The Computer Systems Validation Process

It is an FDA requirement that regulated organizations ensure that all computer systems performing functions under FDA predicate regulations conform to the requirements contained in Chapter 3. In the FDA regulation context, computer systems validation is an element of the SLC. The scope includes all the practices and tools necessary to manage the development and maintenance of the deliverable system. 

All new computer systems must be prospectively validated before going into production. For existing computer systems, concurrent validation may be considered where limited documentation on the appropriate technology exists, and where an acceptable level of confidence can be established by reviewing and documenting the operating history. 

For existing computer systems, retrospective evaluation is discouraged. It is extremely difficult to evaluate a computer system retrospectively, being generally more costly and time consuming than prospective validation. Retrospective evaluation should be used only as a corrective measure in response to deficiencies noted concerning prior validation efforts. See Chapter 19 for a brief discussion on this subject. 

Any deviations raised during the application of a computer system validation procedure shall be documented following the applicable deviation recording procedure. 

The following describes the process for developing and maintaining computer systems in an FDA context. 

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The depth and scope of the validation depends on the category of the software, and the complexity and criticality of the application. Refer to Chapter 7 for details of the computer system validation process. 

The elements to be included as part of the computer systems validation process will vary depending on the category of the software. It is the practice in the FDA-regulated industry to take into account five (5) categories of software. 

Qualification is the process of demonstrating whether a computer system and its associated controlled process/operation, procedural controls, and documentation are capable of fulfilling the specified requirements. Sidebar 10-11 depicts the context of the qualification activities and the computer systems validation process. The physical components of the systems are reviewed and its specific elements, subunits, and parameters are documented. A qualification also serves to verify and document the acceptability of the design, implementation, integration, and installation of the computer system components. The execution of the qualification is the mechanism by which documented evidence is created that verifies that the computer system performs according to its predetermined specification. 

The development model associated with the SLC contains the software engineering tasks and associated work products necessary to support the computer system validation effort. It breaks the systems development process down into sub-periods during which discrete work products are developed. This approach leads to well-documented systems that are easier to test and maintain, and for which an organization can have confidence that the system s functions will be fulfilled with a minimum of unforeseen problems. 

The Computer Systems Validation (CSV) Executive Committee is composed of Validation, Compliance, Regulatory Affairs, and Information Technology senior management. Another possible member of this committee is a Process Innovator. 

Some compaiues would not include CHAZOP as part of the computer system validation. However, the CHAZOP process can provide a formal mechanism for reviewing and assessing a system design. 

FieldNotes user verification can be conducted by following the SOP written by Astrix, which can be downloaded from the Astrix Web site. The SOP contains a script that is typed into the computer system. If the printout matches the SOP script, then verification is complete. A record of this must be placed in the facility archive. This verification process takes 1 h or less. For FieldNotes, calculations are not verified at the field site since the manufacturer feels that the software developer and the sponsors have performed adequate validation of these calculations previously. This may, therefore, require a visit to the sponsor or to the manufacturer to confirm that this important step of the validation process has been completed and is adequately documented. By following the Astrix SOP, the user is simply ensuring that the program operates on their system(s). The SOP script must be typed in exactly as written in order to confirm the printout accuracy. QA must ensure that the verification documentation is properly archived. Just as with any other SOP, this SOP must be approved in writing by field site management to comply with GLP. 

The computer system attached to the instrument provides instrument control, data acquisition, data processing, and reporting. According to the draft Analytical Instrument Qualification chapter of the United States Pharmacopoeia (USP) <1058> The manufacturer should perform design qualification, validate the software and provide users with a summary of the validation. At the user site, holistic qualification that involves the entire instrument and software system is more efficient than modular validation of the software alone. Therefore the user qualifies the instrument control, data acquisition and processing software by qualifying the instrument. ... 

Laboratories using computer technology must assure that they have adequate controls in their delivery of data to the EPA. Computer system validation is the process by which a computer system is shown to consistently do what it is supposed to do and only what it is supposed to do. In effect, the validation study confirms and documents the areas of control and the specifications contained in the GALP requirements. 

The system should include built-in checks of the correct entry and processing of data. In order to verify the validation data, some computer systems may periodically be submitted to a defined group of inputs for which the result is known and the result must be kept and filed. If the results are acceptable, the computer system is operating well, but if the results do not match the expected ones, the computer system is not working properly and maintenance is required. In this situation, all the results obtained from the referred computer system since the last validation verification are consided questionable and must be reevaluated. 

Equipment qualification covers the entire life of a product. It starts when somebody has an idea about a product and ends when the equipment is retired. For computer systems validation, this ends when all records on the computer system have been migrated and validated for accuracy and completeness on a new system. Because of the length of time and complexity, the process has been broken down into shorter phases design qualification (DQ), installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ) [2]. The process is illustrated in Figure 17.1. 

The most important factors for the entire process of equipment qualification and computer system validation in analytical laboratories are proper planning, execution of qualification according to the plan, and documentation of the results. The process should start with the definition of the analytical technique and the development of user requirement and functional specifications. For computer systems, a formal vendor assessment should be made. This can be done through checklists and vendor documentation with internal and/or external references. For very complex systems, it should go through a vendor audit. 

