Systems Validation for 21CFR Part 11 Compliance

21CFR part 11 requires that all systems that govern any cGXP process - including Good Manufacturing Practices (GMPs), Good Laboratory Practices (GLPs), and Good Clinical Practices (GCPs), should be validated. FDA issued a very comprehensive guidance on systems validation. This white paper uses that FDA guidance as an input to define an “easy-to-implement” framework for systems validation. Finally, the paper identifies a best practice, which calls for IT organizations and software vendors to proactively audit their software development and implementation processes on an ongoing basis to identify and correct any systemic issues to lower the cost of compliance.

System Validation is a key 21CFR Part 11 requirement - its primary benefit is to assure quality and performance of the systems deployed to manage any cGxP process. It is the establishment of documented evidence that provides a high degree of assurance that a specific process, managed by the system, will consistently yield a product meeting its predetermined specifications and quality attributes. The ultimate goal of any system validation project is to realize and sustain compliance, while ensuring the peak performance and functionality of those systems.

Framework for System Validation

While various consulting companies have created their own methodologies for systems validation, our experience shows the following framework to be the comprehensive and applies to both -off-the-shelf software or home grown. This framework ensures that the software being deployed is most likely to be compliant with FDA requirements and will continue to sustain the compliance over time. Key elements of that framework include:

Compliance with core 21CFR Part 11 requirements: This element ensures that the software is compliant with key requirements of the regulation, including

Any change to any record is captured in the audit trail and these entries are time stamped with additional information including operator name and why the record was changed
System provides adequate security to prevent unauthorized modification by ensuring role-based access and preventing users from directly updating the database
All system requirements must be clearly defined and approved before any design or coding effort starts. All system functions must be identified at this stage.
System design specification must be clearly documented and design reviews must be done to evaluate the capability of the design to meet system requirements and to identify any problems
Test plans, test procedures and test cases should be developed as early in the development lifecycle as possible
Coding Standards should be well documented and code reviews must be done to ensure that these standards are followed
Multi-level testing methodology including unit test, functional test, integration test and system test must be followed. In addition, stress Testing and disaster recovery testing must be performed to ensure that system performance requirements are met.
Closed-loop change control: This element ensures that proper change control documentation, approval and testing procedures are followed for any changes including, correcting software defects or adding new capabilities for a new version of the software or making changes to software configuration. Change control procedures must be written and well understood through training, to ensure compliance. Unauthorized changes to a validated system, even during the implementation process, can have a detrimental effect on the system integrity.
Facility: This element ensures that the vendor facilities (or an IT organization software development lab) employ adequate security controls to prevent unauthorized access to software, computer rooms and backup media storage rooms.
Organization: This element ensures that the software developers, designers, QA engineers are project managers are trained to perform the technical aspects of their jobs and the company has training policies to ensure they continue to have the right skills on an ongoing basis to do their job.
Validation for intended use: This element ensures that the requirement specifications are developed for the intended use of the system. The system documentation is compared to the intended use specification to identify any gaps. Then the system is tested against the intended use specification to identify any additional gaps. Any major gaps are fixed using the closed-loop change control method described above and retested before the system is validated as ready for intended use.

In summary, system validation is not a onetime project – it is an ongoing process. Through a combination of a good implementation of system development lifecycle and proactive internal auditing of the software development and implementation process, companies can easily comply with the system validation requirements of 21CFR part 11 at a lower cost of compliance.