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Applying New Biologic Manufacturing Technologies Anthony Mire-Sluis Vice President, North America, Singapore, Abingdon, Contract and Product Quality

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Page 1: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Applying New Biologic Manufacturing Technologies

Anthony Mire-Sluis

Vice President, North America, Singapore, Abingdon, Contract and

Product Quality

Page 2: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Investing in New Manufacturing Technologies is Benefiting Production, Compliance and Our Ability to Deliver and Supply Products More Efficiently

• Enable speed to market (R&D and Operations)• Similar Scale and Platform Throughout Develop Cycle

• Reduce capital investment• Smaller Facility, Reconfigurable and Modular Design requires

less capital investment and match of capacity to current need

• Enhance compliance through standardization and application of technology• Rapid and in-line testing provides more real time process data

and control

• New Manufacturing technologies provide robust controls

2

Page 3: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Advances in Manufacturing Have Enabled Quantum Improvements in Operating Performance

Up to 15 fold greater protein output

per unit volume

Key Technical Advances Operational Benefits

Enables smaller bioreactors for same

output (2,000 Liters vs. 20,000 Liters)

Portable equipment and disposable

technology

Eliminates infrastructure for cleaning

and sterilization and ~45 miles of pipes

Standardized, modular, flexible

design

Simplifies changeovers between

molecules (from one week to one day)

Continuous downstream protein

processing steps

Fewer intermediate steps, less

equipment, and faster cycle times

Real-time quality control Real time detection and response ability

We believe we are the first major Biotech to integrate these features into a single commercial facility

Page 4: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

New Manufacturing Platform Delivers the Same Productivity With 75% Less Size

Singapore

Facility

QC Lab

Mechanical

Support

Manufacturing

Utilities

Warehouse

Admin and

Amenities

Amgen Rhode Island750k sq ft ~$1,000M

Amgen Singapore 170k sq ft ~$200M

~75% size reduction

4

Page 5: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Manufacturing Advances Have Dramatic Environmental Sustainability Impact

• Site energy consumption and waste generation is strongly affected by WFI usage

• Reducing cleaning surfaces by >95% reduces water for cleaning

• More efficient processes use smaller vessels and require less water

• Smaller, more efficient site with fewer staff uses less resources overall

• Compared to traditional stainless steel facility of same output:

• 4-5 fold reduction in carbon emissions

• 25 fold reduction in waste water generation

• >50% reduction in total solid waste generation (process + staff)

Page 6: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Our Newest Facility In Singapore is a Reconfigurable Manufacturing Facility

• First commercial facility to employ new manufacturing platform

• Reconfigurable Manufacturing System (RMS)

• Integration of multiple technology platforms

• One building for all site operations and support

• Manufacturing

• Controlled temperature warehouse

• Administration

• Quality control and microbiology laboratories

• Clean utilities

• Facility was built in <18 months

Page 7: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Amgen’s Reconfigurable Manufacturing System is Basis for Facility Design

• High productivity in smaller reactor vessels

• New cell lines highly productive

• New media addition equipment allows for high cell density

• Substantially reduced footprint

• High utilization of single-use equipment

• Single use bioreactors (SUBs)

• Solution preparation in single use mixers

• 95% of the product contact surface is single use

• Connected/continuous purification processing

• Process advances directly to subsequent step

• Elimination of pool vessels between unit operations

Page 8: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Transforming the Mammalian Network Accelerates Commercialization and Reduces Product Approval Risk

Cu

rren

t

pilot plant clinical plant commercial plant

pilot plant commercial plant

Mo

F

CommercialClinical

(Phase 3)

FIH

TOX

Commercial

Process

Development

(CPD)Clinical

(Phase 1/2)

FIH

2KL

2KL 2KL 2KL

20KL

2KL

Clinical (Phase 1-3)

& CommercialTOX

Technology Transfer

TT

Titer < 5 g/L

Titer 20 g/L

(Dmab)

>5 Bioreactors

4-6 Bioreactors

TTTTTT

CommercialClinical

(Phase 3)

FIH

TOX

Commercial

Process

Development

(CPD)Clinical

(Phase 1/2)

FIH

2KL

2KL 2KL 2KL

20KL

2KL

Clinical (Phase 1-3)

& CommercialTOX

Technology Transfer

TT

Titer < 5 g/L

Titer 20 g/L

(Dmab)

>5 Bioreactors

4-6 Bioreactors

TTTTTT

FIH

Tox

Early

PD

8

Page 9: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Amgen Singapore Facility Differs from Conventional Design in Specific Ways

• Central manufacturing suite

• Cell culture through viral filtration

• Closed cell culture (aseptic connections)

• Closed harvest system

• Reduced personnel and maintenance activities

• Area classification

• Closed Processing Systems allow for most operations to occur in an ISO 9 central manufacturing suite

• In-line testing and rapid microbial methods allow for enhanced process control and detection and response to potential quality issues

