Risk Assessment - Design of Single Use Mfg. Facilities ... · PDF filegowning rooms, support areas, ... • Fully scalable single use downstream processing ... Design of Single Use

Risk Assessment and Quality by Design (QbD) for Single Use Mfg. es g (Qb ) o S g e Use gFacilities

Applying risk assessment and QbD principles to design the ideal operation

IntroductionIntroduction• What is a facility design “process”

Wh t i id l bi f t i f ilit ?• What is your ideal biomanufacturing facility?

• What is Quality by Design (QbD) for mfg. facilities?

• Why a risk assessment leads to a Quality by design Facility

• Risk assessment of logistics flexibility vs product risk –

• Risk of logistics bottlenecks

• Risk of spills and product loss

• Risk of mfg. capacity loss

• Conclusions

2

BioMfg Facility Design ProcessBioMfg. Facility Design Process

Ideal facility theIdeal facility attributes, capabilities

the dream…

Risk Assessment of potential facility

The planning…potential facility

designs

“Quality by Design” Facility

The result !

3

Facility

What would your ideal Single Use (SU)What would your ideal Single Use (SU) biomanufacturing operation look like?

Robust and reproducible process

Maximize product quality

Operationally efficient process.

Maximum personal safetyMaximum personal safety.

Low capital cost and operating cost.

Fast start-up and changeover.

Adaptable for other uses/multi-products

4

p p

Why conduct a risk assessment for theWhy conduct a risk assessment for the design of your SU mfg. facility?• It can ensure and even increase product qualityIt can ensure and even increase product quality

• It can help avoid logistics bottlenecks

• It can increase facility production capacity RiskIt can increase facility production capacity

• It can save many millions of capital $

• It can save many millions of operating $

Risk Assessment leads to a better • It can save many millions of operating $

• It can avoid “rework” of the facility to fix problems

• It can help avoid project delays

Quality by Designresult

• It can help avoid project delays

• It can reduce overall project risk

• It f ilit t i FDA/EMA i ti

5

• It can facilitate passing FDA/EMA inspections

Key points of a SU facility risk assessmentKey points of a SU facility risk assessment• Mfg. technologies used

• Flexibility neededFlexibility needed

• (types of drugs, scale, expansion)

• Biosafety level

Logistics planning

Sizing of halls• Clinical or commercial production

• Mfg. capacity needs

• Process flow and people flow

Sizing of halls, gowning rooms, support areas, warehouse• Process flow and people flow

• Materials/capacity flow :

• Raw Materials (carry in, carry out)

warehouse

Functional adjacencies

• Wastes flow (carry out)

• Disposables flow (carry in, carry out)

Utiliti ( i )

j

Space relationships

6

• Utilities (some carry in)

• Cross contamination prevention

What is Quality by Design (QbD)?What is Quality by Design (QbD)?Historically:

• “QbD” is the approach to build quality into the mfg process• QbD is the approach to build quality into the mfg. process

• by studying the performance of the process to establish “process understanding”

• generate data, ranges for critical parameters: “design space” to run the process

• “QbD” practices are recommended by FDA and EMA:

• for “process understanding” and to establish the process “design space”p g p g p

• could reduce process validation burden

7

Extension of QbD Principles beyond “process”Extension of QbD Principles beyond process

• Extending the “QbD” concept to Equipment, Facilities, Operations and Regulatory:

Holistic view of Mfg. Quality:

• Equipment quality: use disposables to eliminate cross contamination

• Facility quality: remove operator to improve environment quality

• Operations quality: operations testing, excellence, training, and support

• Regulatory quality: improved and more robust regulatory package/submission

8

Consider this holistic view of QbD:Consider this holistic view of QbD:

Successful QP x QE x QF x QO x QR

Biomanufacturing =

Total Cost

QP = Process Quality (process understanding)

QE = Equipment Quality (produces and protects product)

QF = Facility Quality (flows, environment controls, space)

QO = Operations Quality (capacity, success rate, logistics)

QR = Regulatory Quality (validation package, robustness)

9

Total Cost = Capital and Operating Cost

How do we optimize the QE equipment quality?How do we optimize the QE equipment quality?

• Employ single use equipment wherever possible

• Eliminate cross contamination potential

• Fully scalable single-use bioreactor... the “engine”engine

• Fully scalable single use downstream processing

• Open technology platform uses best-in-class• Open technology platform uses best-in-class downstream unit operations

• Open platform process automation technology to control and monitor processes

But: single use technologies create l h ll

10

logistics challenges!

