Intelligent (Smart) Facility –Mab Production Revolution

Shanghai, June 13, 2017Jing Zhou / Guangzhou Mab-Venture

Topics to Explore

• New Industrial Revolution -Manufacturing 4.0

• Biopharm Industrial Trends• Challenging • Lean Process• PAT -Implementation of QbD• SU & SS• Smart/Intelligent

Manufacturing• Smart Integration of Hardware

and Software

• Large vs. Small

• Time vs. Space

• Live vs. Dead

• JIT vs. Large Storage

• Manual vs. Fully Automated

• Machine vs. People

• SS (Operation) vsEnvironmental

• Innovation vs. Operation

Be Competitive under the Bottom Line

Earning = Revenue - Cost

Unit Price by Product or Service

Success Rate

COGS

Under Quality control

Quality System

Quantities of Products or Services

BDPDR&D

cGXP Control Environment/ Qualified People

Industry 4.0 —From Smart Factory to Smart Production

Time

Complexity

Industry 1.01784

Industry 2.0

Early 20th Century

Widely Used Electric Power

Steam Engine

Industry 3.0

Electronic、IT、Robotics

Industry 4.0

Internet Of Things

What is Smart Factory?

• “A Smart Factory is a Manufacturing Solution That Provides such FLEXIBLE and ADAPTIVE production process that will solve problems arising on the production facility with dynamic and rapidly changing boundary conditions in the world of increasing complexity.”

• “This special solution could on one hand be related to automation, understood as a combination of software, hardware, and /or mechanics, which should lead to OPTIMIZATION of manufacturing resulting in reduction of unnecessary labor and waste of resource.”

• “On the other had, it could be seen in the perspective of COLLABORATION between different industrial and nonindustrial partners, where the smartness comes from forming a dynamic organization.”

Benefits of Smart Factory

By developing cyber – physical system, and therefore their implementation in smart factories, significant improvements in production systems will be reflected in the form of Robustness at all levels:

•Self organized•Self maintenance •Self refurbishment •Security •Remote diagnosis

•Control in real time •Autonomous management •Transparency •Predictability•Effectiveness •Efficiency

Automation Pyramid

Smart Factory Characters

• Smart Factory Equip needs to be Modularized and Smart：

– Modular System Structure to allow quick and flexible adaption to process/production requirements

– Expandability to allow insert the new Production Module through seamless integration

– Open Platform to allow universal connections for mechanical, Electrical, communication etc. to allow the compatibility of various vendors ;

– Smart parts, each components will have its own Identification number to be monitored through RFID technology

– Continuous Process & on-line Process Monitoring and control through PAT technology etc

– Optimization of Capital Investment & Operational Expense

– Upstream Trend

Expression Rate Enhancement

Perfusion Process

Fed-batch Operation

Depth Filtration Adoption

– Downstream Trend

Resin Binding Rate Increase

Combo-Column to reduce the purification steps

Semi-continued / continuous process

In-line dilution process

– Fill & Finish

Isolation Technology with C background

– Single Use/ Hybrid / SS

– Smart Factory

Biopharm Manufacturing Trends

Manufacturing Steps

Media

Cell Culture

Buffers

Bulk Product(5-20 kg)

PRIMARY

MANUFACTURE

SECONDARY

MANUFACTURE

PACKAGING

Excipients

Mixing

Formulation

Filling

(Dosage Form)

Packaging

Saleable

Product

Harvest/Purification

Fed-batch or

Perfusion

Clarification

Protein A

AIEXPCC

CEXPCC

Virus Inactivation

Nanofiltration

UF/DF

Typical Mab BioProcess Steps

Levels of Biological Product Protection

Degree of Risk3

2

1

Deg

ree

of E

xpos

ure

Facility Flexibility

Single

Product

Multi-Product

Dedicated

Equipment

Multi-Product

Multi-Use

Equipment

Clo

sed

Inte

rmitt

ent

Exp

osur

e

Exp

osed

Traditional 传统 Single Use 一次性使用

Capital Investment vs. Operating Expense

• Operation by Campaigns批次运营

• Multiple Products多品种

• Smaller Quantities小批量

• Year around Operation

常年运营• Single Product 单一产品

• Larger Quantities大批量

Hybrid 混合型

Critical Construction Issues

Constructability

Health

&

Safety

Planning

&

Control

Finishes,

Finishing & ValidationEfficiency

Intelligent (Smart)

