification, operational qualification, and performance qualification. The autoclave is revalidated on an annual basis. The equipment steam sterilization cycle revalidation data for the autoclave are provided in validated archives. 

Validation SOPs are written to provide explicit instruction on how to achieve the standards for those responsible for writing and executing master validation plans for drug, drug-device combinations, diagnostics, pharmaceutical biotechnology, and bulk pharmaceutical chemical products. Included is the ready-to-use template so that one can immediately save time and expense without missing any critical elements. 

The second volume and CD-ROM are designed for individuals specifically involved in writing and execution of master validation plans, development of protocols, and applicable procedures. This book provides a complete, single-source reference detailing conceptual design elements and 139 explicit procedures to provide sterility assurance. 

Extent of Validation Depends on Type of Method On the one hand, the extent of validation and the choice of performance parameters to be evaluated depend on the status and experience of the analytical method. On the other hand, the validation plan is determined by the analytical requirement(s) as defined on the basis of customer needs or as laid down in regulations. When the method has been fully validated according to an international protocol [63,68] before, the laboratory does not need to conduct extensive in-house validation studies. It must only verify that it can achieve the same performance characteristics as outlined in the collaborative study. As a minimum, precision, bias, linearity, and ruggedness studies should be undertaken. Similar limited vahdation is required in cases where it concerns a fully validated method which is apphed to a new matrix, a well-established but noncol-laboratively studied method, and a scientifically pubhshed method with characteristics given. More profound validation is needed for methods pubhshed as such in the literature, without any characteristic given, and for methods developed in-house [84]. 

The activities in the planning phase are commenced after a business need to implement an instrument in the laboratory has been identified. Planning-phase activities include concisely documenting the user requirements and functional requirements of the instrument. Once established, the requirements are then used to evaluate the instrument candidates available from suppliers. A validation plan with deliverables that are commensurate with the class of the instrument being implemented should be developed during the planning phase. 

Validation Plan A validation plan is prepared to highlight the activities and deliverables required in the implementation of the laboratory instrument. The details of the validation plan should be scaled according to the complexity of the system, its intended use, and the impact on the business. A generic validation plan can be used for similar types of laboratory instruments with similar applications. For example, one validation plan can be prepared for the FIPLC. A validation plan typically includes the following sections ... 

Summary Report After completion of the qualification activities, a summary report should be prepared to summarize all the qualification testing and results and deviations from the validation plan as well as include a conclusion to state whether the instrument is ready for its intended uses. Any deviations from planned activities including testing failures and requirements not met by the system should be addressed in the report. The summary report typically includes the following sections ... 

A software validation plan must take into account the risk analyses for the software therefore a critical software must have a high level of confidence and must be submitted to deep validation processes, whereas noncritical software may be submitted to less extensive validation processes. 

Instruments to be used in a GMP environment have to be validated prior to regular use. It is useful to develop the instrument implementation plan as a plan to outline the steps necessary to validate the instrument and to support the use of the instrument through its functional life in the laboratories. The implementation plan should highlight the activities in the validation of the system and will be the guiding document of the project. Typically, the validation plan includes ... 

Develop a validation plan and schedule using your validation master plan as a guideline. 

The primary focus during validation is validation of the content of the spreadsheet itself. Nevertheless, items such as location of storage, security of cells and file, as well as access to the file have to be taken into account. The general validation approach for spreadsheets is not different from other validation approaches and can be arranged in three general sections (1) validation plan, (2) execution of the plan, and (3) validation documentation (protocol). 

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