The Complex Anatomy Of An ADC Tech Transfer

By Ivan Di Bonaventura

Antibody-drug conjugates (ADCs) have emerged as one of the fastest-growing therapeutic modalities in oncology, combining the specificity of monoclonal antibodies with the potency of highly active cytotoxic payloads. As ADC pipelines continue to expand, organizations increasingly face the challenge of transferring manufacturing processes between development sites, CMOs/CDMOs, and commercial manufacturing facilities.

ADC technology transfer refers to the structured process of transferring knowledge, skills, and technologies from one organization or site to another to ensure consistent production of an ADC. Unlike conventional biologics, ADC transfer involves multiple interconnected components: the monoclonal antibody, linker-payload, conjugation process, drug substance, drug product, and analytical control strategy.

Typical Transfer Workflow

A typical technology transfer process can be divided into four main phases:

1. Transfer evaluation: A feasibility assessment on the technical transfer is done, considering various factors such as regulatory aspects, technical expertise, technology, capability, capacity, business strategy, and ownership leading to a final decision and selection of the new receiving CMO.
2. Preparation and Planning: A joint team with clearly defined roles and responsibilities is established, managed by a technology transfer lead, to develop a control strategy — including a risk and gap assessment — define critical quality attributes, define process parameters, and generate a transfer protocol and plan.
3. Transfer execution: The team triggers execution and management of the transfer project in accordance with the sequential phases and activities defined in the transfer protocol.
4. Transfer completion: A transfer report is generated, including all project data, which should confirm the completion and outline further activities based on the product’s life cycle.

Companies often transfer a product from one CDMO/CMO to another for one or more of the following businesses/technical reasons:

1. Capacity Constraints
   The current CDMO may not have sufficient capacity to support launch demand, market expansion, new indications, or portfolio growth.
2. Cost Optimization
   A new CMO may offer lower manufacturing costs, better yields, lower testing costs, and improved supply chain economics.
3. Risk Mitigation
   The sponsor may want to establish a second source, improve business continuity, reduce sole source risk, and increase supply resilience.
   This is particularly important for critical commercial products and specialized technologies such as biologics and ADCs.
4. Performance Issues
   The current CMO may have repeated deviations, delivery delays, low OTIF performance, quality concerns, and poor governance or collaboration.
   A transfer may become necessary when continuous improvement efforts fail.
5. Technology Fit
   The receiving CMO may have better equipment, greater process expertise, specialized containment capabilities, and advanced analytical capabilities.
   For ADCs, for example, containment and analytical expertise can be strong drivers for transfer decisions.
6. Network Consolidation
   Many companies rationalize their CMO network to reduce complexity, reduce oversight effort, consolidate spend, and create strategic partnerships.
7. End of Contract or Strategic Change
   Reasons may include contract expiry, acquisition/divestiture, change in operating model, and /or change in sourcing strategy.
8. Geographic Strategy
   A company may transfer to manufacture closer to key markets, improve regional supply security, reduce logistics complexity, or support localization requirements.

Why ADC Tech Transfer Is Challenging

ADCs are among the most complex biopharmaceutical modalities because:

• They combine biologic and small molecule technologies.
• Multiple manufacturing processes must be transferred and aligned.
• Conjugation is highly sensitive to process changes.
• Specialized containment is required for highly potent payloads.
• Analytical characterization is significantly more complex than for standard monoclonal antibodies.

Conjugation process variability

The conjugation step is frequently the most sensitive operation in ADC manufacturing. Variations in reaction conditions, mixing efficiency, equipment geometry, or material handling can alter drug-to-antibody ratio (DAR), aggregation levels, and potency. Since DAR directly influences both efficacy and safety, maintaining process consistency is essential.

Analytical readiness

ADC characterization requires advanced analytical methods, including DAR determination, potency assays, free payload measurements, purity assessments, and stability testing. Delays in analytical transfer often become the critical path for the overall project. Analytical equivalence between sites must be demonstrated before commercial manufacturing can begin.

Cross-contamination strategy

Highly potent payloads require specialized containment systems and operator protection measures. Receiving sites must demonstrate that facilities, equipment, cleaning procedures, and occupational exposure controls meet the required containment standards before manufacturing activities commence.

