WORKSHOP I

REGULATORY CMC CONSIDERATIONS

FOR THE DEVELOPMENT OF ADCS:
CHALLENGES AND OPPORTUNITIES
Chantal Bullot
Global Regulatory Affairs CMC Biologics Director at Sanofi
Rama Husain
Independant Global Regulatory CMC consultant
Shawn Novick
International Alliance for Biological Standardization
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 PLAN

PRESENTATION:
REGULATORY CMC CHALLENGES UNIQUE TO ADCS
OPEN SESSION:
CHALLENGING REQUIREMENTS AND POTENTIAL
SOLUTIONS IN CONTEXT OF ACCELERATION

Regulatory CMC considerations for the development of ADCs:

challenges and opportunities
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 PRESENTATION:
REGULATORY CMC CHALLENGES
UNIQUE TO ADCS

3
 PLAN

INTRODUCTION
CONTROL STRATEGY
COMPARABILITY
PROCESS VALIDATION
STABILITY
EMA & FDA REVIEW
MODULE 3 DOSSIER STRUCTURE
CONCLUSION
SUGGESTED BIBLIOGRAPHY

Regulatory CMC challenges unique to ADCs

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 INTRODUCTION

Regulatory CMC challenges unique to ADCs

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 HISTORICAL PERSPECTIVE Zynlonta®
approved in US

Polivy® approved in
2021
US (in EU in 2020)
Padcev® approved in
US (in EU in 2021)
Enhertu® approved in
Mylotarg® US (in EU in 2021)
re-approved in
US (in EU in 2019
2018) 2020
Besponsa®
approved in US Trodelvy®
and EU approved in US (in
Adcetris® EU in 2021)
2017 Blenrep®
Approved in US
approved in US
(in EU in 2013) 2018 and EU
2011 Lumoxiti®
approved in US
ADCs with (in EU in 2020,
« highly withdrawn in
Paul Ehrlich potent » drugs
2013 2021)
describes the
“magic bullet 1993 Kadcyla®
Approved in US
and the 1983: ADCs tested
targeted in humans 2000 (in EU in 2014)
therapy
concepts” First ADC
approved in
1913 Monoclonal US Mylotarg®
antibodies (withdrawn in
Production 2010)
6
1975 ADCs tested
in animals
 CLASSIFICATION & GUIDELINES

• Classification of a small molecule (drug/glycan/mask/etc.)

conjugated to a biological molecule (mAb):
• According to FDA, ADC is a combination product that follows biologics
regulation
• According to EMA, ADC is classified as a sub-type of mAb, it is also a
biological

• No specific quality guideline dedicated to ADCs

➢ Both chemical drugs and biologics guidelines apply
➢ Regulatory Benchmarking

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 CMC DEVELOPMENT & ACCELERATED PROGRAMS
Acceleration of Clinical Acceleration of Clinical program
program based on Ph 1 data based on Ph 2 Interim data

Starting CMC Starting CMC

acceleration acceleration

Ph2/3
R&D Non-Clinical Ph 1 Ph 3 /Life cycle management
Ph 2
Filing
Approval

Define QTPP Control Strategy driven by CQAs

pCQAs

Establish Analytical Profile & Methods

Methods Product release

Product Release with qualified methods Transfer & with validated
CMC on critical path: Validation methods
Typical late stage CMC Clinical Sites
Clinical sites Commercial Sites
timelines of 24-36 mo Commercial Sites
compressed to 12-18 mo
Process characterization
Monitoring
& Validation

Comparability

Stability studies
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CONTROL STRATEGY

Regulatory CMC challenges unique to ADCs

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 ADC CQAS

DL

• Control Strategy is driven by CQAs

• Some are tested at point of manufacture, some are tested at DS or DP

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 ADC CQAS

• Small molecule Intermediate CQAs

• Residual solvents and process-related impurities (if they have potential to
contaminate DS)
• Diastereomers, entantiomers, and product related impurities (if they are DL
conjugatable)
• mAb Intermediate CQAs
• HCP and process related impurities (if they may copurify to DS (like ProA))
• Clipping and product related impurities
• Glycosylation, PTMs, and product related properties (AA sequence, structure, etc..)
• DS CQAs
• Drug to mAb ratio and Conjugate Distribution
• Purity: HMW and other mAb related impurities
• Purity: Free drug and free mAb
• Potency and Binding
• DP CQAs
• Required CQAs for parenteral products (particles, sterility, etc..)
• Potency
• Product related impurities
• Process related attributes (like moisture for a lyophilized product, formulation, etc..)
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 SPECIFICATIONS:
SUITABLE FOR FURTHER PROCESSING? OR CQA?
Small Molecule mAb ADC: DS and DP

