dieter schmalzing slides
Post on 13-Feb-2017
230 Views
Preview:
TRANSCRIPT
Dieter Schmalzing, GBQC, South San Francisco
Genentech, A Member of the Roche Group
CMC Strategy Forum Europe 2016
May 9 – 11th, 2016
Marriott Rive Gauche, Paris, France
Considerations for Control Strategies for mAb/mAb
Combination Therapies – An Industry Perspective
Presentation Outline
• Acknowledgements
• Benefits to Patients of Combination Therapies
• Combination Therapies – Differences Matter:
• Nomenclature
• Combinations
• Administration
• Examples:
• Analytical Methods
• Acceptance Criteria – Cumulative Impact Assessment
• Conclusions
Page 2
Page 3
© 2009, Genentech / Proprietary information – Please do not copy, distribute or use without prior written consent.
Acknowledgments
Lynn Gennaro
Richard Seipert
Pat Rancatore
Frank Berendt
Paul Motchnik
Kowid Ho
Lichun Huang
Fabienne Chapalain-Guyomard
Thomas Schreitmueller
Jennifer Mercer
Benefits for Patients
• Many diseases are treated with combination therapies:
• multifactorial causes
• interlinked or parallel molecular pathways
• improved efficacy or safety profiles
• dosing/ patient convenience
• However, combination therapies are often evaluated after approval of
individual medications
• There is a need for their early evaluation (i.e. prior to approval) for
complex and life-threatening diseases
Page 4
Nomenclature (I) Page 5
• COMBINATION PRODUCT - Two or more regulated components,
that are physically, chemically combined as a single entity or
packaged together in a single package (example: drug / device)
• No clear Health Authority definitions on what constitutes a
“Combination Therapy” and what differentiates them
• There is currently no CMC guideline specific for combination
therapy, except WHO’s for small molecules
• Roche/Genentech Internal Usages:
• COMBINATION THERAPY - Two or more medicines administered
as part of a therapy to treat a specific condition:
• Separate Administration
• Simultaneous Administration
Nomenclature (II)
• Many permutations with different complexities are possible
• Suitable Nomenclature is needed to effectively manage this complexity
• Roche/ Genentech Internal Nomenclature:
Page 6
Simultaneous </= 60 min
fixed dose • single pharmaceutical form
co-mixture
• co-mixed at the clinical site
• individual/ co-packed
• mixing: IV bag, vial, syringe
Separate >/= 60 min
individual
• break-time between individual
injections of A then B ≥ 60min
A + B
A B+
A B+
Dependencies of CMC Complexity Page 7
Simultaneous
fixed dose • single pharmaceutical form
co-mixture
• co-mixed at the clinical site
• individual/ co-packed
• mixing: IV bag, vial, syringe
Separate
individual
• break-time between individual
injections of A then B ≥ 60min
A + B
A B+
A B+
Increased
CMC
Complexity
Increased
CMC
Complexity
A B
clinical clinical
commercial clinical
commercial commercial
+
Page 8
Combination Therapies
&
Analytical Methods
Analytical Methods – Combination Therapies (I)
• DS release and stability methods are typically not impacted:
• DS are manufactured and stored separately
• but, DS manufacture for fixed-dose DP must be understood
• DP methods can be partially/ fully impacted:
• fixed dose release and stability
• co-mixture in-use stability, e.g. IV bag
• Separate/ individual DP administration has no method impact
Page 9
API Methods – Combination Therapies (II)
• Possible Impact to Single Product Methods:
• Partial/ complete analytical interference:
• qualitative and quantitative sample read-outs:
• chromatographic, electrophoretic, potency,…
• New isoform formation due to protein A/ protein B interactions:
• interference with with mAb profiles and vive versa
•Risk-based:
• The more similar the molecular make up of the products
• The less discriminatory the analytical technique used
Page 10
Analytical Methods – Charge/ 2 Mabs combined Page 11
Minutes
6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0 12.5 13.0
AU
-0.01
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
AU
-0.01
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
UV - 214nm
mix bag T0
mix bag T0
UV - 214nm
mix bag t24
mAb1
Main Peak
mAb2
Main Peak
CZE
0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0 18.0 20.0 22.0 24.0 26.0 28.0 30.0 32.0 35.0
-20
50
100
150
200
250
300
350
400
1 - 2C4_HER2 CO-ADMIN IEC 050709 #7 [modified by wzkwong]co-mix saline t0 UV_VIS_1
mAU
min
21
mAb1
Main Peak
mAb2
Main Peak
IEC
• Does the partial separation suffice for DP release and stability testing?
• How to set suitable acceptance criteria, e.g. acidic region?
