Assessing and Managing Strategic Risk for Next Generation Processes of Established Brands

Eric R. GarrAssociate Director, Global Product Development and Supply

2BMS Internal Use Only

Our Mission

that help patients prevail over serious diseases.

To

discover,

develop and

deliver innovative

medicines…

3BMS Internal Use Only

Cambridge, MARedwood City, CA

Investing for the Future

Cruiserath, Ireland

Expanding our R&D presence within hubs of scientific excellence and innovation

Princeton Pike, Lawrenceville, NJ

Devens, MA

of total DEVELOPMENTPROJECTS are BIOLOGICS

Over75%

MODERNIZING

FACILITIESthrough improved

technology,

more efficient design

and workspaces that

enable collaboration,

creativity and innovation

• With a growing pipeline, how do we supply product launches from existing facilities that are at capacity manufacturing products with legacy processes?

• Desirable to move towards more balanced facility utilization

Problem Statement

150 M3

40 M3

Commercial

Launch

150 M3

40 M3

Current State Desired State

• Process is the product

• Non-platform tech

• <1g/L bioreactor titers

• Product-specific facilities

• Undefined components

• Little process understanding/characterization

Industry Maturation

• Platform processes

• Flexible, multiproduct facilities

• >5 g/L bioreactor titers

• Process analytical technologies

• Continuous processing

• Chemically defined RMs

With significant advances in bioprocess technology over the past 10 years, there is significant interest in next generation process (NGP) development for legacy programs

• HA Acceptance

– In general, HAs support continuous improvement initiatives for licensed therapeutics

– A Comparability Protocol (CP) filed with the Agency can facilitate a more efficient submission process

– CP should outline motivation for changes, supporting development data, comparability plans, and reporting categories for proposed changes

• Comparability Risk

– Need to demonstrate analytical and bio (PK) comparability

– Strong emphasis on product quality should be applied for any process changes under development

• Market Fragmentation

– Filing in every market is difficult with different timelines towards approval

– Could require running both legacy and NGP depending on market for product

Risks to NGP Development

• Project motivation

• Decision to initiate program

– Proof of concept

– Project targets and milestones

• Risk management paradigm

• Team formation/structure

• Project governance

• Option for project acceleration

Assessing and Managing Strategic Risk for Next Generation Processes – an example

• Mitigate capacity constraints while maintaining product quality

– Targeted yield increase

– Comparable product quality

– Utilize BMS platform technologies, enabling transfer to any site in network

– Improved cycle times

– Robust, boring process

Project MotivationReduce capacity constraints while maintaining product quality

• Things to Mitigate (NGP Wish List)

Glucose-based feedingEvent based process control

strategiesInefficient process flowsUndefined raw material

componentsFacility constraints

Risk Management ParadigmICH Q9 QRM

• As leaders of the project, it was our job to assess risk and propose mitigations to reduce risk to acceptable levels

• It’s also our job to effectively communicate to stakeholders and governance seeking feedback, guidance, and endorsement

“It is commonly understood that risk is defined as the combination of the probability of occurrence of harm and the severity of that harm. However, achieving a shared understanding of the application of risk management among diverse stakeholders is difficult because each stakeholder might perceive different potential harms, place a different probability on each harm occurring and attribute different severities to each harm.”

Technical Project

Team Lead

Analytical

Regulatory

Quality

Drug Product

Team Structure

Technical Lead

(MS&T)

Process Champion (Lifecycle

Management)

Brand Lead (Biologics Strategy)

• The technical project team (TPT) is an empowered matrix team that drives the technical agenda for established brands -Normally a “run the business” team supporting process life cycle

• The TPT was tasked with stewarding the NGP project through process validation and filing

Technical –Department Level (Director and Executive Director level

MS&T)

-Ensures alignment across MS&T organization and provides guidance to

technical teams supporting commercial and late-stage programs

Technical Project Team (Associate Director level across TPT)

-Drives technical agenda for specific programs, drawing on matrix

individuals for expertise from their respective areas

Technical –Network (VP -Executive Director level across

Biologics)

-Senior leaders from across biologics (MS&T, PD, R&D)

providing guidance and endorsing technical workstreams

Operations –Network (VP -Executive Director level across

Biologics)

-Senior leaders across operations, Regulatory and Quality providing

guidance and endorsing workstreams impacting commercial

operations

Full Development Team

-Senior leaders across Commercial organization providing guidance on the direction of established

brands

Project Governance

Process Development Timeline and Results

Q1 Q2 Q3 Q4

Process

DevelopmentProcess Characterization

Go/No Go

Pilot

Runs

Extended

Analytical

Comp.

