selection off conttaiinmentt for fill-finish operations

Containment Forum - Milano November 15th-16th, 2006

Selection of containment Selection of containment

for fillfor fill--finish operationsfinish operations

Containment Forum Containment Forum –– Milano, November 15Milano, November 15thth--1616th th ,2006,2006

Containment from selection to implementation

FOSTER WHEELER ITALIANA FOSTER WHEELER ITALIANA –– Pharmaceutical Division, Milano Pharmaceutical Division, Milano

Germana Molinari

CONTAINMENT

Possible Solution

Personnel gowning

Working area confining

Main containment devices

Possible combinations

Containment connections

Containment isolator

C-RABS

Which combination?

Selection criteria

Decision trees

Case studies

C-RABS on a filling machine and containment isolator on freeze-driers loading/unloading system for the containment of a product, medium potent as liquid (with capability to

generate aerosol) and high potent as solid

C-RABS on a blistering machine to avoid cross-contamination for low potent products

C-RABS on a blistering machine for containment of a medium potent products

Transfer technology for high potent product in capsule department

Pharma scenario

isolationisolation

isolation & containmentisolation & containment

containmentcontainment

Containment

� cross-contamination

� high potent drug

� Containment needs

� very powdery operation

� not very powdery operation

� Product typology

� liquid with aerosol

� powder

� Possible requirement of aseptic process

Possible solutions

Separation between

PRODUCT / PERSONNEL / ENVIRONMENT

Proper combination of:

Working area containmentWorking area containment

&Personnel gowningPersonnel gowning

Possible solutions: personnel

GowningGowning: proper barrier between operator and exposed product

standard uniformstandard uniform “PPPS”“PPPS”sterile suitesterile suite

Possible solutions: working area

ContainmentContainment : : proper confining of activties

with exposed productexposed product

critical operation identification

proper containment device choice

Typical critical critical operations in fill&finish:

Injectables Facility

OSD Facility

liquid

aerosol

non aerosol

powder

freeze-dried

• Dispensing&formulation

• Filling

• Lyo unloading

• Dispensing

• Product transfer

• Tabletting/capsule filling

• Blistering/Bottle filling

(cont’d)

Typical critical working area “enclosure”

Dispensing

Formulation

Filling

Lyo unloading

(cont’d)

Clean RoomClean Room

Barrier TechnologyBarrier Technology

Isolator

OSD Facility

Dispensing

Tabletting/capsule filling

Blistering/Bottle Filling

(cont’d)

Clean RoomClean Room

Barrier TechnologyBarrier Technology

Isolator

Down crossDown cross

OSD Facility

(cont’d)

Closed Closed

process process Containment connectionsContainment connectionsTight closed Tight closed

containerscontainers

Standard Standard

butterfly valvebutterfly valve

Glove boxGlove box

Product transfer

Standard Standard

drumsdrums

linerliner

OpenOpen

processprocess

� Containment connections

� Containment isolator

� C-RABS

� Split valve

� High containment split valve

� RTP port

� Liner

Containment connections: split valves

� Simple operating principle

� Made up of two parts:

- active part sealed on the process equipment

- passive part sealed on the container

� Concept: once docked, the two parts then operate as one

disc and together can be opened to allow product transfer

� Residual powder

Containment connections: split valves

couplingdocking dischargingactive part

(cont’d)

passive part

Containment connections: high containment split valves

� Concept: same as standard split valve

� High containement assurance (inflatable sealing, vacuum, ...)

� High cleaning capability (air purge, CIP, ...)

� Optimized balance between GMP and HSE requirements

Containment connections: high containment split valves (cont’d)

Containment connections: RTP ports

� For the transfer of both sterile and/or toxic products

� Made up of two parts:

- the fixed part (alpha port)mounted on the wall of the isolator

- the mobile part (beta port)sealed to the rigid or flexible container

� Concept:

- 2 sealings meeting at a point

- 4 elements mutually shielding each other’s faces, locked

together by rotation of beta port

Containment connections: RTP ports(cont’d)

Lip seal β part

Lip seal α part

container approach lock by rotation (60°) double door opening

α door β door

β part (container)

α part

Containment connections: RTP ports(cont’d)

� Wide range of products

� β container � β bag

Containment connections: liner

� Stainless steel chute with surrounding liner cartridge

� Liner fized to the chute via a top and a bottom O-ring, both

outside thepowder flow

� High containment; robustness?