PG1

Slide 10

PG1 you might want to show the storngarm automation interface a little larger, since it is a key part of our differentiationpgalliher, 5/3/2011

How do we optimize QF Facility Quality?How do we optimize QF Facility Quality?

• Environmental controls• Functional adjacencies• Logistics planning – carry in and carry out:• Materials/capacity flow :• Materials/capacity flow :

•Raw Materials (carry in, carry out)•Wastes flow (carry out)Di bl fl ( i t)

Logistics bottlenecks

•Disposables flow (carry in, carry out)•Utilities (some carry in)

• Product and capacity risk –p y• Cross contamination prevention • Loss of product during an excursion• Loss of production capacity during an excursion

11

• Loss of production capacity during an excursion

How do we optimize QO Operational QualityHow do we optimize QO Operational Quality

• Understand mfg. capacity needs

U d t d j t t• Understand project management

• Understand mfg. controls

• Understand GMP documentation

• Training and practice runs – practice makes perfect

• Working in partnership with smart customers

• sandbox, engineering runs

• Tox runs

• GMP runs

12

How to avoid conflicts in facility design –How to avoid conflicts in facility design logistics flexibility vs. product safety risk

Manufacturing in a closed system in an open CNC space:

• M t fl ibl l i ti i / t l i ti• Most flexible logistics – carry in/out logistics are very easy

• Highest product risk: high risk of catastrophic product loss in CNC suite

Manufacturing in a multiple clean room facility:

• Least flexible logistics: multiple clean rooms bottleneck carry in/out logistics

• Lowest product risk: multiple clean rooms segregate/protect product

13

Are flexibility and product risk mutually

Strategy 1Single-Use in Segregated

Are flexibility and product risk mutually exclusive?

Single Use in Segregated Clean Rooms• High quality, low risk• Logistical traffic jams

Spill compromises entire• Spill compromises entire clean room

Logistical Efficiency

1

14

Risk Reduction

PG2

Slide 14

PG2 yes, the "carry in/carry out" paradigm rules here. pgalliher, 5/3/2011

Are flexibility and product risk mutuallyStrategy 1Single-Use in Segregated Clean Rooms


Rooms• High quality• Logistical traffic jams• Spill compromises entire clean

room2


Strategy 2SU Closed process in gray space• Highly efficientHighly efficient• High risk of product loss• Spill compromises entire

facility

1

15

Risk Reduction




1 3

Single Use in Segregated Clean Rooms• High quality• Logistical traffic jams


Strategy 2Closed process in gray space• Highly efficient• High risk of catastrophic• High risk of catastrophic

failure

Strategy 3Single-Use, single suite

2g , g

Micro Environments• High quality• Efficient flows• Spill compromises single

16

Risk Reduction • Spill compromises single module

PG5

PG6

Slide 16

PG5 maybe a second graphic of the effect of a spill in a multiple clean roon facility would be helpful.pgalliher, 5/3/2011

PG6 "product risk" vs "safety"pgalliher, 5/3/2011

Are safety and efficiency mutually exclusive?Are safety and efficiency mutually exclusive?


1 3

Single Use in Segregated Clean Rooms• High quality• Logistical traffic jams


Strategy 2Single Use closed process in gray space• Highly efficientHighly efficient• High risk of catastrophic

failureStrategy 3

2 Single-Use, single suiteMicro Environments• Very low risk• Efficient flows

17

Product Risk Reduction

PG7

PG8

Slide 17

PG7 maybe a second graphic of the effect of a spill in a multiple clean roon facility would be helpful.pgalliher, 5/3/2011

PG8 "product risk" vs "safety"pgalliher, 5/3/2011

Are flexibility and product risk mutuallyAre flexibility and product risk mutually exclusive?Logistics bottlenecks in multiple clean room

MEDIA BUFFERg p

facility:

LABSU.S.P.

U.S.P.

LOCKERS/GOWNING

EQUIP.PREP

C.I.P./

D.S.P.

D.S.P. WAREHOUSEOFFICES

C.I.P./S.I.P.