Factory

Tracebility

Cost Control

Risk Management

Quality

Chain

Management /

Communications

Flexibility/Adaptability/Expandability

Safety/Security

LEAN

Life Cycle Drug Development

PRECLINICAL TESTING Laboratory animals

Development Chemistry Laboratory

‘KiloLaboratory’

PilotPlant Production

CLINICAL PHASE 3

Patients(large group)

PRODUCT LAUNCHRESEARCH

DISCOVERY & PATENT

CLINICAL PHASE 2

Patients(small group)

CLINICAL PHASE 1

Healthy volunteers

REMAINING PATENT PERIOD

4 - 10 YEARS 3 - 6 YEARS 9 - 12 YEARS

batches of material ranging from grams to tonnes

PRODUCT

A

B

C

D

E

F

G

H

Lean Development for Capable Processes

Preclinical

Testing

File

IND at

FDA

Phase I Phase II Phase III File

NDA at

FDA

FDA PRODUCTION

Robust “Designed for Manufacture” process minimises scale up and gives fastest possible production start up.

Early “Design for Manufacture” process development gives fastest possible production of clinical trials material.

Maximum Life Cycle Cost

Savings

URS – Road Map for QbD implementation

URS

Product Development

Process Development

Facility Design

IQ, OQ

Development Implementation

Process Validation

ProductManufacturing

Regulations

Quality Product

PAT

PATTechnology

• Utilization of process and unit operation modeling software packages

• Specification and implementation of proven on-line analyzers to replace outdated off-line methods

• Implementation of Statistical Process Control methods related to PLC and DCS systems

• Use of statistical analysis to pinpoint critical quality attributes

• Utilization of risk assessment methods to evaluate potential process changes

• Process improvement studies such as FMEA analysis of automated process systems

PAT

医药工业界

变量输入 固定工艺 变动的最终产品

变量输入 可调工艺一致的最终产产品

将质量建立于工艺过程而非产品的质量检验!

现有之典范规则

未来 PAT典范规则

典范规则之转移

• PAT -强调对工艺了解的重要性

– 以助基于风险的审批决定和闯新

– 用合适的手段进行风险认知,管理,及控制

• 以工艺检测仪表现场测量及控制物质的物理与化学属性，以达到现时报告的目的．

• 在产品周期内，提高对该产品知识及其工艺开发知识的利用

• 一设计，分析，控制生产的体系．该体系通过现场测量原材料，生产中物料，及其工艺流程的关键质量和性能，

而达到保证最终产品质量的目的．

PAT – 完成QbD的工具

CONTROLLED PROCESS

Constantoutput

Control Strategy

Feed forw ard Feed back

Variableinput

Raw materials

I n-process

m aterial

Environm ent

Process Param eters

Real-t ime qualit ym easurem ent( Real-t ime-release)

