Regulatory Considerations and Standardization Pathways for Immune-Related Recombinant Proteins in the Development of In Vitro Diagnostic Reagents

I. Typical Applications of Immune-Related Recombinant Proteins in IVD

In the field of in vitro diagnostic (IVD) reagents, immune-related recombinant proteins primarily serve as calibrators (standards), quality controls, and coating antigens/antibodies. Taking tumor marker, autoantibody, or infectious marker detection as examples, recombinantly expressed antigens (such as HPV L1 protein, HIV p24) can replace natural extracts, reducing biosafety risks and enabling large-scale production consistency. In addition, recombinant proteins used for antibody screening and pairing have optimized sequences that can improve detection sensitivity and specificity.

II. Basic Requirements Under the Regulatory Framework

According to China's "Measures for the Registration and Administration of In Vitro Diagnostic Reagents" and related guiding principles, IVD reagents using recombinant proteins as raw materials must meet the following basic requirements:

Raw material traceability and identification: The gene source, expression host, culture method, and purification route of the recombinant protein should be clearly defined, and physicochemical characterization data such as amino acid sequence, molecular weight, and isoelectric point should be provided.

Biological activity and stability: Sufficient immunoreactivity must be maintained throughout the shelf life of the reagent, typically demonstrated through accelerated aging studies and real-time stability studies.

Batch-to-batch consistency: Performance comparison reports from at least three consecutive batches of raw materials, demonstrating that key indicators (such as binding constant, linear range) meet predetermined specifications.

III. Standardization and Metrological Traceability

To ensure comparability of test results across different brands or batches of reagents, immune-related recombinant proteins should be traceable to international or national standards where possible. For example, for cytokine detection kits, WHO international standards (such as those provided by NIBSC) can be used for value assignment. Manufacturers should establish internal secondary standards and verify their accuracy through collaborative studies or external quality assessment (EQA) programs. Meanwhile, the traceability chain must be clearly described in registration submission materials, accompanied by uncertainty analysis. In addition, the newly revised "Regulations on the Supervision and Administration of Medical Devices" strengthens the registrant's obligation to evaluate raw material changes; any process adjustments affecting protein structure or activity should be subject to a change application or supplementary verification in advance.

IV. Future Trends: Intelligent Design of Recombinant Proteins

With the development of structural biology and computer-aided design, immune-related recombinant proteins are evolving toward "engineered" approaches—for example, incorporating non-natural amino acids to enhance antigenicity, or expressing multiple epitopes in tandem to cover more detection targets. While these innovations improve diagnostic sensitivity, they also present new challenges for regulatory review, requiring manufacturers and regulatory authorities to jointly explore reasonable verification protocols.