EMPLOYING LEAN METHODOLOGIES TO IMPROVE PRODUCTION PROCESSES AND REDUCE CYCLE TIME

GREG GUYER| BRISTOL-MYERS SQUIBB

LEADER, BIOLOGICS DEVELOPMENT AND OPERATIONS

2

Our Mission:

To discover, develop and deliver innovative medicines…that help patients prevail over serious diseases.

23 NEW BIOLOGICS APPROVED BY FDA IN 2014- 2015

3

4 7 6 6 6 4 11 12

2008 2009 2010 2011 2012 2013 2014 2015

FDA BLA Approvals

BIOLOGICS MANUFACTURING

2014 2017 2020

Forecast of Bulk Kilograms Needed to Meet Product Demand (1,000s Kg/Yr)

~13

~40

New to Market

Clinical

Commercial

Source: http://www.americanpharmaceuticalreview.com/Featured-Articles/188840-Global-Biomanufacturing-Trends-Capacity-and-Technology-Drivers-Industry-Biomanufacturing-Capacity-Overview/

A PERIOD OF UNPRECEDENTED GROWTH

MAJOR VOLUME DRIVERS:Biosimilars

Clinical Pipelines

PD-1, PCSK-9

Potentially Alzheimer’s Molecules

~22

Over 900 BioPharma Products in Some Stage of Clinical

Development in US and Europe

77% Produced in Mammalian Systems

ResultsCustomer

Imp

rove

CONNECTING PURPOSE, PROCESS, AND PEOPLE

Strategy execution requires not only informing people as to the “what, when, and where” but also as to the “why”

Process

How value is createdWithin the organization

People

How people are upskilledAnd managed

Purpose

How customer needs areUnderstood and converted

Into strategy

How the process is continually improvedby the people and how problems are solved

How strategy is converted into behaviors and how communication is created

How strategy is deployed into the organization and how governance is created

This cycle occurs at each successive level of the organization in cascading fashion

Known as an “A3 cascade” and is used to communicate and deploy strategy

throughout all levels of the organization

STRATEGY PLANNING & DEPLOYMENT

Points – Selects aspirational targets to aim for

Aligns – Helps us agree to, and keep our focus on, the same goals

Adjusts – Provides a check of our annual strategy so we can make changes

HOSHIN

(Direction)KANRI

(Management)

Leader Session

Pre-Catchball

Catchball Session

Alignment (A3) Tracking

Renewal

Hoshin Kanri is a management process that:

DEFINE OPERATIONAL EXCELLENCE

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WAY OF THINKING

1. Executing your strategy more reliably and rapidly than your competition.

TOOL PERSPECTIVE

2. Lean & Six Sigma

OPEX DEPLOYMENT- IT’S AN EVOLUTION

2018- 2020

Purpose

2016

Processes

Foundational Tools (5S,

Gemba)

People

Project for certification

20142012

Manufacturing

Lean Practitioner

Six Sigma (GB, BB)

Lean Leader

OpEx Sponsor

Lean Master

MBB

PD

M&ST

Lean Labs

Project important to “you”

Project important to “us”

GMS

Project linked to A3VSM

Siloed in BU

E2E

BMS

Absolute certainty with practical flexibility

OUR STRATEGIC IMPERATIVES

BIOLOGICS

Speed toPatient

Speed toMarket

Increase Capacity/ Productivity

Develop People

Speed toMarket

Increase Capacity/ Productivity

Develop People

OUR STRATEGIC IMPERATIVES

BIOLOGICS

Speed toPatient

Fast to First in Human (F2FIH2.0)1

2 Upstream PD Standardization

FAST TO FIRST-IN-HUMAN (F2FIH2.0) EXAMPLE TIMELINE

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O N D J F M A M J J A S

Year 1

O N D J F M A M

Year 2

Tox Study & Final Report

IND Prep

J J A S

Select Lead Select Candidate INDGo to Clinic

Clone Selection/RCB MCB Prod

Process Development

DS Analytical Development

O N D

DP Analytical Dev

Tox Formulation FIH Formulation

Tox Mfg Test

GMP DS Mfg

DP Mfg

DS Stability

DP Stability

Former23 MonthTimeline

FAST TO FIRST-IN-HUMAN (F2FIH2.0) EXAMPLE TIMELINE

12

O N D J F M A M J J A S

Year 1

O N D J F M A M

Year 2

Tox Study & Final Report

IND Prep

Accelerated16 MonthTimeline

Select Lead Select Candidate INDGo to Clinic

Clone Selection/RCB MCB Prod

Process Development

DS Analytical Development

J J A S O N D

DP Analytical Dev

Tox Formulation FIH Formulation

Tox Mfg Test

GMP DS Mfg

DP Mfg

DS Stability

DP Stability

Initial CLD

(RACIR)Multiple

Candidate Sequences

Clone Selection/RCB

Platform Fit & Development Verify Final Clone

DS Analytical Development

DP Analytical Dev

Tox Form. FIH Formulation

DS Stability

DP Stability

DS IND Stability (Tox Lot)

DP IND Stability (Tox Lot)

UPSTREAM PD STANDARDIZATION

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Twelve scientists, three sites, multiple pathways

