Validation life cycle

The terms instrument qualification and instrument validation are sometimes used indiscriminately. In this chapter, the term qualification refers to the site preparation and the testing employed to demonstrate that the instrument is properly installed in a suitable environment and the performance meets the predetermined specifications for its intended use. Qualification is a part of the whole validation life cycle. Validation refers to the process to provide assurance that the instrument is suitable for the intended application throughout the lifetime of the instrument. Installation qualification (IQ), operation qualification (OQ), and performance qualification (PQ) are performed to provide evidence that the user requirement specifications (URSs), functional requirement specifications (FRSs), and design qualification (DQs) have been met. The sequence of requirements setting and qualification events as well as the relationships between IQ, OQ, PQ and URS, FRS, and DQ are generally illustrated by the V diagram shown in Figure 2. Installation qualification demonstrates the fulfillment of the DQ. Similarly, OQ demonstrates the fulfillment of the functional requirements and PQ demonstrates the fulfillment of the user requirements. 

The decommissioning of an instrument is the last step in the validation life cycle. When an instrument is no longer required in the laboratory and is ready for retirement, the following activities and related recordkeeping are required ... 

Figure 1 Validation life cycle of water and air system. (From Ref. 2.)... 

Supplementing a validation maintenance program (also called continuous validation life cycle) that includes a mechanism to control changes to the system and establishes and carries out scheduled preventive maintenance, including recalibration of instruments. 

The integrity of quality-related critical parameters and data must be maintained throughout each phase of the validation life cycle, including the supplier design and development phases. 

Industry groups and regulatory authorities have debated and addressed the issues surrounding computer system validation, with the PDA [4] and GAMP Forum [3] providing industry guidance on validation life-cycle methodology and documentation. 

Providing documented evidence to achieve and maintain the validated status and uphold GMP compliance requires a systematic approach and rigorous controls throughout all phases of the computer system validation life cycle. Formal testing at key stages in the life cycle will provide records to demonstrate that predefined requirements have been met and that the computer system is fully documented. 

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... 

Traceability and accountability of information to be maintained throughout validation life-cycle documents (particularly important in relating qualification tests to defined requirements). The mechanism (e.g., matrix) for establishing and maintaining requirements traceability should document where a user-specified requirement is met by more than one system function or covered by multiple tests... 

The established methodology for computer system validation enables identification and control of each life-cycle phase and its associated document deliverables. It is also recognized that throughout the validation life cycle there is a level of dependency on the methods, services, and resources of the computer system supplier. 

The validation life-cycle phases align closely with the project stages for new computer system applications. With this in mind, it is recognized that a significant proportion of the documentation required for validation may be generated by a well-controlled and -documented project. 

The pharmaceutical manufacturer must ensure that personnel are trained to an appropriate level in GMP and validation planning and requirements to enable them to adequately perform their function. This applies to any resource used in connection with GMP compliance and validation life-cycle activities and documentation. A training program should be in place and individual training records maintained. The records and suitability of external resources used by suppliers or contractors should also be examined. 

The regulatory authorities require the pharmaceutical manufacturer to maintain guidelines and procedures for all activities that could impact the quality, safety, identity, and purity of a pharmaceutical product. This includes procedures for implementing and supporting the validation life cycle and for process operation. 

Configurable software packages—validation life cycle with qualification of the hardware and application software... 

A fundamental objective of a computer system applied to automate a pharmaceutical GMP operation is to ensure the quality attributes of the drug product are upheld throughout the manufacturing process. It is therefore important that quality-critical parameters are determined and approved early in the validation life cycle. The exercise should be undertaken to a written procedure with base information from the master product/production record file examined and quality-critical parameter values and limits documented and approved for the process and its operation. In addition, the process and instrument diagrams (P IDs) should be reviewed to confirm the measurement and control components that have a direct impact on the quality-critical parameters and data. This exercise should be carried out by an assessment team made up of user representatives with detailed knowledge of both the computer system application and process, and with responsibility for product quality, system operational use, maintenance, and project implementation. This exercise may be conducted as part of an initial hazard and operability study (HAZOP) and needs to confirm the quality-related critical parameters for use in (or referenced by) the computer control system URS. 

Approved critical parameters and data are not open to interpretation at any time throughout the system validation life cycle. This is particularly important where design and development activities are not directly controlled by the pharmaceutical manufacturer. 

As with all validation life-cycle documents, a validation plan is a formal document produced by the pharmaceutical manufacturer. The plan should require that all validation documentation is under a strict document control procedure, with issue and revision of documents controlled by means of an approval table, identifying the name, signature, date, and level of authority of the signatory. 

Both supplier and customer signatures on the activity schedule can provide a record, for control of the design and development phase of the validation life cycle in support of DQ. The activity schedule can also be used to identify tasks that require input from the pharmaceutical manufacturer. 

In summary, the planning phase of the validation life cycle encompasses all the up-front preparation activities and documentation, including ... 

It is imperative that these are in place to support the validation life-cycle activities that follow. 