Risk Assessment (PC)

Document

Decision

Milestone

Tech Transfer

Q1 Q2 Q3 Q4

Go/No Go

Fit Assessment

IPC

VC

D (

cells

/mL)

CQ

A

Improved cell growth and productivity

Demonstrated consistency and comparable CQAsRange

ERG

Score

DRM

ScoreDH Score

SEG

ScoreConsensus Ranking

32 8 1 4 4 Medium

4 4 1 4 4 Medium

2 2 1 16 8 High

8 2 1 4 4 Medium

8 16 1 8 8 High

8 1 4 16 16 High

8 8 1 4 8 High

8 8 1 8 4 Medium

16 8 1 1 8 High

32 8 4 32 16 High

32 16 4 32 16 High

8 16 1 4 8 High

2 8 1 16 8 High

4 4 1 0 4 Medium

TP

UT

S

NGP Risk from Process ChangesProcess changes highlight need for robust analytical strategy

CQAs Assay MethodsProcess Step

USP C1 C2 C3 UF/VFBiological Activity:

In vitro activity* Cell-based bioassay + ++Target binding* SPR-based binding kinetics + ++

Glycosylation variants:

Charge variants iCIEF +++ +++ ++

Oligosaccharide profiling Peptide mapping +++ +++ ++

Product-Related variants:

Deamidated variants* LC-MS peptide mapping + ++ + + +Methionine oxidation variants* LC-MS peptide mapping + + + + +

Product-related Impurities:

HMW species* HPLC SEC + +++LMW species* HPLC SEC +

Process-related Impurities:

HCPs ELISA + +++ ++DNA qPCR + +++ ++Viral contamination ++ ++ ++ ++ ++

* stability indicating attributes +++ significant impact to CQA;++ impact to CQA; + incidental impact to CQA;

• With the changes implemented for the NGP process, highest levels of risk determined to be glycosylation and clearance of process-related impurities from cell culture and early purification steps respectively

Analytical comp and PK will be critical for success of program

• Mitigations:o Robust comparability plano Extended characterization

at different stage gates of implementation

Overall Program Risk Table

Risk Description Risk Type Mitigation

NGP not analytically comparable to Current Gen

at scale. NGP analytical

Comparability• Planning for PK / Safety study if needed.

PPQ Execution Risk: No complete at-scale runs

available prior to initiating PPQProcess Validation

• Request 2-3 USP-only large-scale Dev runs

• Request Dev Run DSP to be executed in BDB pilot lab

with representative equipment scale

• Request for additional Engineering Runs

PPQ Strategy: 3 PPQ runs planned for six

bioreactor facilityProcess Validation

• Bioreactor equivalency already established

• Alignment on validation strategy through Type C

meeting

DS is shown to be not biocomparable to

Current Gen DS

PK Comparability

Risk to

Schedule

• Perform NHP PK study with small-scale material prior

to PPQ to ensure material from NGP process is

comparable

Project Timeline – Implementation Option 1

NGP Process Characterization

Deliverable: Process Control Strategy Doc

Key Milestones

Pilot Runs

(500L)

NGPProcess ReadyFor Transfer

Site Process Transfer

Docs / Recipes / Automation

Process ValidationFacility Fit

Analytical In-Process

Methods Upstream

PK Study

Submission Prep Activities

DP

Conversion

DS Stability - PPQ

DP Stability

Pilot Run DS Stability

Analytical In-Process

Methods Downstream

MS&T

Manufacturing

Stability

Dev

Runs

Long Lead Time Order Equipment

Delivery, Install & Qualification

Raw Materials Procurement & Delivery

Large Scale

Comparability Package

HA Filing NGP

Site

PK Study Start-up Activities

Linear low-risk timeline

Dev Run Campaign

Validation Campaign

DP Conversion

PK Start

Project Timeline – Implementation Option 2

File NGPOption 2

NGP Process Characterization

Deliverable: Process Control Strategy Doc

Key Milestones

Pilot Runs

(500L)