Identity RP-HPLC / MS Peptide mapping Peptide mapping

Purity RP-HPLC HPLC and CE-SDS assays; DAR

Oligosaccharide profile
Drug load distribution

HPLC and CE-SDS assays

Product related HPLC* (evaluate impurities HPLC and CE assays HPLC and CE assays: Naked
Impurities for whether they can antibody; cleavages; aggregation
conjugate)
Process-related Solvents, elemental DNA, HCPs, Virus, etc. Residual solvents, DTT, Free
impurities impurities drug/mask/small molecule;
Elemental impurities (DP)
Potency NA Binding Binding, cell-based potency

Effector functions
Safety NA Endotoxins Endotoxin & BioBurden (DS)
Sterility, endotoxin, particles,
Bioburden etc.. (DP)

General Moisture, pH, Osmo, etc.. pH, Osmolality, DS: Formulation verification
Properties Formulation (assures DP: Formulation verification (pH,
stability) Osmo, other tests) and DP
related like moisture, fill volume, 12
etc..
 CHARACTERIZATION

• mAb Intermediate: Fully characterize as a DS

• Amino acid sequence / substitutions
• 2 & 3D structure
• Oligosaccharide sites and structures
• Impurities (deamidation/oxidation/cleavages/etc..)
• Binding and effector function
• Product related variants (impurity or not)
• Small Molecule Intermediate: Characterize as an API
• Variants – Separate, Identify and determine conjugatability
• Impurities
• Verify Molecular sequence
• ADC
• DAR, conjugation sites, distribution
• Binding (2 &3 D structure)
• Efficacy profile (charge variants, size variants, conjugation site
variants, free-mAb interference? etc..)
• Impurities are characterized (small molecule and any in DS/DP)

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 QUALITY CHALLENGES: UNDERSTANDING VARIABILITY
• Speed to Market: Typical timeline vs Accelerated provides little time for validation and
there are 4 manufacturing processes which require attention
• Variability Challenge: 6 DP lots use 1 DL lot, 3 mAb lots, and 2 DS which limits variability

Drug/Linker: 1
batch feeds 6 DP
Drug Substance: Drug
1 lot feeds 3 DP Product
mAb: 1 lot
feeds 2 DP

• Relations between quality attributes? Do we need to test everything everywhere? For

instance – Glycans and/or HMW (see case study)

➢ Goals:
➢ Try to encourage sample variability early (be aware of potential for process
changes)
➢ Define specifications based on a relevant & non redundant control strategy;
monitor and control the manufacturing process
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COMPARABILITY

Regulatory CMC challenges unique to ADCs

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 COMPARABILITY

Starting
Drug
material
DS DP
Starting
mAb
material
If change on the drug or the antibody
(or their starting materials),
comparability on DS? DP?
How many batches?
Which quality attributes should be
selected for comparability?

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MANUFACTURING PROCESS
VALIDATION

Regulatory CMC challenges unique to ADCs

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 PROCESS VALIDATION
STANDARD
APPROACH
Starting material(s) Drug
3 Val Lots 3 Val Lots

Linker DS DP
3 Val Lots 3 Val Lots 3 Val Lots

mAb
3 Val Lots

Linear sequencing of validation requiring completion of PPQ for the

one component before advancing to the validation of the next may
delay submission of the MAA/BLA

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 STABILITY

Regulatory CMC challenges unique to ADCs

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 CUMULATIVE STABILITY STUDIES

Request is often to evaluate stability of 1 DP batch produced from 1 mAb

batch at end of shelf-life and 1 DS batch at end of shelf-life

Antibody batch

DS batch

DP batch

Last several years…

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EMA & FDA REVIEW

Regulatory CMC challenges unique to ADCs

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 EMA REVIEW

• Standard review through centralized procedure

• Dossier review coordinated by Committee for Medicinal
Products for Human Use (CHMP)
• Designation by CHMP of 2 main assessors from EU
Member States: “Rapporteur” and “Co-Rapporteur”
• Support from Biologics Working Party (BWP)

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 FDA REVIEW
CDER review through collaborative process between Office of
Biotechnology Products (OBP) and Office of New Drug Products
(ONDP)

Subject FDA Office

• mAb OBP
Intermediate
• DS
• DP
• Drug-Linker ONDP
Intermediate
• DS

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MODULE 3 DOSSIER
STRUCTURE

Regulatory CMC challenges unique to ADCs

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 ADC MANUFACTURING SCHEME

Drug

Drug-Linker
Intermediate
Linker
ADC DS ADC DP

mAb
Intermediate

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ADC COMPONENTS AND DOSSIER IMPACT

3.2.S section
4

Dedicated 3.2.S section?

