Learnings from EBE Cross-Industry

informational sharing session on development

and licensing of biologics/device combination

products

Serge Mathonet, Sanofi R&D

May 9, 2016 - EU CMC Strategy Forum, Paris

Scope

• Focus was on prefilled autoinjector/pen e.g. single-use, disposable, handheld

mechanical injection device integrating a prefilled syringe, that administers,

over a defined period, a fixed dose of high concentration monoclonal

antibodies solution into SC tissue. mAb concentration would typically range

from 50 to 150 mg/ml with self-delivery time for 1ml up to 20 seconds

• EBE set a topic group early 2015 to address/share CMC challenges

associated with bringing these products to the market through organizing a

cross industry information sharing session

• At the time of the cross-industry information sharing session (April 2015),

only Simponi (RA) and Cosentyx sensoready prefilled pen (Psoriasis) has

been approved for commercialisation. To date two addtional mAb products in

prefilled pen presentations have been approved (Praluent and Repatha -

hypercholesterolemia).

2 | EU CMC STRATEGY FORUM MAY 9,2016 – EBE SATELLITE SESSIION

EBE cross-industry information sharing session in

Novartis Basel, Switzerland April 30, 2015

Full day cross-industry informal sharing session on prefilled pens/prefilled pen

injectors focusing on technical/regulatory challenges to be overcome to ensure

first pass BLA/MAA approval

Agenda items:

• Workshop on commercial control strategy from components to the combined product, setting acceptance criteria and shelf life establishment (Meg Leahey, Leahey

Global Regulatory CMC Biologics and Device CMC group for combination products, Pfizer

• Device Development Cosentyx Sensoready Pen - Wolfgang Papst, Senior Expert

Packaging and Device

• How to achieve 21 CFR Part 4 compliance for a legacy prefilled syringe product -Mike Wallenstein, Senior Compliance professional, Novartis

• Agency advice on location of device information and content in Module 3 -Serge

Mathonet, Global RA-CMC Biological Product , Sanofi R&D

• Simponi Smartjet AutoInjector BLA/MAA and Post-approval Filing Overview, Jason

Lipman, Global RA CMC Medical Devices and Combination Products, Amgen

3 | EU CMC STRATEGY FORUM MAY 9,2016 – EBE SATELLITE SESSIION

• Focus on learnings from the Workshop on commercial

control strategy from components to the combined

product

| EU CMC STRATEGY FORUM MAY 9,2016 – EBE SATELLITE SESSIION4

Key Learnings/Questions (CQA/Control Strategy)

• Risk-based approach for control strategy is based on data from

- Hazard Identification and Human Factors studies as foundation for

risk management plan that is basis for control strategy

Device Risk Management (ISO 14971 [3] and IEC 62366) versus Quality

Risk Management for drug constituent (ICH Q9)

• Learnings from clinical trials to be included in development of control

strategy and acceptance criteria

- e.g. injection time; BLGF might be based on literature

• Functional specifications and Acceptable Quality Limits (AQL’s

managed through site quality system) set based on usability, clinical

performance and safety but also taking into consideration components

specifications / AQL and aging effect

• Understanding of assembly process /product characterisation drive any

drug product attributes on final release5 | EU CMC STRATEGY FORUM MAY 9,2016 – EBE SATELLITE SESSIION

Key Learnings/Questions (CQA/Control Strategy)

• There is an overlap in functional release testing with drug product

attributes – potential opportunity to streamline but to date experience

has been 5+ functional tests on release

- Lean approach to eliminating sources of component variability, introducing

best in class components, device design change shall allow optimising system

integration, minimize product complaint rate to best standard and reducing

the amount of functional release testing

• Use same principles and tools as for CQAs but might look at using

different terminology to differentiate and need to clearly define

• Good practice is to establish these with risk management plan with key

consideration to usability and safety

6 | EU CMC STRATEGY FORUM MAY 9,2016 – EBE SATELLITE SESSIION

Key Learning/Questions (Functional Testing)

• Strive to keep additional functionality/ product testing to a minimum for

routine batch release

- For those functionality aspects of the device that would not be influenced by

the presence of product, is there an opportunity for these to be “validated” and

not part of the routine batch to batch testing (in-process or release)?

• Possible inputs into control strategy:

- Device constituent supplier testing, in-coming and in-process testing as it

relates to either on-line or stage testing

- Is there an opportunity to demonstrate acceptable functionality for device

based on data sets obtained earlier than final release testing and thus not

retested on release?

| EU CMC STRATEGY FORUM MAY 9,2016 – EBE SATELLITE SESSIION7

Functional performance control strategy Matrix

Critical

Quality

Attributes

Device

Developmen

t

Product

Validation

Control Strategy

Supplier

testing

Incoming

and In-

process

testing

Release Stability

Effective

Functional

ity

Safety

Efficacy

(both

device and

product

related

attributes)

Design

Control

Process and

Risk

Assessments

Characterisati

on Studies –(demonstrate no

adverse impact

to quality from

process

handling)

Human Factor and

Usability

Evaluations

Design Verification

Dose accuracy ISO

11608-1

Additional

functionality

testing per device

design

Container Closure

Integrity (if

applic.)