Page 10: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Bioreactor

operations

Harvest

Operations

Column

chroma-

tography

and viral

inactivation

Na

no

filtra

tion

Inoculu

mP

rep

UF/DF

DS Fill

The Closed Processing Controls Negate the Need for Conventional Physically Segregation of Cell Culture, Harvest, and Purification

Purification Operations:

• CIP and SIP to render

closed

Harvest:

• rotating mechanical

equipment, cell debris

Bioreactor Operations:

• CIP and SIP to render

closed

Single use and sterile connection technology provides for superior segregation and contamination controls

Page 11: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Facility Design and Operation Mitigates Risk of Product Contamination

• Closed operations

• Aseptic connectors or aseptic tube weld

• Gamma-irradiated components and tubing

• No process transfer piping

• Concurrent cell culture, campaign harvest and purification

• Faster production cycles, reduced hold times

• Single-use equipment

• No process transfer piping

• No stainless steel hold tanks or reactors in central suite

• 95% reduction in surface area requiring cleaning

Page 12: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Examples of Sterile Connections

Aseptic Connectors

Tubing Weld

Page 13: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

FVIP Feed

Column 1 Column 2

Viral Filtration

UF/DF

Surge Tank

P

Total Process

Time: ~10-14 hrs.

Overall Time

with Cleaning

FT – Viral Filtration

Ultrafiltration

Diafiltration

Connected Purification Process Reduces the Need for Large Hold Tanks

Page 14: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Design Controls Enable a Combined Solution Preparation Area

• Engineering controls to eliminate cross-contamination

• Solution mixing vessels in segregated alcoves

• HEPA filtered downflow above vessels

• Antistatic single use plastic powder transfer sleeves and connections to mixing vessels

• Mixing vessels are single use

• Gamma-irradiated single use vessels and tubing

Page 15: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

However, Single Use Systems (SUS) have created a complex supply chain

• A science- and risk-based approach is used to characterize raw materials

• It is critical to understand the underlying science with each technology in the supply chain to reduce the risk

• The science drives raw material specifications and change controls for suppliers

• Understanding the process and raw material inputs can control the risk of unexpected performance

• Working transparently with suppliers is key to risk mitigation

15

Page 16: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

What are we doing to understand the risk profile for single use plastic technologies?

Elements of the Risk profile includes:

• Supply Chain • On-site technical due diligence visit to supply chain

• Build relationships with key technical personnel at supplier

• On-going Technical group exchanges

• Industry competitive intelligence

• Raw Material Characterization and Biological Impact • Review of supplier validation technical package

• Characterization studies to link variability for form, fit and function

• Extractables and Leachables with model solvents

• Raw Material Qualification • Correlate raw material variability to process parameters

• Finalize raw material specifications based on process variability

• Continuous monitoring / verification of performance• Correlate supplier process variability to film performance

• Establish quality control testing to insure consistent performance

For Internal Use Only. Amgen Confidential.

16

Page 17: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

17

System Complexity

Low Moderate High

Imp

ac

t to

pro

cess

Low Buffer Storage ConcentrationClarification

Recovery

Moderate Transport

Shipping

Mixing Cell Culture

Fermentation

High Freeze

Thaw

Fill and Finish Purification

Product Storage

An understanding of three key areas is required:

1. Supply chain and manufacturing process

2. Material characterization and biological impact

3. Continuous monitoring / verification of performance

The level of understanding will depend on risk and application

Page 18: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

What are we doing to understand the risk for integrity of the bioreactor bags?.....

• Key levers for impact :

• Variability in film

• Variability in the welding process

• Strength of weld

• Bag design

• What is the variability of each stage (lot-to-lot)?

• What incoming, in line and release testing is used?

• Benchmark bag handling techniques

• Can we predict “good” and “ bad” bags?

18

Page 19: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

19

POLYMERS

Monomers

Catalysts

Additives

CONVERTING

Molding

Extrusion

Casting

ASSEMBLY

Welding

Mechanical

STERILIZATION

Gamma

E-beam

PACKAING

SHIPPING

Boxes

Bins

Shippers

The disposable supply chain for single use systems is complicated

Each step can impact the quality, cost, and performance of the product

Establishing transparency and a change control process is critical to reducing

the risk profile

Page 20: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Polymer Morphology is a function of the equipment and process used to extrude the film…..

20

Processing Equipment determines polymer morphology of the film surface and the

levels of extractables remaining in the film

Blown Film Process

Page 21: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Process control is critical to producing quality film….

