Booking options
£1,149
Course Images
ADC Therapeutics CMC: Impurities Management and Control Strategy
Highlights
Delivered Online
3 days
All levels
Dates
View Dates Hide Dates
- Delivered Online• to
- Delivered Online• to
- Delivered Online• to
Description
Course Goal
To provide a comprehensive, end-to-end framework for developing and managing CMC strategies for Antibody-Drug Conjugates (ADCs) with focus on Drug-Linker (D-L) intermediate and control strategy. The course will equip participants with the scientific rationale and practical tools to develop, justify, and defend robust impurity control strategies for Drug-Linker (D-L) intermediates used in ADC manufacturing. The programme bridges biologics manufacturing, small-molecule chemistry, bioconjugation science, analytical development, quality assurance, and regulatory affairs. Participants will learn to create integrated control strategies that address the unique multi-component complexity of ADCs, accelerate development, and reduce programme risk.
Duration
3 half-day sessions (virtual)
Trainer
This course is delivered by Dr Osama Chahrour, a Principal Scientist at AstraZeneca and Chair of the company's Impurity Advisory Group, with deep expertise in CMC impurity management for complex modalities including ADCs. Osama has directly influenced regulatory policy, having presented to the EMA Quality Working Party (QWP) and successfully advocated for the adoption of alternative impurity limits to ICH Q3A for ADC drug-linker intermediates. His research underpins the course content, with key publications including: "Risk Evaluation of N-Nitrosamines in Drug-Linker Intermediates Used To Generate Antibody–Drug Conjugates" (Org. Process Res. Dev., 2024), "Risk Assessment and Control of N-Nitrosamines in Antibody–Drug Conjugates: Current Industry Practices" (Org. Process Res. Dev., 2024), "Impurity Qualification Requirements for Drug-Linkers Related Impurities Used to Generate Antibody-Drug Conjugates" (Regul. Toxicol. Pharmacol., 2025), and "Purge Factor Analysis and Proposal for Non-conjugatable Impurity Clearance in Post-conjugation Purification of ADCs" (Org. Process Res. Dev., 2026). He also collaborates with EFPIA and the IQ Consortium on industry-wide impurity control standards.
Outline
1- Foundations of ADC CMC
The hybrid regulatory framework: Navigating the absence of a dedicated ADC guideline; application of ICH Q5 (biologics), Q3A/Q3B (small molecules), Q6B (specifications for biologics), Q8–Q12 (QbD/lifecycle), Q14, and ICH M7 (mutagenic impurities)
Why D-L Impurity Control Requires a New Paradigm
What makes ADC CMC unique: The convergence of biologics and small-molecule regulatory paradigms
Positioning the D-L intermediate: How the D-L fits within the overall ADC control strategy (antibody intermediate → D-L intermediate → ADC DS → ADC DP)
2- Establishing an Integrated Impurity Control Strategy
A Science-Based Proposal for the Identification and qualification threshold of Organic Impurities in Drug-Linker Intermediates Used to Produce Antibody-Drug Conjugates
Linking D-L CQAs to final ADC product quality, safety, and efficacy.
Impurity Landscape in ADCs
Setting impurity limits for D-L intermediates: Toxicological justification for higher thresholds than ICHQ3A
Fate and purge analysis.
D-L intermediate specifications.
Chiral impurity control: Specification limits and justification for diastereomeric/enantiomeric purity
Payload Platform Toxicities and the Grouping/Surrogate Approach: the auristatin class — grouping and worst-case surrogate assessment, the camptothecin class — grouping and worst-case surrogate assessment
3- Non-Conjugatable Impurities: Purge Factor Analysis and Specification Justification (This section includes a workshop)
Foundations — Purge Factor (PF), Required Purge Factor (rPF), and Purge Ratio (PR)
Conservative estimation of PFs
Sieving factors for reagents, solvents, leachables, and buffer components
Workshop: Constructing a Specification Justification Plot, Participants calculate for a representative ADC, apply Equations and construct a control space plot, and identify the specification value below which no experimental purge study is required.
4- Why D-L Impurities Pose Minimal Toxicological Risk (Core reference: Chahrour et al., Reg. Tox. Pharm. 2026, 164, 105974), (This section includes a workshop)
The molecular weight dilution effect, Daily exposure analysis, The intermittent dosing mitigating factor, Cumulative lifetime exposure vs. ICH M7
The proposed qualification threshold: 1.0% w/w or 1 mg/day, whichever is lower (increased from ICH Q3A's 0.15%)
Scientific justification combining all four lines of evidence
Workshop: Participants apply Equations to their own ADC programmes, determining daily exposure, molar exposure, and years to breach ICH M7 limits.