Before

UPSTREAM PD STANDARDIZATION

14

No Clone Selection Required

Clone Selection Required

Production Culture Can

Begin Almost Immediately

Twelve scientists, one site, two pathways

Current

UPSTREAM PD STANDARDIZATION

0

5

10

15

20

25

Before After

Mo

nth

s

Commercial Upstream DevelopmentTotal Months for Development

0

2

4

6

8

10

12

14

Before After

Tota

l Nu

mb

er

Number of Different Approaches to Commercial Upstream Process Development

Multiple methods to development, left up to the process development lead

Savings of approximately 6 months in development time

Estimated 40% Reduction in Median Cycle Time

Increase Capacity/ Productivity

Develop People

OUR STRATEGIC IMPERATIVES

BIOLOGICS

E2E Cycle time & throughput: DS to DP1

2 Tech Transfer

Speed toMarket

KEY PRODUCT E2E CYCLE TIME & THROUGHPUT INITIATIVES

Site A: Vial Thaw Bottle Fill

Site A: Bottle Fill Disposition

Site C:DS Receipt -> Fill -> Inspection -> Pack/Release

2014 BASELINE: ~E2E 300 (D)

~55D ~125D ~115D~5D

Site B: Thaw Ship

Site A: Vial Thaw Bottle Fill

Site C: DS Receipt -> Release for fill

2015 DS FOCUS:

~E2E 220 (D)

~55D ~65D ~71D~5D

Site B: Thaw Ship

Site A: Disposition

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Site A: Vial Thaw Bottle Fill

2016 DP FOCUS: ~E2E 218 (D)

~55D ~65D ~69D~5D

Site B: Thaw Ship

Site A: Disposition

Site C: Fill -> Inspection -> Pack/Release

Site C: DS Receipt -> Release for fill

Site C: Fill -> Inspection -> Pack/Release

Development Runs (if needed):

At-scale upstream only

Provide cell culture process performance early and product quality comparison

− Harvest & purification at lab/pilot scale

Engineering Runs:

Full scale cGMP execution

Upstream, Downstream, Cryogenics processes

At-Scale demonstration of PPQ readiness

Process Performance Qualifications (PPQ) Runs:

Process consistency and capability to meet In-Process Control (IPC) plan defined ranges

Consistency & Conformance: Demonstration that the process and equipment yield a robust and controllable process

Regulatory Submission:

File multiproduct requiring a post-approval submission (PAS)

Development Run (N=1)

Multi-Tiered Approach

Engineering Runs (N=4)

PPQ Campaign (N=8)

Regulatory Submissions

TECH TRANSFER

5x Scale-Up

Challenging facility configuration due to previous product- Concerns about cell culture performance- Must maintain CQA profile!

BMS USP-only Dev Run

Engineering Run .. n

PPQ Run(s)

TypicalDevelopment

RunEngineering

RunPPQ

Run(s)Analytics Analytics

Pilot Centrifuge

Engineering Run 1

Highly compressed timeline, mitigated risk via in-depth process understanding, robust analytics, process modeling and reliable scale-down/pilot models

Confirmed upstream performance while allowing recipe implementation and operational readiness

Considerable reduction of facility downtime, minimized disruption to supply

Analytics

Analytics

TECH TRANSFER

Knowledge Transfer

Facility Fit

Risk Assessments

Process Operational Description

Speed toMarket

Increase Capacity/ Productivity

Develop People

OUR STRATEGIC IMPERATIVES

BIOLOGICS

Increase Capacity/ Productivity

Lean Labs1

Problem Statement

2015+2012

Analysts dedicated to techniques/Testing Activity =Long Cycle times

Small Testing Groups = Poor Lead-times

Poor Right First Time

Poor Layout & Flow excessive space with poor testing flow =TIMWOODI (Waste)

2013 2014

Engaged & Empowered Workforce

Increased Capability >30%

Reduced Deviations >40%

Predictable, Optimized Cycle Times

Cost Savings 645,000 Euros

Improved Customer Service (PRA 90%)

Shared Learnings

Collaboration Capacity Demand Tool

Visual Management &

Huddles 5S & VMI

CapabilityReview

Start Point Results

Levelling, Flow & Standard Work

Flexible Workforce

Waste Elimination

Data Collection

Develop Business

Case

Approve Business

Case

Business Case

Work-streams

IdentifiedLevelling Review

Standard Work Plans

Capability Review

Build Capability

Layout & Consumable Assessment

Merge Workstreams

Visual Management

OPEX Capability

Development Paths

Layout Changes

VMI Solution

Leader Standard

Work

DataReview

Yellow Belts

2014 Silver Recognition

BETTER PRACTICE: PILOT SITE RECOGNIZED BY PEX

LEAN LAB RESULTS ACROSS GMS

API Site DS Site DP Site

Results: decreased deviations, increased capacity, and cost savings

Engaged & Empowered Workforce

Increased Capability >30%

Reduced Deviations >40%

Predictable, Optimized Cycle Times

Cost Savings 645,000 Euros

Improved Customer Service (PRA 90%)

Shared Learnings

AreaProductivity Gains

By Analyst

Microbiological Control 60%

Chemistry 19%

In-Process 50%

Bioseparations 148%

Bioanalytics 61%

Cycle Time ReductionProduct A: 25%Product B: 63%

Productivity Increase:Product A: 62%Product B: 44%Product C: 40%

Levelled Work for Analysts;Issues are discussed daily;More analyst engagement & commitment to schedule

Increased visibility in the work in Queue and overall performance of the lab

Speed toMarket

Increase Capacity/ Productivity

Develop People

OUR STRATEGIC IMPERATIVES

BIOLOGICS

Develop People

Re-Training1

INNOVATIVE APPROACHES FOR BIOLOGICS RE-TRAINING

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Selected top talent from API plant that was retooling for biologics Partnered with National Institute of

Bioprocess Research and Training (NIBRT) to create state of the art development for like facility

Developed expertise in LSCC and CMB

Win for our employees and for BMS

PRESENT AND FUTURE

Continuous learning and application of Lean techniques, tools and talentsCan be deployed to your focused priorities with real resultsNeed to integrate innovation into business, manufacturing and analytical processesCore skilled team to train practitioners

QUESTIONS?

26BMS Internal