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

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