5- Establishing Comparability of D-L Intermediates Following Manufacturing Changes (This section includes a workshop)
ADCs frequently undergo expedited regulatory pathways, driving iterative D-L manufacturing changes before comprehensive process understanding is established ICH Q5E (biologics comparability) does not address D-L intermediates; ICH Q6A (small molecules) does not address conjugatability. We present a solution which is based on a two-dimensional comparability framework. This section includes a workshop.
Workshop: Participants apply the FMEA scoring, assign Tier/Level per attribute, and navigate the decision tree for a hypothetical D-L supplier change scenario
6- N-Nitrosamine Risk Assessment for D-L Intermediates and ADCs
Key risk-mitigating factors for D-L intermediates: Mass dilution, downstream purification, Low clinical dose, Intermittent dosing schedules
Simplified risk assessment workflow for D-Ls: Focus on intentionally added nitrosating agents and vulnerable amines, Assessment of N-nitrosamine Drug-Linker Related Impurities (NDLRIs) — a unique ADC consideration, When full confirmatory testing is warranted vs. when paper-based assessment suffices
Integration with the broader impurity control strategy: How nitrosamine assessment fits within the overall D-L quality risk management framework
7- Analytical Strategies and Method Qualification/Validation
Orthogonal analytical toolkit for ADC characterisation: DAR determination: HIC, native SEC-MS, RP-HPLC (reduced subunit), Aggregation/fragmentation: SEC-MALS, Charge heterogeneity: icIEF, CEX, Free drug/unconjugated payload: RP-HPLC, LC-MS/MS, Glycan profiling: HILIC-FLD-MS, Peptide mapping and site-of-conjugation confirmation: LC-MS/MS, Multi-Attribute Methods (MAM): Single-platform approaches for simultaneous CQA monitoring
Phase-appropriate method validation: From early development through BLA/MAA submission
Reference standard strategy: Establishing and qualifying ADC reference materials
8-Mutagenic impurity assessment
Application of ICH M7 to linker-payload synthesis with consideration of ADC dosing regimens and Threshold of Toxicological Concern (TTC) adjustments
9- Case Studies: End-to-End Application
RSM position determination for D-L Intermediates
Application of Dolastatin 10 surrogate for impurity level justification
Health authority questions the 1.0% qualification threshold, Building the response using: daily exposure data, iTTC comparison, ICH M7 cumulative lifetime argument, and surrogate compound assessment
Frequently Asked Questions
What are the recomended papers to read pre or post the course?
- Gong, H.H. et al. "Control Strategy for Small Molecule Impurities in Antibody-Drug Conjugates." AAPS PharmSciTech 2018, 19, 971–977.
- Fernandez-Cerezo, L. et al. "Strategies for UF/DF-Based Impurity Removal in the Post-conjugation Purification of Antibody-Drug Conjugates." Org. Process Res. Dev. 2023, 27, 1258–1268.
- Chahrour, O. et al. "Risk Assessment and Control of N-Nitrosamines in Antibody-Drug Conjugates: Current Industry Practices." Org. Process Res. Dev. 2024, 28, 3078–3084.
- Chahrour, O. et al. "Risk Evaluation of N-Nitrosamines in Drug-Linker Intermediates Used To Generate Antibody-Drug Conjugates." Org. Process Res. Dev. 2024, 28, 3085–3093.
- Chahrour, O. et al. "Impurity Qualification Requirements for Drug-Linkers Related Impurities Used to Generate Antibody-Drug Conjugates." Reg. Tox. Pharm. 2026, 164, 105974.
- Fernandez-Cerezo, L.; Chahrour, O. et al. "Purge Factor Analysis and Proposal for Non-conjugatable Impurity Clearance in Post-conjugation Purification of ADCs." Org. Process Res. Dev. 2026, DOI: 10.1021/acs.oprd.5c00463.
What is the delivery style?
Lectures, worked examples, case studies, interactive workshops, and panel discussion
Reviews
Material Covered
Facilitator
Organiser
Resources Provided
Location/Delivery
Communication
Unverified
Unverified