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Many questions those had been raised across the pharmaceutical industry regarding need of computer system validation and its requirements. There is a big question that how much validation we should do and what activities we should do to carry out successful validation. This document represents history of computer system validation, why it is necessary to do, regulatory requirements for computer system validation and last but not least validation master plan which is a very important for successful completion of computer system validation. Here in these papers, main focus is on what is validation master plan, contents of validation master plan with regards to different validation life cycle models and risk based approach to minimize the risks associated with computer system validation.
In 21st century use of computer system is spreading everywhere in the world. Pharmaceutical Industries are using computer system in most of areas to make each and every task fast, automatic and accurate. As computer is a human made machine, it might make a mistake so correct functioning of the system is very important to get higher efficiency of the system in terms of accuracy, reliability and consistency. Therefore, validation of the computer system becomes a necessary task to check its performance ability. As Planning and scheduling plays a major role in any project, computer system validation master plan is very important to carry out all validation activities with positive outcomes. Purpose of this term paper is to share our thoughts and understanding to develop Computer system validation Master Plan. Contents of validation master plan give whole framework of the computer system, how its design, installation and performance will be evaluated, how it will be validated and how its validated state will be maintained till its retirement.
If you do not document then it proves that you did not do anything so, documentation is very critical part of any project. Therefore, final validation report is the final and very important activity during computer system validation. Computer System Validation Master Plan includes all kinds of documentation regarding validation activities performed during validation, planning of validation process, change control management and system maintenance documentation as well.
3.0 History of Validation
Validation was 1st introduced by two FDA officers Ted Byers and Bud Loftus, in the mid 1970’s to improve quality of pharmaceutical products. There is a big problem or an issue behind each new technology; validation concept has also emerged from some major problems happened in pharmaceutical market. It was implemented in response to problems in the sterility of LVPs in pharmaceutical manufacturing. In earlier times, validation was done only for main production process but later on it was done in some additional areas also like environmental control, media fill, equipment sanitization and purified water production.
4.0 Why Computer System Validation??
Testing an entire system at the end is not considered proper and sufficient evidence that every component within a system fulfills the required specification. Appropriate computer system Validation Master Plan (VMP) will provide a high degree of assurance that all steps and processes are included in validation process which are essential to evaluate and implement computer system.
5.0 Requirements for Computer System Validation
Section 211.68 of the US cGMP regulations states Specific requirements for computer system.
Mechanical, automatic, electronic or other types of equipment, including computers or related to computer systems should perform their functions satisfactorily. These instruments or equipments may be used in the manufacture, processing, packing, and holding of a drug product. If this sort of equipment or instrument is used, it shall be calibrated, inspected, or checked on regular basis as per the written program in order to ensure proper performance of the system. There shall be maintained written records of those calibration checks and inspections.
Only authorized personnel shall be accessible and responsible for changes in master production and control records or other records exercised over computer or related systems.
Authorized personnel shall be assigned for checking formulas or other records or data input to and output from the computer or related system for accuracy.
Complexity and reliability of the computer or related system shall be the basis to decide the frequency and degree of input/output verification
There shall be maintenance of a backup file of data entered into the computer or related system except certain data including calculations which are performed in connection with laboratory analysis are excluded by computerization or other automated processes. Along with appropriate validation data, a written record of the program shall be maintained in such cases.
For assurance that backup data are precise and complete and to ensure that backup data are secure from alteration, inadvertent erasures or loss, hard copy or alternative systems (For example; duplicates, tapes, or microfilm) shall be designed and maintained.
Some specific guidance documents have been developed by the FDA for computer system applications in other FDA regulated areas. The Industry Guide is one of the most important from them, which includes general principal of Software Validation that deals with development and validation of software used in medical devices. Draft guidance on computer systems used in clinical studies is more recently released by FDA. This draft guidance states FDA’s expectations related to computer systems and to electronic records generated during clinical studies.
Computer system validation issues are taken into consideration by several industry organizations and private authors because of their special importance.