Provide sufficient detail to the supplier to produce a cost, resource, and time estimate to engineer and document the computer system within a validation life cycle... 

The URS can contain a large number of requirements and should therefore be structured in a way that will permit easy access to information. The requirement specification must be formally reviewed and approved by the pharmaceutical manufacturer. A number of general guidelines apply to this specification (and all validation life-cycle documents). 

Suppliers with system development and project execution procedures in line with validation life-cycle requirements are well placed to deliver the appropriate level of validation support documentation. The existence of supplier test... 

The FDS will also form the basis for contractual acceptance testing, both at the supplier s premises (factory acceptance test, FAT) and on delivery to the site (site acceptance test, SAT). With suitably compiled test procedures these traditional contractual acceptance tests may be incorporated with the qualification testing required by the validation life cycle. 

Ensure that the software code or configuration is to a standard that will ensure clear understanding and support maintenance and modification of the software throughout the system validation life cycle... 

The supplier will normally apply GEP in covering the two parts of this contractual acceptance test, namely FAT and SAT. However, and if required by the pharmaceutical manufacturer, it should be possible to structure acceptance testing to include the enhanced level of verification, testing, and documentation that are necessary for the in situ qualification under the validation life cycle. 

A satisfactory FAT report for the computer system also supports DQ by finalizing predelivery testing for the design and development phases of the validation life cycle. 

Qualification is the process of establishing appropriately documented verifications and tests that provide a high level of assurance that a computer system will operate in accordance with predefined specifications. The specific approach to be used for each level of qualification should be outlined in the project validation plan and needs to focus on the critical parameters, data, and functionality of the computer system. While there are no absolute lines to be drawn between qualification testing of a computer system, it is recognized that the qualifications listed below provide the necessary control and continuity throughout the validation life cycle and must be approved for the system to be released for use in the GMP environment. 

On completion of the DQ process the pharmaceutical manufacturer s qualification summary report must record the completion of the DQ and acceptance of the system at site for the in situ qualifications required by the validation life cycle. 

Documentation will typically comprise validation life-cycle documents and procedures, SOPs, training records, quality records and procedures, process and engineering data, drawings, manuals, and spares list(s), and includes copies of the software. These originate from both the pharmaceutical manufacturer and the supplier. The documents must be verified as approved and on file under a document control system. The documentation must be located or stored in a controlled environment. 

The report may follow the same format as the validation plan to aid cross-reference and must review all the key validation life-cycle documents. Any deviations and associated corrective actions should be reviewed, and any concessions on the acceptability of qualification test results examined. 

This phase of the computerized operation is usually the longest phase of the validation life-cycle, covering the operational period of the computer system in pharmaceutical manufacturing. 

During this period, and as relevant, the validation fde must be updated with current and approved validation documentation that continues to provide evidence of a controlled and satisfactory validation life cycle and that will enable inspection readiness. 

Consideration should be given to periodic revalidation to ensure the computerized operation remains capable of achieving the intended results. The extent of revalidation will depend upon the nature of the changes and how they affect the different aspects of the previously validated computerized operation. Unless circumstances demand, revalidation does not necessarily mean a full repeat of the validation life cycle. As appropriate, partial requalification may be acceptable. For instances in which new qualification testing is undertaken it is advisable to retain the original qualification summary reports in the validation file or quality system archives, marked superseded with cross-reference to the new documents. 

Auditable validation life-cycle documents and software Procedures/records Change control Configuration control Document control On-site work procedures System security (closed and open systems)... 

The implementation group must align its activities to the validation life-cycle documentation to ensure the design and application engineering necessary to implement the change is conducted in a structured manner and to ensure any retesting of the system is conducted at a level necessary to embrace all change issues. 

In most instances and due to the system validation life cycle, a modification to a high-level document will invariably affect lower-level documents. These lower-level documents are called dependant documents, and it is important to identify and update all affected documents. 

Table 1 lists 12 steps in the process validation life cycle for a new process, starting with definitions of the product and the process [5]. Each step needs to be documented, using approved validation plans and/or protocols. 

Table 1 Twelve Key Steps in the Validation Life Cycle of a New Process... 

PQ is intended to demonstrate that the process will function correctly in its normal operating environment. The demonstration may involve pilot lots, commercial-scale lots, or carefully designed simulations of either. In the case of drug substances, PQ protocols often involve individual modules (e.g., steps, unit operations) of a new process prior to pilot or commercial scale-up of the full process. When a given critical process parameter cannot be simulated at less than commercial scale, all other process parameters are often established first, to avoid potential interference with the first commercial batch that must involve the sensitive parameter. The three full-size lots required to authorize commercial distribution can, if desired, represent key PQ experiments however, there is no limit to the number of subsequent commercial lots that can also continue to be considered part of the PQ step in a validation life cycle. 

It is important to recognize that the validation life cycle and validation change control continue as long as the related product remains in the marketplace. Validation change control is a formal monitoring system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect validated status and cause corrective action to be taken that will assure that the system retains its validated state of control. 

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