End-product testing

Adaptable process

Product/Process Development

Process Validation/PPQ

Ongoing/Continued Process Verification

Develop Control

Strategy based

on Product

Quality

Attributes

Demonstrate

effectiveness of

control and

establish

variability in

commercial

manufacture

Monitor process

performance and

variability during

product life-cycle

THESE ACTIVITIES CHARACTERISE RISK TO A PATIENT

CRITICALITY LIKELIHOOD DETECTABILITYX X

ALIGNMENT OF PV APPROACH

Relationship Among QbD, ASTM, and PAT

QbI QbD

Inspection/Outcome Control/Process

Just-in-timeAfter Fact

PATReal time analysis

Raw materialIntermediates

Final ProductFinal Product

ASTM 2500ImplementationSMEGEP

Root Cause Analysis

Trend

Product Life Cycle Quality & Risk Control

Product Development

ProcessDevelopment

ProcessScale-up &

Tech Transfer Manufacturing

Risk Control

Product Quality Control Strategy

Process Understanding

Risk Assessment

Process DesignSpace

Product Knowledge

Risk Assessment

Product DesignSpace

Risk Control

Product Quality Control

ImplementationBest Available

Technology

Understanding Implementation

Risk Review

Ris

kC

om

mu

nic

ati

on

Risk Assessment

Risk Evaluationunacceptable

Risk Control

Risk Analysis

Risk Reduction

Risk Identification

Review Events

Risk Acceptance

InitiateQuality Risk Management Process

Output / Result of theQuality Risk Management Process

Ris

kM

an

a ge

me n

tto

ols

ICH Q9 Quality Risk Management

ICH Q9 质量风险管理

Process understanding

Formulation & Process design

Process control Concept

Product release Concept

Review the submission

Regulatory strategy

Manufacturing Concept

The Quality Risk Mmanagement Process

Five Steps:

1. Initiation

2. Risk AssessmentRisk Identification

Risk Analysis

Risk Evaluation

3. Risk ControlRisk Reduction

Risk Acceptance

4. Output/Result

5. Risk ReviewReview Events

Risk Assessment Fundamentals•What could go wrong?•What are the consequences (severity)?•What is the likelihood (probability) it

will go wrong?ay f•ocus on thQuestions:•Is the risk above an acceptable level?•What can be done to reduce or eliminate risk?•If the risk were to be controlled, what is the appropriate balance among benefits, risk, and resources?•Are new risk introduces as a identified risks being controlled?

Risk Control

Activities for controlling risk (numbered by priority):

• Elimination by design

• Reduction to acceptable level

• Further risk analysis

Typical Control Hierarchy

Biopharmaceutical ManufacturingAutomated Controls and Monitoring Systems

Typical Scheme for Supporting GMP Unit Operations

BMSNon-Validated

EMSValidated

Data HistorianValidated

HVAC ControlsValidated

CleanroomsTrending and alarms for:ΔP, T, %RH)WarehouseRaw MaterialsFinished Product

HVACAHU BlowerAnd Damper Controls

Plant UtilitiesAlarms for:BoilersChillersWaste NeutElectrical GenFire ProtectionWater StorageUtility SupplyNatural GasElectricalWater

Process EquipmentBioreactorsChromatography

BMSValidated

Process UtilitiesAlarms for:WFI/PW/PSCIPCDAProcess GlycolNitrogenOxygenCold RoomsFreezersIncubators

Smart Integration – Bottom up Vision: Facility

harmonizationSmartMESFlexible,

powerful MES

SmartSystemsUniversal or

SmartSwitch

Controllers

SmartPartsIntelligent

Components

SmartPartsTrue plug and play components

Automation platform independence

Distributed Control

Enhanced performance (dynamic range, precision)

Reduced cost

Managed complexity

Plug & Play

SmartMFC SmartTxSmartPump

SmartSystems: Universal Controllers

Universal Controllers

can adapt to ANY

bioreactor from ANY

vendor

Full line of controllers for

any vessel type or size

designed for rapid

scale-up and process

transfer

Universal Controller Concept

Finesse G3 Controller Family (Upstream)

SmartSystems Enable Customer Choice

“One controller fits all”

Separate measurement /

automation layer from

physical skid

Skid is defined by vendor

Interface example: agitation,

weight (load cells), TCU

Physical skid vs Controller

Enable user process using

multiple vendor skids

Facilitates scale-up/down

and mix-and-match of skids

Defined by automation

USP available now; DSP

available

Seamless Integration

Seamless control of process skids from any vendor

Clinical Trial Manufacturing

21

Development Pre-Clinical

G3FlexModular & Customizable

cGMP, Any vessel type/size

Engineer to order

G3Lab UniversalR&D, small scale

Configure to order

G3Lite/G3 ProPilot through cGMP, large scale

Configure to order

SmartVessel

(3,15L)

SmartGlass (1, 3, 7, 15L)

Universal Controllers

Universal controllers = flexible usage

Single-Use Bioreactors

(up to 250L with VAB)

SmartRocker

(10, 20, 50L)