Guidelines for computer validation has been developed by the Good Automated Manufacturing Practices Forum (GAMP)
A validation reference book for the validation of computerized analytical and networked systems has been published by Huber
A technical paper comprises of validation of laboratory data acquisition system has been developed by the Parenteral Drug Association (PDA)
6.0 Validation Master Plan
The Validation Master Plan is a document that describes how the validation program will be executed in a facility. Even though it is not mandatory, it is the document that outlines the principles involved in the qualification of a facility, defines the areas and systems to be validated and to provide a written program for achieving and maintaining a qualified facility with validated processes. It is the foundation for the validation program and should include process validation, facility and utility qualification and validation, equipment qualification, cleaning and computer validation. The regulations also set out an expectation that the different parts of the production process are well defined and controlled, such that the results of that production will not substantially change over time.
All validation activities should be described in a validation master plan which should provide a framework for thorough and consistent validation. A validation master plan is officially required by Annex 15 to the European GMP directive. FDA regulations and guidelines donââ‚¬â„¢t mandate a validation master plan, however, inspectors want to know what the companyââ‚¬â„¢s approach towards validation is. The validation master plan is an ideal tool to communicate this approach both internally and to inspectors. It also ensures consistent implementation of validation practices and makes validation activities much more efficient.
7.0 Contents of Computer System Validation Master Plan
Purpose & Scope
Roles & Responsibilities
Risk Based Approach
System Acceptance Criteria
Vendor selection & Assessment
Computer System Validation Steps
Configuration Management and Change Control Procedures
Back-up and Recovery
Error Handling & Corrective Actions
Contingency Planning and Disaster Recovery
Maintenance and Support
Validation Deliverables & Documentation
Templates & Validation Examples
7.1 Purpose and Scope
In 21st century development and manufacturing of each and every medicinal product utilize computer system. Therefore proper functioning and performance of software and computer systems play critical role to maintain consistent, reliable and accurate data. US FDA and other major regulatory agencies have specified regulations and guidelines to ensure that computer system is suitable for its intended purpose.
To perform computer system validation in an efficient way with positive outcomes, development of validation master plan early in the system development life cycle is very important. Computer System Validation Master Plan includes the system developer, information technology group, end user and regulatory or compliance unit. System owner or sponsor should develop validation master plan, document and approve it for successful completion of validation. Organization management must have adequate control over each validation activity and performer to achieve desired validation goal with use of available resources in defined time duration.
Computer system validation master plan covers complete system development life cycle which includes validation during system design and development until system will retire.
Moreover, it wraps all aspects of validation process with consideration of vendor, end user, application, hardware and software, interfaces to other systems, personnel training, documentation and system management as well as validation itself after the system is put into use.
7.2 Roles and Responsibilities
There is no regulation in FDA Guidance Document for roles and responsibilities to perform computer validation. Specific organizational structure is responsible for proper distribution of work to achieve the validation target.
Various departments involved in computer system validation:
Vendors of commercial of the shelf systems
7.2.1 Responsibilities of End Users: Out of all above departments end users are more responsible for validation of computer system to have better control over the system performance. They should write the specifications, create test cases and perform on-going testing with support of validation groups and QA people.
7.2.2 Responsibility of Validation Groups
Management of validation activities based on business objectives, applicable federal and international regulations, industry standards that pertain to the validation of GXP system.
7.2.3 Responsibilities of QA
All validation activities are monitored by QA. QA is the leader for vendor assessment, documentation & verification of validation activities with compliance of applicable regulations. QA has authority to review and approve validation documents such as requirement specifications, SOPs for planning & development of VMP, test plans, test results and final validation reports.
An additional important role: Leader to initiate to do necessary tasks if tasks don’t happen as they should do.
7.2.4 Responsibilities of IT Department
Design, development & installation of network infrastructure involves IT department. They are not responsible for validation but give suggestions on testing requirement & frequency and assessment of risks associated with the system.
Major part of the VMP is to determine the need of validation and how it is related to SDLC of the product development. The Validation Master Plan is a document that describes execution of validation program. It outlines system qualification principles, defines sub-systems to be validated and provides a written program for achieving and maintaining a qualified system with validated processes.