DMF?

3
2

1
Dedicated 3.2.S section?

1- Monoclonal Antibody Intermediate

2- Linker
3- Drug Intermediate
4- Antibody-Drug Conjugate: DS
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SEVERAL OPTIONS FOR MODULE 3 ORGANIZATION

One single 3.2.S section (example) Separate 3.2.S sections

3.2.S DS 3.2.S. Drug-Linker Intermediate
3.2.S.2 DS Manufacture 3.2.S. mAb Intermediate
3.2.S.2.4 Control of critical 3.2.S. DS
steps and intermediates
3.2.S.4.1 Drug-Linker
Intermediate
3.2.S.4.2 mAb
Intermediate

ICH M4 “when more than one DS is used in a DP, information

should be presented separately as one complete DS section
followed by other complete DS sections”

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 CONCLUSION

Regulatory CMC challenges unique to ADCs

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 CONCLUSION

Due to their multicomponent nature, the CMC challenges unique to

ADCs are:
• ADC characterization: there are numerous quality attributes and the
inherent structure of ADCs is difficult to characterize
• ADC control strategy: it should be product specific and non-redundant
• ADC manufacturing process: it is variable and long making it a time
challenge to follow standard approaches, in particular for process
validation and stability
• Regulatory Dossier organization and content definition: there are
several options for the dossier organization and the level of details to
be provided, in particular for the intermediates, is not clear

On accelerated timelines, risk-based approaches and strong justifications

are key for comparability, validation and stability strategies

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SUGGESTED BIBLIOGRAPHY

Regulatory CMC challenges unique to ADCs

30
 BIBLIOGRAPHY

• Shapiro MA, Chen X-H. Regulatory considerations when developing

assays for the characterization and quality control of antibody-drug
conjugates. American Lab Aug. 27, 2012.
http://www.americanlaboratory.com/913-Technical-Articles/119843-
Regulatory-Considerations-When-Developing-Assays-for-the-
Characterization-and-Quality-Control-of-Antibody-Drug-Conjugates/
• Miksinski SP, Shapiro M (FDA). Regulatory considerations for antibody-
drug conjugates. AAPS Meet October 18, 2012.
www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalPro
ductsandTobacco/CDER/UCM341177.pdf
• Hamilton GS. Antibody-drug conjugates for cancer therapy: The
technological and regulatory challenges of developing drug-biologic
hybrids. Biologicals. 2015 Sep;43(5):318-32.
• Gong et al. Control Strategy for Small Molecule Impurities in Antibody-
Drug Conjugates. 2018 Apr;19(3):971-977.

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 BIBLIOGRAPHY

• Beck, A., et al. Strategies and challenges for the next generation of
antibody-drug conjugates. Nature Reviews Drug Discovery v.16,
p.315-337 (2017)
• SamareshSau, et. al. Advances in Antibody-drug Conjugates: A new
Era of Targeted Cancer Therapy. Drug Discovery Today, v. 22, p.1547-
1556 (2017)
• Ruesch, M., et al. Strategies for setting patient-centric specifications
for biotherapeutic products. Journal of Pharmaceutical Sciences, v.
110, p771-784 (2021)
• Dean, et al. OBP, CDER, FDA, Silver Spring, MD, United States
Targeting cancer with antibody-drug conjugates: Promises and
challenges. MABS 2021, VOL. 13, NO. 1, e1951427 (2021)

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THANK YOU

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 EXPERIENCE SHARING:
CHALLENGING REQUIREMENTS
AND POTENTIAL SOLUTIONS IN
CONTEXT OF ACCELERATION

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 WHAT ARE THE PROS AND CONS FOR DIFFERENT STRATEGIES
FOR MODULE 3? CAN THERE BE A COMMON DOSSIER FOR ALL
REGIONS THAT USE THE ECTD?

Strategy 1 Strategy 2

One single 3.2.S section Separate 3.2.S sections

3.2.S DS 3.2.S. Drug-Linker Intermediate
3.2.S.2 DS Manufacture 3.2.S. mAb Intermediate
3.2.S.2.4 Control of critical 3.2.S. DS
steps and intermediates
3.2.S.4.1 Drug-Linker
Intermediate
3.2.S.4.2 mAb
Intermediate

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CASE STUDIES: YOU DECIDE!

