Outlook on Next Generation Technologies and Strategy Considerations for ADC Process Development and Manufacturing
Abstract
In the chapter, we review new conjugation technologies from the standpoints of process development and manufacturability and identify potential process hotspots. We briefly review recent progress in conventional conjugation methods and assess, for instance, how new linkers impact process. We also consider antibody modeling and its untapped potential to help design ADCs. We address outsourcing options and trends and provide an overview of single use technologies. Finally, strategies for efficient early process development to ensure CMC consistency across clinical phases and manufacturing scales and ensure readiness for accelerated regulatory approval paths are discussed.
Keywords
ADC Process development Analytical development Scale-up Manufacturing GMP Drug substance Drug product Bulk drug substance DS DP BDS Conjugation technologies Site specific Bridging Thiobridge Conventional cysteine Engineered cysteine Lysine Serine Unnatural amino acid Non-natural amino acid Maleimide Valine-citruline Maleimidocaproyl Thiosuccinimide Haloacetamide Click chemistry Azide Cyclooctyne Glycan Enzyme Enzymatic ligation Transglutaminase Seleno mAb AmbrX Eucode Xpress THIOMAB Glycoconnect Fleximer Hydraspace Auristatin Ozogamicin Talirine Maystantin Quaternary amine Glucuronide Linker Payload Aggregate Aggregation Stability Hydrophobicity DAR Drug antibody ratio Modeling Antibody Probody Extracellular Bispecific TFF HIC Chromatography Tangential flow filtration Regulatory approval CMC Accelerated approval Single use Outsourcing CMO CQA Critical quality attribute Toxicity Cytotoxicity MTD MED Therapeutic index PK PDAbbreviations
- ADC
Antibody Drug Conjugate
- ADC
Antibody Drug Conjugate
- BDS
Bulk Drug Subtance
- BDS
Bulk Drug Subtance
- BLA
Biologics License Application
- BLA
Biologics License Application
- Cit
Citruline
- CMO
Contract Manufacturing Organization
- CQA
Critical Quality Attribute
- Cys
Cysteine
- DAR
Drug Antibody Ratio
- DL
Drug Linker
- DoE
Design of Experiments
- DP
Drug Product
- DS
Drug Substance
- DSI
Drug Substance Intermediate
- FIP
First In Patient
- HIPS
Hydrazino-Pictet-Spengler
- MED
Minimum Effective Dose
- MFG
Manufacturing
- MTD
Maximum Tolerated Dose
- NNAA
Non-Natural Amino Acid
- PBD
Pyrrolobenzodiazepine
- PEG
Polyethylene Glycol
- PK
Pharmacokinetics
- POC
Proof Of Concept
- PPE
Personal Protection Equipment
- QA
Quality Attribute
- QbD
Quality by Design
- SME
Subject Matter Expert
- SPAAC
Strain promoted azide–alkyne cycloaddition
- SUT
Single Use Technology
- TFF
Tangential Flow Filtration
- TI
Therapeutic Index
- UAA
Un-natural Amino Acid
- UF/DF
Ultrafiltration/Diafiltration
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