Validation is the documented evidence that a process, an analytical method or a system is suitable for its intended purpose and reliably delivers the specified results. In clinical pharmacology, non-clinical development and the GMP environment, it protects the reliability of data, product quality and indirectly the safety of trial participants. Scope and depth of the evidence depend on the intended use and the risk.
Subjects of validation
The generic term encompasses several technically different applications. Analytical validation proves that a test procedure is suitable for its purpose. ICH Q2(R2) mentions, among other things, specificity or selectivity, accuracy, precision and working range as possible performance characteristics, the selection of which depends on the measurement task. A validation protocol should define the intended purpose, the performance characteristics to be evaluated and the corresponding acceptance criteria; the results are summarized in a report.
Process validation concerns manufacturing processes. According to EudraLex Volume 4 Annex 15, it must be demonstrated that a process operating within established parameters can effectively and reproducibly produce a medicinal product meeting its predetermined specifications and quality attributes. It considers the relevant process parameters and quality attributes over the life cycle and includes changes as well as ongoing process verification. Analytical methods and manufacturing processes are therefore different validation objects, but can interact closely in a GMP control strategy.
Life cycle, risk and documentation
Validation is not a one-time final test. Annex 15 requires a planned approach over the life cycle of facilities, equipment, utilities, processes and products. A validation master plan or an equivalent document describes, among other things, strategy, responsibilities, status, change management, deviation management and acceptance criteria. Deviations from pre-defined criteria are to be recorded, investigated and taken into account in the conclusion.
A risk-based approach focuses the evidence on functions and parameters whose failure can significantly compromise product quality, patient safety or data integrity. For analytical procedures, a change to the product, the process or the procedure may require partial or full revalidation; its scope is to be justified scientifically and on a risk basis. For computerized systems, Annex 11 also requires a documented risk assessment and a controlled handling of changes, deviations and data migrations.
Differentiation from qualification, verification and Computerized System Validation
Qualification and validation are linked in GMP, but are not synonymous. Qualification primarily refers to facilities, equipment, utilities and infrastructure and documents that they are installed as intended and function within the intended range. Annex 11 explicitly separates this for computerized systems: The application is to be validated, the IT infrastructure to be qualified. Only on this basis can the suitability of a manufacturing process or an application be reliably evaluated.
Verification is a targeted confirmation that a single specified requirement or a result is met, for example through a check, a reconciliation or a system suitability test. It provides important single proofs, but does not replace the validation of the intended overall purpose via defined acceptance criteria. Computerized System Validation remains a separate glossary entry: It deals in-depth with the life cycle and data integrity of computerized GxP systems. This entry classifies CSV only as a special application of validation.
Relevance for clinical trials
In clinical trials, validation is particularly relevant where laboratory findings, electronic data or GMP-related processes support decisions on dose, safety or efficacy. An unsuitable bioanalytical method can falsify exposure data; inadequately controlled data transfers can lead to contradictory data sets. For GMP-relevant computer systems, Annex 11 requires that their validation proves the suitability for the intended use and the controlled state. Audit trail, authorization concept, backups, recovery and controlled changes are central aspects here, depending on the risk.
Full-service CROs such as Mediconomics support the planning and documentation of trial-relevant validation activities, the coordination of qualified laboratories and service providers as well as the verification of data flows and interfaces. They connect clinical project management, data management, quality management and medical writing so that requirements, risk analyses, test protocols, deviations and releases are comprehensibly available for audits, inspections and the clinical study report.
Frequently Asked Questions (FAQ)
When is an analytical method to be validated?
For regulatory application, it should be demonstrated that the procedure is suitable for its intended purpose. ICH Q2(R2) describes the selection and evaluation of suitable validation tests and allows a phase-appropriate application in clinical development.
Does every change automatically lead to a full revalidation?
No. Changes must be evaluated under change control. Depending on the affected performance characteristics, a partial revalidation may be sufficient; the decision must be justified scientifically and on a risk basis.
Does Annex 11 apply to every system of a clinical trial?
Annex 11 applies to computerized systems in GMP-regulated activities. For clinical systems, their purpose, GxP relevance, data integrity risks and the respectively applicable requirements must be evaluated.
Regulatory references
- ICH Q2(R2), Validation of Analytical Procedures – describes the suitability of analytical procedures for the intended purpose and the selection of performance characteristics.
- EudraLex Volume 4, Annex 15, Qualification and Validation – regulates principles for facilities, equipment, utilities and manufacturing processes.
- EudraLex Volume 4, Annex 11, Computerised Systems – requires risk-based validation of applications and qualification of the IT infrastructure in the GMP environment.