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 CASE STUDY - CONTROL OF ATTRIBUTES:
OSMOLALITY

PROCESS Mfg range

(N=5)
mAb Intermediate 295-305 mOsm

Proposed spec 270-330 mOsm

Freeze
DEV data span 250-350 mOsm

Thaw 250 300 350

Buffer exchange for conjugation • Is the proposed osmolality specification

(270-330 mOsm) acceptable?
• Pros: Yes. Why?
Reduce and conjugate
• Cons: No Way! Why?

Diafilter and Buffer exchange

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DS
 CASE STUDY: HMW
WHAT LEVEL OF CONTROL AT THE MAB?

mAb Release with SEC

Freeze

Thaw
Question: How stringent should the
control of the HMW be for the mAb Buffer exchange for conjugation
intermediate?
Reduce and conjugate
Tight: Control as a DS: accounting for
safety and mfg consistency
Diafilter and Buffer exchange
Loose: Control as ‘suitable for further
processing’: potential for broad
specification or IPC test DS Release with SEC
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 CASE STUDY: DAR

• Proposed specification: DAR = 4.0±0.5; profile comparable to reference

• Question: Is the Proposed Commercial specification acceptable? Or should sponsor

place ranges around each species?

• Information/Justification:
• DAR is controlled by process ratios (mAb: Drug: reductant) and further
monitored by “Profile comparable to reference” and potency

• Pros: Sounds OK. Why?

• Cons: You must control the range for each species. Why? 39
 CASE STUDY: UNCONJUGATED MAB
*FDA 1997 PTC: “The amount of free antibody …in the final product should be determined
and limits set” (concern re: competition)

• Do we need a specification for

unconjugated mAb if it is present
in low quantities?
• Info:
• Unconjugated mAb spiked into DS
does not inhibit potency 10mg/kg free mAb

• YES! Of course you do! WHY? And 10mg/kg free mAb+

how do you set it? 2mg/kg ADC
2mg/kg free
mAb+2mg/kg
• Not Necessary: WHY? And how do ADC
you justify that decision? 2mg/kg ADC

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 YOU DECIDE: CONCLUSIONS

• Intermediate Controls should be based on assuring

suitability for use in further manufacturing
• Some controls typically expected for API and DS may
not be appropriate for Intermediates
• Attributes of mAb are not necessarily CQAs
• It is OK if conjugation ends up modifying mAb
attributes
• Use of the same assays for mAb and DS may not be
appropriate

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CASE STUDY: CONTROL OF EFFECTOR FUNCTIONS

• IgG1 ADC with effector functions

not claimed as Mode of Action
• CDC and ADCC surrogate binding
assays developed
• Glycosylation profile for
comparability assessments

What control strategy would you

recommend for effector functions?

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 EFFECTOR FUNCTION CHART

Does the mAb intermediate / DS induce effector

functions?

Yes
Same order of magnitude as
molecules for which effector
functions are claimed
clinically relevant
Yes No
mAb intermediate and DS
may induce effector functions
which are not claimed as
MOA but may contribute to ?
the overall MOA of the ADC

?
?

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 WHAT IS YOUR COMPARABILITY STRATEGY WHEN YOU
HAVE A CHANGE IN THE DRUG OR THE MAB PROCESS?

• Would you recommend to assess comparability at the DS and / or DP levels? In which cases, is a
DS and / or DP comparability required?

Example 1: Drug-linker intermediate

Change of manufacturing site
• What would you do?
• In case of comparable pre- and post-change drug-linker intermediates
• In case of differences in purity or impurity profile of the drug-linker intermediate

Example 2: mAb intermediate

Scale-up and change of manufacturing site
• What would you do?
• In case of comparable pre- and post-change mAb intermediates
• In case of differences in mAb intermediate

• Did you experience using plateform / process & product knowledge to leverage studies for the
comparability assessment?

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 CASE STUDY: PROCESS VALIDATION DECOUPLING

• Given the extremely long manufacturing chain involving linker, drug, mAb, DS and DP, could
decoupling be considered for process validation?
• e.g. using a mAb pre-PPQ batch representative of the commercial process for
manufacturing of DS PPQ batches

• Did you try to propose alternatives to standard process validation?

• Was it successful?
• What specific considerations would you recommend?
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