Mastering IVD Analytical Validation Under IVDR
Analytical validation is the cornerstone of in vitro diagnostic (IVD) development. Under the European Union’s In Vitro Diagnostic Regulation (IVDR; EU 2017/746), it provides evidence that an IVD device performs as intended—accurately, reliably, and consistently within its defined scope. For both CE-marking manufacturers and laboratories operating under Article 5(5), analytical validation sits at the center of the performance evaluation framework in Article 56 and Annex XIII.
Core Parameters of Analytical Performance
The IVDR requires a full demonstration of the analytical performance characteristics in Annex I, Section 9.1(a). These include:
- Trueness (Bias): Closeness of agreement between measured values and a reference (ISO 5725-1; JCGM 200:2012).
- Precision: Repeatability and reproducibility across instruments, operators, and time (CLSI EP05-A3; ISO 20776-2).
- Accuracy: Combination of trueness and precision; essential for reliable results.
- Analytical Sensitivity (Limit of Detection, LoD): Smallest analyte amount distinguishable from background (CLSI EP17; MM06).
- Analytical Specificity: Ability to measure only the target analyte, avoiding cross-reactivity and interference (ISO 15193; CLSI MM09, MM26).
- Linearity: Proportional response across a defined concentration range (CLSI EP06, EP10).
- Limit of Quantification (LoQ): Minimum (and where relevant maximum) concentrations quantifiable with acceptable error.
- Cut-off Values: Thresholds separating positive from negative results (CLSI EP12, EP24).
- Reportable Range: Span of values that the assay can report reliably.
- Metrological Traceability: Link results to references through a documented calibration chain (JCGM 200:2012).
- Stability: Shelf-life and in-use stability (ISO 18113-1; EN ISO 23640).
- Specimen Type & Stability: Validate all relevant sample types and storage conditions (CLSI M47).
If a parameter does not apply, provide robust justification. Regulators expect clear reasoning. Use harmonized standards and consistent definitions wherever possible. The CLSI Harmonized Terminology Database helps align terminology across documents and communications.
Challenges and Common Pitfalls
- Ambiguity in Intended Use: Vague claims misalign studies and weaken evidence.
- Suboptimal Study Design: Studies should be statistically powered with predefined acceptance criteria.
- Uncontrolled Pre-analytical Variables: Validate collection, transport, and storage; justify them in the Performance Evaluation Plan (PEP).
- Software Validation Gaps: Algorithm-driven IVDs require software lifecycle controls (IEC 62304; IEC 82304-1).
- Inadequate Traceability: Link raw data to the Analytical Performance Report (APR) and Performance Evaluation Report (PER).
- Lifecycle Oversight: Changes to reagents, software, or protocols may trigger revalidation. Maintain PMS and PMPF to stay compliant.
Strategic Solutions
At MDx CRO, teams combine regulatory, scientific, and statistical expertise to streamline analytical validation. Key services include:
- Gap assessments against IVDR, MDCG, and CLSI guidance.
- Custom analytical study design aligned with ISO 13485 and Annex XIII.
- Software validation support with cybersecurity oversight.
- Technical file preparation for Notified Body review.
- Integration of PMS and PMPF into performance lifecycle management.
Conclusion
Analytical validation is more than a regulatory obligation—it forms the foundation of diagnostic credibility. When executed well, it shows that an IVD is accurate, safe, and clinically effective. With IVDR bringing heightened scrutiny, manufacturers should use clear definitions, rigorous justifications, and harmonized standards to achieve strong validation and long-term market success.
Need help building audit-ready analytical validation under IVDR? MDx CRO designs compliant studies, strengthens traceability, and prepares technical files for faster, smoother reviews. Contact us today.
