2022-04-21-世界卫生组织-Guideline_for_the_production_and_quality_control_of_monoclonal_antibodies_and_related_products_intended_for_medicinal_use_57页_529kb

Post-ECBS Monoclonal Antibodies Guidelines Summary

The World Health Organization (WHO) has updated its guidelines for the production and quality control of monoclonal antibodies (mAbs) and related medicinal products, replacing Annex 3 of its Technical Report Series No. 822.

1. Introduction & Purpose:

• The 1991 guidelines are outdated due to significant technological advances, especially in recombinant DNA technology and plant-based systems.
• The new guidelines provide scientific advice for both National Regulatory Authorities (NRAs) and manufacturers.
• Applicable to various mAb types (isotypes, fragments, single-domain, bispecific, Fc-fusions, PEGylated, co-formulated/a cocktail' products), regardless of the intended therapeutic mechanism.
• Covers manufacturing (Part A) and provides guidelines for NRAs (Part B). Emphasizes GMP.

2. Terminology:

• Defines key terms like adventitious agents, antibodies (mAbs, fragments, recombinant), bispecific antibodies, co-formulated mAbs, contaminants, biological activity, and Platform Technology.

3. General Considerations:

• mAbs are large, complex proteins with significant heterogeneity impacting quality, safety, and efficacy.
• Technology evolves (hybridoma, phage display, transgenic animals, human B-cells, rDNA).
• Understanding heterogeneity and its impact (glycosylation, charge variants, N-terminal pyroglutamate, C-terminal lysine, glycation, deamidation, disulfide bond variations, etc.) is crucial for quality control.
• Quality by Design (QbD) is recommended for product development.
• °Production involves careful control of biological and chemical processes.

4. Manufacturing and Quality Control (Part A):

• Host Cells/System: Use proven cell lines (stably clonal, e.g., CHO) or alternative systems (plant, insect, microbial). Platforms can accelerate product development.
• GMP: Adhere strictly to WHO GMP principles (using relevant guidance for pharmaceuticals and biological products).
• PPQ: Conduct Process Performance Qualification (PPQ) at commercial scale.
• Reference Materials: Establish clear characterizations, referencing WHO (NINs, classes, lines) or other defined standards.
• Source Materials: Control media, raw materials, reagents. Avoid animal-derived materials where possible; use chemically defined media.
• Production: Validate the process. Minimize impurities (HCPs, hcDNA, endotoxins, etc.). Purification involves chromatography and filtration. Validated clearance studies for impurities are essential.
• Control of mAb Substance/drug sub: Extensive characterization (appearance, identity, pH, concentration, potency, heterogeneity, impurities). Controlled manufacturing steps. Potency assays (binding, effector functions) are vital.
• Preparation and Control of Final Bulk: Include approved excipients. Validate processes.
• Filling and Containers: Follow GMP, ensure container compatibility, maintain integrity.
• Control of Final Product: Functionality testing (potency, heterogeneity, bioburden/endotoxin). Perform release tests approved by the NRA.
• Records and Retained Samples: Maintain comprehensive, traceable records.

5. Guidelines for NRAs (Part B):

• NRAs assess products on a case-by-case basis, based on a risk-based approach and scientific principles.
• Ensure manufacturers provide full, accurate information to justify production and control strategies.
• Verify adherence to GMP and other requirements. Review batch records, process descriptions, test specifications.
• Potency assays must be scientifically sound.
• Official Release: MAb products must fulfill all national requirements and generally align with these WHO guidelines.
• Focus on verifying safety, efficacy, and quality through legal control.

Overall Focus: Ensuring consistent quality, safety, and efficacy of mAbs through rigorous production, control, characterization, and adherence to GMP principles, reviewed periodically by NRAs.