AI

Subassemblies

testing (e.g

performance

testing on AI

to be used in

commercial

manufacturing,

assembled with

reference PFS)

In-coming

testing on

subassemb

lies as

critical

raw

material

component

In-process

testing

during

manufactu

re

Functiona

l testing

Functional

testing

Overall

expiry of

combination

product

Expiry of

device/

functional

components

(Aging

effect)

Validation Studies (PQ versus PV)

| EU CMC STRATEGY FORUM MAY 9,2016 – EBE SATELLITE SESSIION8

Setting PFP specifications and control strategy

Test Impact Acceptance

criteria

rationale

AQL Control

Strategy

(Supplier, Incoming, CIPC, Release,

Stability)

E /Bio-

activity

PK/

PD

S- Drug/

Device

Immuno

genicity

Usabili

ty

Injection Time X X X x HFS/Clinical

experience

Comme

nsurate

to

criticalit

y and

device

supplier

capabilit

y

-Syringe incoming testing (silicon,

BLGF)

-Bulk PFS BLGF release/stability

testing

-IJT testing PFP Release/Stab

Dose Accuracy X X X X Delivered

volume shall

be no less than

labeled

volume

-CIPC filling weight consistency – bulk

PFS process

-Expellable volume – bulk PFS release

-Dose accuracy PFP release/stability

testing

Injection Depth X X X X Based on prior

knowledge on

sc tissue depth

-Device supplier testing (Inj. Depth

Assembled AI)

Container closure

integrity (dye

ingress)

X X -CCP: e.g. insertion force/assembly

force

-CCIP: PFP Visual Controls

-CCIT PFS release/stability testing

-PFP stability testing

9

Setting PFP specifications and control strategy

Test Impact Acceptance criteria

rationale

AQL Control

Strategy

(Supplier, Incoming,

CIPC, Release, Stability)

E /Bio-

activity

PK/PD S- Drug/

Device

Imm

uno

geni

city

Usability

Needle cover

activation force

(NCAF)

X AI not

usable if

higher force

needed

EN 894-3*:, 35 N.

Commens

urate to

criticality

and

device

supplier

capability

-Device supplier testing

(NCAF Assembled AI)

- PFP release/stability

testing case by case

Actuator Button

Activation force

(ABAF)

x AI not

usable if

higher force

needed

MIL-STD-1472F*

maximum force for pushing of

buttons with 23 N,

minimum force for unintended

activation with 5 N

- Device supplier testing

(ABAF Assembled AI)

- PFP release/stability

testing case by case

Visual

appearance and

defects

- Visible

particles

X X USP<1>, <790>/EP

2.9.20)

Essentially/Practically

Free from visible particle

0.65 %

major

defect)

- Visual inspection of PFS at

end of manufacturing and

on¨PFS stability testing

10

Applicable standards

MIL-STD-1472F, Department of Defense Design Criteria Standard: Human Engineering (5)

EN 894-3: Safety of machinery – Ergonomics requirements for the design of displays and control actuators – Part 3:

Control actuators

CEN/TR 614-3: Safety of machinery – Part 3: Ergonomic principles for the design of mobile machinery

IEC 62366: Medical Devices – Application of usability engineering to medical devices (IEC

62366:2007)

Criticality scoring (severity x likelihood)

• Device related attributes

- Criticality scoring e.g.

Severity levels

• Life-threatening (death could occur)

• Results in permanent impairment of body function or permanent

damage to a body structure.

• Necessitates medical or surgical intervention.

• Temporary or reversible (without medical intervention).

• Limited (transient, minor impairment or complaints).

• No adverse health consequences

• Hazard cannot be assessed with the data currently available.

Likelihood

• e.g. Through tracking of Device adverse event and technical complaints in

clinical trials or commercial setting

• CQA like attributes

- E.g. Injection time

Same approach to criticality scoring as for drug CQA

| ADC kick-off meeting | Ursula Busse | 2016-01-21 | ADC challenges | Business Use Only11

2016 priorities for the Topic Group

• Develop

- Case study on risk based approach to Prefilled pen control strategy

- Position Paper on Module 3 Dossier organization /requirement for

Device and CMC information

- Case study on post-approval change assessment

Introducing New site - Pre-filled pen assembly, labeling, packaging

Introducing Device changes e.g. Auto Injector design change, syringe

changes, component changes

| EU CMC STRATEGY FORUM MAY 9,2016 – EBE SATELLITE SESSIION12

Thank You to the Topic Group members

• Serge Mathonet (Sanofi, Global Regulatory Affairs CMC Biologics)

• Maged Darwish (Roche, Technical Regulatory, Biologics)

• Mike Wallenstein (Novartis Pharma, Senior Compliance professional)

• David.M.Ottolangui (GSK, Device Technology GSK)

• Heather GUERIN (Janssen, CMC Regulatory Affairs Device expert)

• Meg Leahey(Pfizer, Global Regulatory CMC Biologics and Device CMC group

for combination products (Pfizer, Ireland at the time, now with BMS)

• Amanda Matthews (Pfizer, Regulatory CMC)

• Feuerstein, Ulrike (Abbvie, Primary Packaging Development for parenterals ex

CMC Submission groups for prefilled pens)

• Rajiv Gupta (Medimmune, Device Development)

13| EU CMC STRATEGY FORUM MAY 9,2016 – EBE SATELLITE SESSIION