API Methods – Size/ 2 mAbs Combined Page 12
Minutes
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
RF
U
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
mAb1+2
Main Peak
CE-SDS non-red
• Could absence of separation of A, B constitute a suitable method?
• How to set suitable release and stability criteria?
• Could the sum, e.g. of aggregates A + B be specified?
Page 13
Combination Therapies
&
Cumulative Impact Assessment
Risk-based Approach – Background
•The performance of a combination therapy could be undesirably impacted
due to the combination of their constituents A, B,…:
• cumulative effects
• synergistic effects
• product-related impurities
• process-related impurities
• contaminants
•Risk-based impact assessment should be performed:
• theoretical and/ or experimental
•Risk dependents on:
• administration type for combination therapy
• characteristics of constituents
• indication
• patient population
Page 14
Page 15
• Separate administration of two biologics, with one or more marketed
products, including ≥60 min wait time:
• no special considerations due to established safety profile of marketed
product
• only applicable for similar indications and patient populations
• decreased risk to patients as a result of the 1 hour break time
• Administration of two biologics, within <60 min wait time:
• Physicochemical attributes and impurity levels should not exceed
those expected for a single product
Risk-based Approach – Strategy
Risk-based Approach – Endotoxin Page 16
• Compendial pyrogenic dose limit:
• </= 5 EU/kg body weight/ hour, for parenterals
• others, e.g. for intrathecal
• Separate >/=60 minutes:
• there is no further impact assessment required
• single agent acceptance criterion are not impacted
• Simultaneous </=60 minutes:
• individual endotoxin AC must be assessed to meet, when combined, pyrogenic
dose limit
• Fixed-dose:
• direct testing at final DP level
• might require additional assessment of DS limits or DS lot selection
• Co-mixture:
• assessed at individual agent DP level
• might require lot selection, if sum of acceptance criteria exceed dose limit
Risk-based Approach – HCP Page 17
• Possible Risks Associated with HCP:
• immunogenicity/ safety
• adjuvant – enhances immune response of DP
• enzymatic activity – impact on product stability and efficacy
• Challenges:
• there is no official generic limit, e.g. WHO
• inherent complexity of HCP mixtures
• analytical dependencies
• time-break might not alleviate risks
• Possible Strategies to Reduce Risk:
• DS lot selection – keep total DP HCP levels at a minimum
• in-house generic phase-dependent HCP limits – keep sum within
• commercial + clinical product + time-break – summation might not be
needed
• HCPs from different host cells – possibly less risk
Risk-based Approach – In-use Stability Study, 24 h Page 18
mAb1
Main Peak
mAb2
Main Peak
IEC
0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0 18.0 20.0 22.0 24.0 26.0 28.0 30.0 32.0 35.0
-20
50
100
150
200
250
300
350
400
1 - 2C4_HER2 CO-ADMIN IEC 050709 #7 [modified by wzkwong]co-mix saline t0 UV_VIS_1
mAU
min
21
• 2 mAbs combined in saline IV bag
• partial overlap of charge profiles across all charge-based techniques
• No separation of mAbs using size-based techniques
• Assays known to be stability indicating
No change </= 24 hrs for both mAbs studied individually and co-mixed
Minutes
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40R
FU
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
CE-SDS
Risk-based Approach – High Molecular Weight Species
19
• Soluble aggregated forms of therapeutic proteins:
• can enhance immune response
• lead to formation of anti-therapeutic antibodies
• restrict sum of aggregates to tightest acceptance criterion of constituents
• Simultaneous administrations require special consideration:
• possible formation of heterologous HMWS, defined as aggregates of product 1
and product 2:
• potential increased immunogenicity
• two target antigens being bound to an aggregated HMWS of two molecules.
• Assessments can be performed as a theoretical exercise:
• knowledge of pathways involved in the MoAs
• propensity of heterologous HMWS formation due to molecular make-ups, e.g. pI,
hydrophobicity difference
• experimental verification needed extend depends on outcome of theoretical
exercise
Page 20Summary
• There is a need for early evaluation of combination therapies for complex and
life-threatening diseases
• The effective management and execution of CMC activities for combination
therapies requires suitable and aligned nomenclature
• Combination therapies are created un-equal and warrant a risk-based and
phase-dependent approach for their control systems with unique challenges
• Simultaneous vs separate administrations have different risk profiles
• Methods, shown to be suitable for an individual mAb, should be assessed for
combination products – What is a suitable separation?
• Combination therapies require evaluation of acceptance criteria for individual
single therapy products for contaminants, product- and process-related
impurities – What is a suitable acceptance criteria, e.g. A+B, A, B,…?
• Molecular interactions between mAbs can occur and should be watched out for
Doing now what patients need
next
top related