Validation of computer systems is not a once off event. But it is a part of the complete SDLC. This cycle includes planning, specification, programming, testing, commissioning, documentation, operation, monitoring and modifying.
New systems should be validated when it is going to use to solve an existing problem. While for an existing system it starts when the system owner brings the system into a validated state. System retirement with successful existing data migration is the end of validation. Validation planning, defining user requirements, functional specifications, design specifications, validation during development, vendor assessment for purchased systems, installation, initial and ongoing testing and change control are steps of validation beginning to system retirement.
Validation process is typically broken down into life cycle phases because of complex and time consuming process. One model that is frequently used is the V-model.
For true commercial off the shelf system with no code development for customization V-model is quite complex. 4Q model with just four phase best fits for COTS system.
4Q Lifecycle Model
Both the 4Q and the V-model are lack of retirement phase. Hence it is not suitable when systems require to be configured for specific applications or when additional software developed by the user’s firm or by a 3rd party is required which is not included in the standard system. In this case following model is preferred.
System Integration Combined with System Development
If there is no vendor, the software needs to be developed and validated by following the steps on the left side of the diagram. Programmers need to develop functional specifications, design specifications and the code and perform testing in all development phases under supervision of the quality assurance.
If users want to purchase system from vendor, they compare the vendor’s responses with their own requirements. If all vendors fail to meet user requirements, then requirements may be adjusted or additional software is written following the development cycle on the left side of the diagram. The vendor is selected based on the users’ technical and business requirements.
To decrease testing requirement more standard with less customization software should be used. GAMP has developed software categories based on the level of customization. Category one and two define operating systems and automated systems firmware are specified in category 1 and 2 respectively. Both of these have less important as compare to 3rd, 4th and 5th category. Each computer system is associated to third, fourth and fifth categories.
Standard software package. No customization.
Examples: MS Word (without VBA scripts). Computer controlled spectrophotometers.
Standard software package. Customization of configuration.
LIMS, Excel spreadsheet application where formulae and/or input data are linked to specific cells.
Networked data systems.
Custom software package. Either all software or a part or the complete package has been developed for a specific user and application.
Examples: Add-ons to GAMP Categories 3 and 4, Excel with VBA scripts.
Risk Based Approach
Risk based approach is widely used in the industries, not only the pharmaceutical industries but other industries also adopting this concept. Recent studies show that the pharmaceutical industries are widely using this concept for the development of new soft ware. In the pharmaceutical industries, particularly in the testing of computer system this is very useful. As we know the how important is the GXP approach in the pharmaceutical industries which is mainly based on the computer system for documentation and storage of data and also for operate other operations. So, the verification or the validation of computer system is very important. Proper functioning of the computer system is necessary for the pharmaceutical industries.
7.4.1 Define the System Inventory:
To determine the inventory of the computer systems and software it involves the following:
System Boundaries: First step is deciding the boundaries of the system.
Document process: Document all the processes of the organizations which used the application.
Define functions: the functions performed by that particular system is define properly and also the other which support the application.
Identify data: Data used in the process should be clearly defined and show that are compliance with the FDA.
Identify existing controls: This involves the identification of the existing process controls.
7.4.2 Risk Assessment:
Risk assessment should be performed to determine or identify the critical data.
The risk assessment process includes:
Functions Performed or Data used
Subsystem Affected by the Function
Reasons for Failure
Likelihood of Failure
Consequences of Failure
Detection of Failure
7.4.3 Gap Analysis:
The Gap analysis is performed mainly to identify the shortcomings of the existing design and other process controls. After the identification next step is the develop the plan and strategy to minimize the associated risk.
For example, the existing system has not certain specifications to perform adequate tests. This kind of risk would be minimized by adopting needed specifications. This may involve the addition of new software or upgrade the old version or hardware to the existing systems.
7.4.4 Prioritized Validation Plan:
All the activities in detailed should be included into the Validation Master Plan. The main focus should be on the compliance during the development of the plan to minimize any non-compliance and be in the regulations required by the agency. All the groups of the organization should be involved in the validation master plan of the complex computer system like stakeholders, including operations, engineering, IT, and also QA groups. So, all the process and procedures and also other related parameters performed by these groups should be considered.