21

Feed

Moisture content

Rate

Bulk Density

Weighing accuracy

Polymer Formulation

Extruder

Screw design

Wear

Temp Profile

Temp Control

Screw speed

Backpressure

Die/Air ring

Design

Temperature

Bubble

Blow up ratio

Freeze zone

Guage

Temperature

Winding

Temperature

Gauge

Rate

Blocking

Collapse

Temperature

Gauge

Black specs

Page 22: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Films and leachables can impact processes in various ways

• Impact on other process steps

• Small concentrations of preservatives can interact with silicone tubing, depressing filter bubble points

• USP Class VI testing is NOT representative of cell culture requirements

• Consider impact of films on media and SUS performance

• Impact on cholesterol dependent cells

• Impact of multiple passages

• Users have reported sensitivity of certain cell lines to certain films

• We have made similar observations for bags used for media holds

22

Page 23: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Raw Materials Drug Substance

Process

Labs (release and

in-process)

Drug Product

Process

Cold Chain

Management

Advances in Analytical Technology Are Providing Opportunities for PAT Improvement Across the Manufacturing Process

• Process Analytical Technologies are “a system for designing, analyzing, and controlling manufacturing through timely measurements…with the goal of ensuring final product quality.”

PAT includes data acquisition and application from raw

materials to patient delivery

Page 24: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Traditional Paradigms for QC Testing Limit Real-time, Data-driven Decisions and Impact Disposition Cycle Time

Workflow

Analytical cycle time limits information availability for real-time decisions

Incoming QA/Manufacturing

SamplingChain of Custody

QC TestingElectronic Systems

Data for Decision

Page 25: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

MoF analytical and testing strategy is to move Product Testing On Line/At Line

HPLC

Cap. electro.

Identity bioassays

Host cell protein

ProA ELISA

Host cell DNA

MMV DNA qPCR

Color, app., clarity

Osmolality

pH/conductivity

UV concentration

Potency

Bioburden/endotoxin

Bioreactor analysis

UV concentration

Light scattering

Bioburden

Endotoxin

pH/conductivity

Color/Clarity

Bioreactor analysis

UV concentration

Light scattering

Bioburden

Endotoxin

pH/conductivity

Color/Clarity

Appearance

Current Near Future Future

Rapid UHPLC

Appearance

Cap. electro.

Identity bioassays

Myco./MMV qPCR

Mass Spec

Rapid UHPLC

Myco./MMV qPCR

QC/Micro Lab

Automation

At-line

Page 26: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Handheld Technology can be used for Raw Materials and Cell Culture Medias

Raw

Material

ID

Release RM

for Process

Raman

Supplier:

SRE Program (i.e.

implement Raman for

certain raw materials)

A

BC

MVA Analysis to increase RM

understanding

A. Single Outlier - Troubleshoot

B. Clustering – Sudden Change

C. Drifting – Gradual Change Over Time

Part of RM Info Mgmt (RMIM) Initiative

Verifies RM

Doc,

Appearance &

Container

Integrity

Incoming

Raw Material

Spectra

NIR

RMIS:

Spectral and

eCoA data

storage

RMIM

AAA, bench-top NIR or FTIR

Analysis

Duration: < 1 hour

Duration: 0.5 to 3 days

Pass Fail

Legend:

Current Process

Proposed Process

Raman

OR OR

Passing

ID

Page 27: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

• Comparison of UV 20% peak max and on-lineMALS triggers for peak pooling, assessment of resulting product quality by off-line SEC

• Different elution profiles from lot to lot affectproduct quality due to variable HMWS in tail

• On-line MALS detector provides predictivemeasure and better control of product quality

Process Analytical Technology Provides for Better Control During Purification

On-line MALS Detection for HMWS Control

Real-time data for peak pooling improves product consistency

0

2

4

6

8

10

%HMWSSEC

Elution Volume, mL

100 110 120 130 140 150 160 170

142

144

146

148

150

152

154

156

158

kDaMALS

400

600

800

1000

mAUUV

200

Lot 1Lot 2

0

0

1

2

3

4

5

6

7

Lot 1 Lot 2

%H

MW

S

20% Peak Max trigger

MALS trigger

0

2

4

6

8

10

%HMWSSEC

Elution Volume, mL

100 110 120 130 140 150 160 170

142

144

146

148

150

152

154

156

158

kDaMALS

400

600

800

1000

mAUUV

200

Lot 1Lot 2

00

2

4

6

8

10

%HMWSSEC

Elution Volume, mL

100 110 120 130 140 150 160 170

142

144

146

148

150

152

154

156

158

kDaMALS

400

600

800

1000

mAUUV

200

Lot 1Lot 2

0

HMWS

Page 28: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Implications of PAT Strategy for Manufacturing

• Integration of operational quality control with manufacturing

• Facility design should allow for at-line testing

• Production testing personnel should integrate into manufacturing organization

• Scaling data-based decision making capabilities

• PAT will increase relevant, actionable data acquired

• Facility staff needs

• Increasing real time quality assurance on the floor

• Flexibility to accommodate both current and future molecules

Page 29: Applying New Biologic Manufacturing Technologies...QC Lab Mechanical Support Manufacturing Utilities Warehouse Admin and Amenities Amgen Rhode Island 750k sq ft ~$1,000M Amgen Singapore

Thank You!