Supply chain complexity

ADC manufacturing relies on specialized raw materials, linker-payload components, and qualified suppliers. A disruption in any part of the supply chain can delay manufacturing campaigns and jeopardize project timelines.

Regulatory comparability

Regulatory authorities expect evidence that product quality remains unchanged following a site transfer. A robust comparability strategy is therefore critical to support global submissions and ensure uninterrupted supply.

Key Success Factors

Organizations that consistently deliver successful technical transfers typically focus on five strategic pillars.

1. Comprehensive Transfer Readiness Assessment

Prior to transfer initiation, the process must be sufficiently mature, documented, and characterized. This includes process understanding, analytical readiness, development history, and regulatory impact assessment. Early identification of gaps significantly reduces downstream execution risk.

2. Strong Knowledge Management

Critical process knowledge often resides with experienced scientists and operators rather than within formal documentation. Structured SME-to-SME interactions, workshops, process walkthroughs, and embedded support during initial manufacturing campaigns are essential for preserving tacit knowledge.

3. Early Analytical Transfer

Analytical transfer should begin as early as possible. Qualification of reference standards, method equivalency protocols, equipment comparability, and side-by-side testing help prevent delays during engineering and validation stages.

4. Risk-Based Governance

Cross-functional teams from manufacturing, MSAT, quality, regulatory affairs, EHS, and supply chain should jointly review risks throughout the project life cycle. Regular risk assessments allow teams to identify potential issues before they affect GMP execution.

5. Robust Engineering and Validation Strategy

Engineering runs provide a critical opportunity to verify equipment suitability, process performance and knowledge, operator training, and analytical readiness before proceeding to process qualification. This stage should be viewed as a risk reduction exercise rather than a routine operational activity.

Contract Considerations For Process Transfer

Many transfers are delayed because transfer rights, technical support obligations, or intellectual property (IP) provisions are not clearly addressed in the existing agreements. As sponsor transfer evaluation is ongoing, make sure that the below obligations are already established:

1. Technology Transfer Rights
   Verify that your company has the contractual rights to transfer manufacturing documentation, analytical methods and reports, and transfer process validation data.
2. Intellectual Property Ownership
   Clearly define ownership of product IP, process IP, analytical methods, and process improvements.
   Typical risk: The outgoing CMO claims ownership of process optimizations implemented during commercial manufacturing.
3. Exit and Transition Support Obligations
   The contract could require and specify the outgoing CMO to provide dedicated SMEs’ support cost, training support, documentation packages, and process troubleshooting support.
4. Confidentiality and Third-Party Disclosure
   The agreement should explicitly permit disclosure of manufacturing information to the receiving CMO, analytical laboratories, and/or consultants supporting the transfer.
5. Material Supply During Transfer
   Define obligations for the incumbent CMO to provide reference materials, retention samples, and stability samples. This helps support analytical transfer and comparability activities.
6. Regulatory Support Obligations
   The outgoing CMO should support comparability packages, regulatory responses, and historical manufacturing data requests.
   Contractual obligations are not trivial and take significant time to negotiate. Assuring legal coverage ahead of transfer execution is one of the most important and underestimated factors.

Conclusion

ADC technology transfer is one of the most demanding activities in pharmaceutical manufacturing. The combination of biologics, highly potent payloads, sophisticated analytics, and complex supply chains creates unique challenges that require careful planning and execution.

Organizations that invest early in process understanding, analytical readiness, risk management, and cross-functional collaboration are significantly more likely to achieve successful transfers, maintain product quality, and ensure uninterrupted patient supply.

Ultimately, ADC tech transfer should not be viewed as the movement of a process from one site to another. It is the transfer of an integrated manufacturing ecosystem — including knowledge, analytics, quality systems, and operational excellence — required to consistently deliver a highly complex therapeutic product.

About The Author:

Ivan Di Bonaventura, Ph.D., is a scientist and outsourcing expert with a decade of experience in pharmaceutical manufacturing, including peptide drugs and antibody-drug conjugates. His experience includes management positions with Seagen, now part of Pfizer, and AC Immune. He received his Ph.D. from the University of Bern.