7.4.5 Execute Plan:
After the approval of the validation plan, it should be implemented including all the controls as required and also the retrospective development if necessary. First validate the highly priority functions.
7.4.6 Training & Training Plan:
As the system is validated and implement the new technology the personnel should be trained as per the requirement.
All personnel related to development and use of GXP computer system must be properly trained to perform computer system validation in a very efficient way to achieve desire goal without any failure during validation process.
Requirements of Personnel:
Educational Qualification and Experience
Roles of personnel required to be performed
Training Plans and Records
Education Qualification and Experience:
System developer and system user should have qualification requirements stated in 21 CFR Part 11 Regulation for electronic records and electronic signatures. Each personnel engaged in computer system validation should have enough technical background of computer systems and some experience of GXP computer system handling.
Roles of personnel required to be performed:
Management should assign specific roles and responsibilities to each person. Individual role description should be prepared and kept up to date to show during inspection.
Training Plans and Records:
Organization should develop training plans at specific intervals to manage the staff development in order to aware all personnel regarding GXP principles of computer system. Training procedures and plans must be documented and maintained to comply with regulatory requirements. There should be audit and periodic review of personnel performance and/or training records. The personnel should be given supplementary training if necessary.
7.5 System Acceptance Criteria
1) The system is installed according with design specification based on manufacturer recommendations and cGMP guidelines
2) Instruments are calibrated, identified, and entered in to calibration program
3) Software and hardware systems are verify and confirmed as per specification
7.6 Vendor Selection & Assessment
Vendor selection and assessment play critical role to get computer system with high efficiency. To validate a computer system, not only vendor is responsible but user is also responsible for overall validation. System owner should assess the activities of commercial off-the-shelf system developers to determine necessary additional efforts to ensure that computer system is fully validated for its intended use.
Vendor selection and assessment is based on vendor qualification to assure that vendor has developed a system which meets all regulatory and user requirements specification for quality.
Answers of following questions are essential for vendor assessment.
“What type of assurance do you have that the software has been validated during development?”
“How can you be sure that the software vendor did follow a quality assurance program?”
Answer of above questions using risk based approach:
Documentation regarding the experience of working with the vendor.
Working experience of other end user with particular vendor to be useful when your company has no experience with that vendor
Assessment checklists to verify the identification and performance of validation activities
3rd party audits
Independent assessment of the software system and/or development process
Direct vendor audits
For actual assessment of the vendors’ quality system and software development and validation practices.
Final procedure should be based on justified and documented risk assessment.
Computer System Validation Steps
7.7.1 Design Qualification and Specifications:
Detailed specifications related to functioning and operating of the computer system is stated in Design Qualification. It also explains various important decisions regarding the selection of supplier.
All the required functional and performance criteria of computer system should be included in the DQ, for the successful implementation of the intended application and fulfill all business requirements. There can be huge business and technical impact if there are errors in DQ occurs. Hence it is wise decision to invest adequate time and resources in the DQ phase.
Design Specification generally includes the following steps:
Brief description of the task assigned to the computer system which it is expected to perform
Explanation related to the proposed use of the system
Explanation regarding the intended environment within the system (For example, the network environment)
Description regarding the selection of the functional specifications, system requirement specifications and vendor
Vendor assessment and selection process description
Description of the final selection of functional specification, the system requirement specifications and final supplier selection
Description related to the final system specifications’ development and documentation
A well documented procedure should be followed in the development of user requirement specifications. Involvement of representatives of all user departments in this process is the most important point to consider here.
Following key attributes should be included in the user requirements:
Necessary – There may be drastic increase in development, maintenance and support costs as well as validation cost due to unnecessary functions.
Complete – Add all functions initially with caution without missing them because at a later stage it will be much more expensive than including them initially.
Feasible – There must be implementation of all specified functions on time because that will delay the project.
Accurate – All functions must be accurately specified to solve the applications problem.
Unambiguous – Developer must avoid wrong interpretation and guessing.
Testable – Functions that are not able for test applications cannot be validated.