G3Lab Universal Controller

BioProcessing Flexibility Across Platforms & Brands

Universal Controllers

Control any bioreactor in your process train1

ATMI

2%2

Thermo Fisher

SUB/SUF

84%2

Merck Millipore

7%2

Sartorius

1%2

Xcellerex

6%2

Notes: 1) Not limited to current bioreactor generations; 2) Percent of 2016 cumulative bioreactor installations

Universal Controller: 30–2000L

SmartSystems: Universal SoftwareUniversal Software Network for Upstream and Downstream

A cost effective Control platform

DeltaV Network

Operator

Station

Professional Plus

Station

Finesse T300 Controller for Glass and SmartRocker

DV Controller

Application Station and

Historian

TruBio native interface = control and monitor any Finesse or DeltaV equipment

One common user interface with remote capability

Unified process recipe + off-line analytics database

26

DeltaV Software and Network

TruBio, TruPur and TruChrom

Cost effective DeltaV licensing

Both native DeltaV and SCADA versions

Modbus comms standard (lowest DST)

Fieldbus, Profibus or DeviceNet available

TruBio/TruPur/TruChrom features

Commercial Off The Shelf (COTS)

Highly configurable and expandable

Sophisticated control algorithms

Parameter update in real-time

Sensor redundancy and calibration

Plant LAN

Third Party Controllers: Sartorius/Applikon upstream or Palll/GE downstream

OP

C

OP

C

Analyzers: Nova 100, 300, 400, BioProfile Flex

Any OPC

Compliant

Instruments/Equip

ment

TruBio SCADA interface = control and monitor any OPC Compliant equipment

OPC

SERVER

Downstream HarmonizationPhase 0: OPC connection

Phase 1: SmartSwitchPhase 2: Universal Controllers

DeltaV Network (Dedicated, redundant process LAN)

Plant LAN

OperatorStation

Professional Plus Station

Application Station andHistorian

DV Controller

OPC

ClarificationChromatography

(Affinity/CEX/AEX)

Virus RemovalUltra-filtration Sterile filtration

OPC OPC OPC

Centrifugation Filtration

nativeOPC

BufferPrep

native native native nativenativeOPCnativenative

New Capabilities for the BPD Workflow

Upstream Downstream

Cell line development

and media

optimization

Mixing, cell culture and

fermentationHarvest and collection Purification

Bulk storage and final

fill

Mycoplasma and viral detection

QC and analysis

Freedom™ CHO

cell lines

Process development and

media optimization services

Gibco™ cell culture media,

feeds, and enhancers

Single-use fermentors,

bioreactors and mixers

BioProcess containers

inSITE™ Integrity

Testing System

POROS™ harvest and

separation products

Storage and transport

POROS™ chromatography

resins

CaptureSelect™ affinity

ligands and resins

Transfer assemblies

Host cell DNA, protein and

protein A quantitation

Storage and transport

BPCs, manifolds and

containers

Acclimate™ single-usefrozen handling system

Cell factories

Large volume liquids

Large volume liquids

Shaker flasks and rigid

containment

Production chemicalsGMP warehousing, sampling and lot control

Sensors

Lab-scale Controllers

Lab-scale BioreactorsDS Controllers/Skids

Software (TruChrom)

Controllers

Software (TruBio)

Sensors

SmartFactory

Pump Tower Skids

Software

US Controllers/Skids

Software (TruPur)

Sensors

Software (TruBio)

LegendGrey text: Legacy BPD capabilities

Red text: Finesse expanded capabilities

GMP Facility

Our under-construction “SMART”

cGMP manufacturing facility at

Guangzhou Bio Island, generates

Mab materials for clinical trials &

commercial launch.

Multiple Product Lines

Facility for Future

Maximum Flexibility,

Adaptability, and Expandability

Global Compliance

Our Platform – cGMP SmartFactory

• Fit for purpose – In Line With Corporate Strategy

• Continuous/Lean Process

• Smart Facility/ Smart Modulars/ Smart Parts

• Smart Team/ Smart People

• Smart System Compliant With Regulations

• Smart Execution

• Smart Operation is the Competitive Advantages

Summary