Whether a control system comprises distinct instruments for nominal control functions and process monitoring, or an integrated control system, a nominal set of control function tests are necessary. The tests described encompass both controller capability and equipment performance. These tests may be completed during the FAT as part of a separate computer system validation. 

Computer System Validation Controlling the Manufacturing Process... 

Whatever the validation approach, the fundamental requirement for computer system validation is to establish documented evidence that provides a high degree of assurance that the system consistently operates in accordance with predetermined specifications. The EC guide to GMP also requires periodic critical revalidation to be considered to ensure processes and procedures remain capable of achieving the intended results. 

To maintain control of the computer system throughout its conception, implementation, and operational use in a GMP environment, it is required that the computer system application must be validated in a way that will establish auditable documented evidence that the computer system does what it is expected to do. As applicable, this needs to be carried out in conjunction with plant equipment to provide a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes. The methodology to achieve this is based on a recognized life-cycle mode. 

The process for implementation and prospective validation of computer systems outlined in Figure 3 depicts the system application activities within each life-cycle phase and identifies key issues and considerations for each step. The process includes for evaluation of both the computer system product and the system supplier s working methods. The same life-cycle approach may be applied to validate the associated control and monitoring instrumentation [9]. 

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. 

In the case of a computer system applied to a live manufacturing process and integral with plant equipment and the process itself, the project validation plan should specify the relationship of the computer system qualification activities and documentation with that of the corresponding plant equipment qualification and process validation. Indeed, the qualification activities and documentation of these elements of a computerized operation are sometimes combined. 

The computer system URS needs to describe the levels of functionality and operability required from the computer system, its application, and the location with regard to the process. Definition of approved and accurate manufacturing and process data is a key objective of the URS and is essential in order for the computer system supplier or integrator to fully understand and develop the computer application and to engineer the field instrumentation and electrical controls. This must include the quality-related critical parameters that are fundamental in determining and ensuring the satisfactory quality of a drug product. Parameters, data, and functions that are necessary to uphold GMP must always be considered as firm requirements and candidates for validation. 

Quality-related critical parameters, data, and functions are essential for specification and contract considerations, system design and development, qualification testing of the computer system, and PQ for the validation of the process. GMP-related system requirements need to be traceable throughout the specification, design, development, testing, and operation of a system. This can readily be achieved by having a traceability matrix that will identify corresponding sections and data in the key life-cycle documents. 

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 issue of a satisfactory and approved PQ summary report, it is demonstrated that the computer system supports the computerized operation, and conditional on satisfactory process validation is available for use in the GMP operating environment. 

On satisfactory completion of the computer system qualifications, with PQ conducted in conjunction with a successful process validation, a final report must be prepared by the pharmaceutical manufacturer s validation team. This is normally referred to as the validation report. The objective of the report is to give an overview of the results of the execution of the validation program for the computerized operation and to draw a conclusion as to the suitability of the computerized operation for pharmaceutical manufacturing. This may be unconditional use or there may be restrictions. In the latter case the proposed remedial ac-tion(s) must be approved and, as applicable, considered under change control. A schedule to complete any outstanding actions must be documented and progress formally reported. 

The ongoing evaluation process should also consider system decommissioning in readiness for eventual system retirement. Initially a plan should be prepared to identify GMP requirements and the validation considerations for system retirement. Then, in readiness for the actual decommissioning, a detailed procedure is required specific to the current operation of the computer system and its GMP-related quality-critical data. Any retesting required in support of decommissioning is to be included in this procedure. 

Responsible People. The first part should list the computer system and the person responsible for the validation process, for example, the department head of the user group the responsible user. The other people responsible for the review, implementation, and approval of the protocol should also be listed. 

All projects have a life of their own and each person has a different methodology and timing for getting the job done. Success in computer systems validation will depend on the operating committee s ability to keep the process moving. One means of project control is a tracking format that identifies the key steps in the validation process and the anticipated and actual completion dates. 

Steering Committee/Operating Committee monitoring of the administrative process for computer systems validation. 

The validation of computer systems is an exercise in project management. The fact that computers are involved does not mean that the approach will be significantly different. It does mean that the responsible users will be the focal point of computer systems validation they will have to assume the responsibility for validation of the computer systems they use just as they are responsible for all other compliance aspects of their operation. MIS will play a key role since their computer expertise and interface with the suppliers is required throughout the process. 

During the implementation or update process, the introduction of a computer validation management cycle will provide a top-down approach to integrate computer systems validation strategies in order to support the project. Figure 5-1 suggests a computer validation management cycle. 

Each phase of the SLC must be controlled to maximize the probability that a finished system meets all quality, regulatory, safety, and specification requirements. If an SLC approach is applied properly, no additional work will be required to validate a system. For each SLC period and event, computer systems validation requires that the development processes are documented work products. As explained in Chapter 2, phase gate verification activities performed during each event may be a perfect place to review and quantify the quality of all products needed to support the next phase. 

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