Uniquely identified – These sorts of specifications can be linked to the test cases.
7.7.2 Installation Qualification:
Verification regarding the computer system has been established as per design specifications, installed properly in the selected environment, and that environment is suitable for the normal operating condition and use of the instrument is the goal of Installation Qualification. Before and during installation the list of steps below should be recommended and followed.
For installation site requirements owner should consider manufacturer’s recommendations
Test the site for the execution of the manufacturer recommendations
Evaluate computer hardware and software received from vendor with purchase order ( which includes, software , spare parts and accessories)
Verify documentation for entirety and un-ambiguity (For example, operating manuals, standard operating procedures for testing , maintenance instructions, safety and validation certificates)
Test computer system hardware and peripherals for any type of damage
Install hardware (which includes, computer, peripherals, cables, network devices)
Follow the manufacturer’s recommendation to install software on computer
Check for the correct software installation, (For instance, whether all files accurately copies on the computer hard disk, utilities to do this task are proper for that software).
Ensure back-up copy of that particular software
Organize network devices and peripherals, (For example, printers and equipment modules)
Categorize and make a list of all hardware description (which includes drawings for networked data systems)
Prepare a list of description of all software installed on the computer
Store design and pattern settings either electronically or on paper
List SOPs and equipment manuals
Prepare and organize an installation report
7.7.3 Operational Qualification:
Demonstration of functions of a computer system according to its functional specifications in the selected environment is the target of Operational Qualification (OQ) process. Computer system functions and utilization of those functions for particular use is the major point to be considered before OQ testing is done.
Documented and justified risk assessment is the basis for determination of extent of testing. Basic Criteria to consider here are:
Impact on Business Continuity
Impact on Product Quality
Information taken from the Vendor on Type of Tests and Test Environment
Complexity of System
Level of Customization
Whenever the system is developed for a specific user, most extensive tests are essential. All functions must be tested by the specific user in this case. Tests are performed for functions which are highly critical for the operation or for functions that can be influenced by the environment.
The GAMP Categories 3, 4, or 5 are well enough to justify the level of customization. Category three states the standard software without customization and configuration setting. Category 4 identifies a configurable system and Category 5 involves fully customized system. Extent of testing increases from the lower risk and standard system to the higher risk with full customization.
7.7.4 Performance Qualification:
PQ is the process which demonstrates that a system consistently performs as per the specification suitable for its regular use. For regular preventive maintenance of computer system it must work in a manner that consistent performance is achieve throughout life cycle, For instance, introduce changes to a system in a controlled manner and regular testing to ensure consistency.
Checking and testing of the computer system with total applications is the practical definition of the PQ. For example, proper testing of running system in which important type of system performance characteristics are considered and compared with documented predetermined limits.
Generally PQ testing activities includes,
To verify and prove that the entire applications work as intended, complete system testing is done. For instance, performance qualification for computerized analytical system is carried out by introducing and running a well distinguished sample through the system and compare the results with previously obtained results.
Regression testing: Data files are reprocessed and compared the result with previous result
System is scanned for regular virus
Computer systems are audited at regular time intervals
7.8 Configuration Management and Change Control Procedures
User can make any change in computer system validation because there is a possibility of an error in the program set for the computer system or due to different function specifications of computer hardware or software. Initiation, authorization, implementing, testing of any changes to written specifications, programming codes or hardware system should be done as per written procedures. A specific form is required to initiate, authorize and document any change.
All tasks related to change control procedures should include in validation master plan and should be documented in validation report. User should test part of the program that has been changed. Moreover, User should do regression testing for entire program to ensure that program will run normally after any change made in it.
7.9 Back-up and Recovery
Back-up and recovery is required in case of system failure to store existing data to e available in future. There is a more than one strategies for back-up and recovery. Different approaches include policies and procedures which facilitate consistent approach for system back-up and recovery to various system infrastructures. This would be useful to simplify back-up & recovery management. To reduce the variability in management of recovery, standardization desktop configuration is the best approach. One can use thin client computing architect ring concentrates recovery process to decrease workload and personnel req
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