NGPProcess ReadyFor Transfer

Site Process Transfer

Docs / Recipes / Automation

DS 6xRuns Eng / PPQ

Test & ReleaseFacility Fit

Analytical In-Process

Methods Upstream

PK Study – Option #1

First MarketApprovalOption 1

Submission Prep Activities

DP

IV

DS Stability - PPQ

DP Stability

HA MeetingPK Plan

Pilot Run DS Stability

Analytical In-Process

Methods Downstream

MS&T

Manufacturing

Stability

Clinical

LS Dev

Runs

PK Study – Option #2

Long Lead Time Order Equipment

Delivery, Install & Qualification

Clinical DS 3xRuns

Test & Release

DP-IV

& Release

Raw Materials Procurement & Delivery

Large Scale

Comparability Package

File NGPOption 1

Site

Clinical Stability: DS & DP

PK Study Start-up Activities

Option #2

PK Study Start-up Activities

Option #2

PK Study INDOption 2

Supplying PK from clinical scale reduces time to file by 12 months

Time Savings

Clinical Material Supporting PK and LTSS – Risk

Primary Risk: Clinical DS is not comparable to NGP at-scale DS and can not be used for PK study

Risk Level: Med – Likely that Pilot & Clinical runs will meet comparability criteria and be highly similar, however, no full-scale NGP data available at time of decision

Risks Impact Mitigation

1. Process differences: SUBs, USP&DSP USP & DSP Scale, Depth filter vs C-Fuge)

2. No at-scale NGP data available: decision based on small scale and pilot scale

3. Analytical testing site risk: if commercial testing site is not used

If Clinical DS cannot be used for the PK study:

• Schedule push – significant delay to submission timing versus option 2

• Financial loss- cost of the batches at Clinical site (RMs + OPEX)

• Process characterization complete prior to Clinical DS Runs

• Decision point: PK study will not be initiated until Dev Run comp data available

• Additional Dev Runs added• Request QC testing support for

Clinical and large scale Dev Runs• Evaluate DP fill at commercial site

Campaign

Pilot Phase 1Ten passages in shake

flasks, Wave and stirred tank bioreactors

500-L SUB Depth FiltrationEquivalent column bed

height and linear velocity

Scaled on surface area and product load/area

Pilot Phase 2 NC NCPilot solids-ejecting

centrifuge followed by depth filtration

NC NC

Clinical NC 1-kL SUB Depth Filtration NC NC

Development Run NC Commercial SSPilot solids-ejecting

centrifuge followed by depth filtration

NC NC

Commercial PPQ NC NCFull-scale solids-ejectingcentrifuge followed by

depth filtrationNC NC

1. Process Scale Differences Technical risk mitigation for clinical runs

Inoc / Seed Biorx

Production Biorx

HarvestColumn Chrom

UF/DF/VF

2. Cell Culture Scale-up Technical risk mitigation for scale-up and validation campaign

• To mitigate risk to PK study material and validation campaign, upstream only Development runs performed at commercial scale with supporting purification done at pilot scale

– Facility controls allows for Upstream only development runs to be performed in parallel with a commercial campaign

– Purification at pilot scale determined to be low risk from a technical perspective

– DS testing performed in validated QC lab to eliminate testing bias –Risk #3

3. Analytical Strategy & Testing Sites

# Campaign Purpose In-process DS Release DS Stability

1 Pilot - Demo• Process lock demonstration

• Comparability data setAnalytical Analytical Analytical / QC

2 Clinical Supply• PK-Safety Study

• LTSS for NGP DSAnalytical QC QC

3Dev Run (USP

only)

• Demonstration of USP scale-

up to Large Scale-kL

QC (USP)Analytical (DSP)

QC N/A

4

Large Scale-kL

commercial-

scale Validation

• PV

• DS stability

• DP Stability

QC QC QC

• Analytical comparability plan developed with guidance from ICH Q5E and FDA draft guidance• Cross site campaign material tested in same QC laboratory to eliminate potential lab-to-lab bias

Governance Outcomes

• Technical Governance Forums

– Technical risks and decisions endorsed by senior leadership through five technical governance forum appearances

Key decisions – Pilot analytical comp and process lock; process control strategy; Clinical campaign comparability and NHP design; Tech transfer readiness

• Operational Governance Forums

– Operational risks and strategy decisions endorsed by senior leadership through five governance forum appearances

Key decisions – Project endorsement; Validation strategy; PK and filing strategy; Go-no-go for validation

• With many legacy biotherapeutics reaching the end of their lifecycle, and growing new product pipelines, there is increasing desire to apply state-of-the-industry bioprocess technologies to licensed products, lowering cost of goods and improving facility efficiencies

• There is significant risk to making major changes to licensed processes including analytical and biocomparability. Market fragmentation could make complex biopharma supply chains even more complex.

• An integrated risk management approach where an empowered matrix team assesses risk and communicates effectively to the proper governance forums is essential for project success

Conclusions

THANK YOU