WASH

PLANT UTILITIES

CLEAN UTILITIES

18

UTILITIESUTILITIES

Are flexibility and product risk mutually exclusive?exclusive?Micro-environment logistics-open facility suite:

LOCKERS/GOWNING LABS

FlexFactory

OFFICES WAREHOUSE

PLANT UTILITIES

19

PLANT UTILITIES

Single use (carry in-carry out) Logistics and

max

g ( y y ) gFlexibility

Single usel i ti llogistical efficiency

and FlexibilityFlexibility

100% closed CNC environment

Multiple CR suite facility

Mini cleanroom

min

20

environmentfacilityroomOpen facility


MEDIA BUFFER Spill/excursion

Are flexibility and product risk mutually exclusive?Capacity loss due to spills:

LABSU S PU S PLOCKERS/GOWNING

EQUIP.

pevent compromises 50% of line

p y p

LABSU.S.P.

U.S.P.

GOWNING PREP

C.I.P./S.I.P.

50% of line capacity

D.S.P.

D.S.P. WAREHOUSEOFFICES WASH

PLANT UTILITIES

CLEAN UTILITIES

21

Are flexibility and product risk mutually l iexclusive?

Capacity loss due to spills:

LOCKERS/GOWNING LABS

FlexFactory Spill/excursion event

icompromises 13% of line capacity

OFFICES WAREHOUSE

p y

22

PLANT UTILITIES

% product risk due to spill/excursion

highMicro-environments - safety in numbers

Operators in clean room

Operators NOT i l

Riskin clean room

low

100% closed CNC Multiple suite Mini clean

23

environmentp

facilityroomfacility

Achieving “safe efficiency”Achieving safe efficiency

• Upstream/downstream in shared spaceshared space

• CEMs provide clean environment for unit ops.p

• Operator removed from clean-room

• Eliminates multiple clean-rooms

• Cost space and logistics• Cost, space and logistics improvements

• Efficiency gains

24

PG3

Slide 24

PG3 labor reduction, gowing reduction, containment of spills (limited to one unit op)pgalliher, 5/3/2011

Applying operating knowledge to optimizeApplying operating knowledge to optimize facility design

• Platform is borne from • Platform is borne from years of hands-on use and experience

• Customers avoid learning hard lessons

’ l d l dwe’ve already learned

• Personnel, material and waste flows and waste flows optimized

25

Other strategies to enhance manage riskOther strategies to enhance manage risk and reduce cost

•BridgeSourcing

•SOP development and Training•SOP development and Training

•TransPlantTransPlant

•CMO partnerships

•Multi-Product manufacturing

26

PG4

Slide 26

PG4 why do we need "CMO partnerships" if you have "bridgesourcing"?

Maybe "bridgeSourcing" needs explanation?

what about engineering runs, regulatory support, PD, etc? see attached FF services deckpgalliher, 5/3/2011

The End-ResultThe End ResultGains from optimizing from a blank slat

FlexibilitySpeed yp

Less Risk EconomicsLess RiskHigher quality

Economics

27

The Xcellerex Solution

• Disposables

The Xcellerex SolutionFlexFactory Biomanufacturing Platform

• Disposables minimize cross contamination

• O t • Operators removed from clean room

A i f • Automation of quality assurance

• Minimal product Less Risk risk due to spillsLess Risk

Higher quality

28


• Open suite


Open suite, easiest logistics

• Compact clean room Flexibilityclean room architecture

• Modular

y

• Portable

• Multiple product manufacturingmanufacturing

• Ability to TransPlant™ to customer

29

customer

The Xcellerex SolutionThe Xcellerex SolutionFlexFactory Biomanufacturing Platform

Speed

• Faster carry in-carry out logisics

• Faster product pchangeovers

• Rapid expansion of mfg capacityg p y

• 6-18 months vs. 3-5 years for new capacityp y

30


f d


• Better mfg. and logistics labor efficiency

L l f • Less loss of production capacity due to excursion

• Lower capital cost (50%-75%)

L ti Economics• Lower operating costs (20%)

• Higher assettili ti

Economics

31

utilization

XDR Bioreactor/XDM Mixer installations >350 WWXDR Bioreactor/XDM Mixer installations >350 WW

32

FlexFactory ProjectsGermany

Denmark

y j

Netherlands

Switzerland

KoreaXcellerex

St. Louis

JapanRussiaPolandTexas

Australia

LOI or signed contracts

33

Pending

Xcellerex Strategic Rationale – QbD g QFlexFactory®

Dramatic improvements in mfg. quality, product protection

and SU logistics flexibility can be achieved with a fresh,

holistic comprehensive QbD approach to biomanufacturing

Equipment QbD

Facility QbD

Regulatory QbD

Services/Training QbD

34

Documents

Risk Assessment - Design of Single Use Mfg. Facilities ... · PDF filegowning rooms, support areas, ... • Fully scalable single use downstream processing ... Design of Single Use