� Sampling options

Containment isolator: main features

� Tight enclosure in negative pressure

� Exhaust system through double HEPA filter

� Exhaust system able to increase the fan speed in case of serious

damage on the glove (break of the glove). Safety inflow velocity

throught the glove-hole of 0,7 m/s

� Interlocked closed doors during production

� Use of gloves to access any working area needed to be reached

by operator during production

� Contained transfer of materials

� Capability for WIP

Containment isolator: material transfer

� Mouse hole with local protection

� RTP port (bags/containters)

� Containment split valve

� Airlock chamber

� Liner

� Push-push system for filters

� Continuous

� Batch

Containment isolator: cleaning

�Spray Guns

� Automatic

� Manual

� Spray Balls

� only fixed positions

� not fixed

RABS: definition

Restricted

Access

Barrier

System

“Restricted Access Barrier System (RABS) is

an advanced aseptic processing system that

can be utilized in many applications in a fill-

finish area. RABS provides an enclosed

environment to reduce the risk of contamination

to product, containers, closures, and product

contact surfaces compared to the risks

associated with conventional cleanroom

operations.” ISPE definition, August

RABS: main features

� Rigid wall enclosure

� Unidirectional air flow system providing an ISO 5 environment

� Surrounding room classification ISO 7 minimum in operation

� Interlocked closed doors during production

� Use of gloves to access any working area needed to be reached by operator during production

� Aseptic transfer of materials

RABS: tipes

� Passive RABS

� Active RABS

� Open RABS

� Closed RABS

� Air handling system

� Independent unit

� Integrated with room HVAC

� Containment grade

� Air exhausted into the production room

� Aseptic application

� Air recirculated and exhausted outside

� Containment application

Passive RABS

�air handling unit integrated with

room HVAC

� possibility to additionally protect

an area outside

Active RABS

� air handling unit independent

from room HVAC

� outside area protection possible

as option

� possibility to specifically treat the

air in the RABS

Air inlet

ventilatore ventilatore + +

filtro HEPAfiltro HEPA

“Filter Fan Unit”“Filter Fan Unit”

da HVAC + filtro HEPAda HVAC + filtro HEPA

Open RABS

� air exhausted in the room

� no possibility to create

differential pressure (+ or -)

AIR FROM THE ROOM

Closed RABS

� air not exhausted into the

production room but

recirculated and exhausted

outside (return duct and exhaust

� proper for powder handling

(depending on OEL)

� possibility to create differential

pressure (+ or -)

� possibility to specifically treat the

air in the RABS

RABS: application

� O-RABS

� Aseptic process

� C-RABS

� Barrier to avoid cross-contamination for liquid and solids with medium

potency

� Containment barrier for high potent liquid with capability to generate

aerosol

� Containment barrier for medium potent solids with not very powdery

operations

CONTAINMENT

Possible Solution

Personnel gowning

Working area confining

Containment isolator

C-RABS

Which combination?

Selection criteria

Decision trees

Case studies

C-RABS on a filling machine and containment isolator on freeze-driers loading/unloading system for the containment of a product, medium potent as liquid (with capability to

generate aerosol) and high potent as solid

C-RABS on a blistering machine to avoid cross-contamination for low potent products

C-RABS on a blistering machine for containment of a medium potent products

Transfer technology for high potent product in capsule department

-Dispensing

Formulation

Filling

Lyo unloading

OSD Facility

Dispensing

Tabletting/capsule filling

Blistering/Bottle Filling

(cont’d)

OSD Facility

Product transfer

(cont’d)

Which combination?

� Product potency

� Product diffusion capability

� Operation duration

� Possible combination with aseptic processing

� low potent

� medium potent

� high potent

� aerosol generation

� powder spread

� occasional

� shift basis

Selection criteria: GMP & HSE

GMPGMP HSEHSEGMPGMP

++HSEHSE

Selection criteria: decision tree

Working area protection

LIQUIDLIQUID

aerosol?

Potency

C-RABS (only for cross-contamination)

Hp: no PPE use Hp: no PPE use

Standard approach

C-RABS (for personnel safety)

Containment Isolator

Very High

Medium

Selection criteria: decision tree(cont’d)

almost not

powdery? Y

C-RABS (only for cross-contamination)

C-RABS (for personnel safety)

Containment Isolator

Potency

SOLIDSOLID

Working area protection

very powdery?

Very High

MediumY

Selection criteria: decision tree(cont’d)

Product transfer

SOLIDSOLIDOpen process allowed

Closed process with butterfly valves

Potency

Medium

LowClosed process

with standard split valves

Tight closed process with

high containment valves

Tight closed process

with RTP ports and glove box

Very High

CASE STUDIES

� Injectables Facility� C-RABS on filling machine and isolator on Lyos

loading/unloading system for the containment of an API

medium potent as liquid (with capability to generate

aerosol) and high potent as solid

� OSD Facility

� C-RABS on a blistering machine to avoid cross-contamination

for low potent product

� C-RABS on a blistering machine for containment of medium

potent product

� Transfer technology for high potent product in a capsule

facility

CASE STUDY 1CASE STUDY 1

CASE STUDIES: analysis

batch startbatch start

batch endbatch endstopstop

containmentmaterial

transfer

intervention

Case 1: RABS and isolator for containment and aseptic processing

� Aseptic filling and freeze-drying of a product medium potent as liquid and high potent as solid, with capability to generate aerosol

C-RABSC-RABS

vial washer depyrogenatingtunnel

filler

capper external washer

GradeC GradeB GradeB

GradeC

GradeD

isolatorisolator

Lyos withautomatic

loading/unloadingsystem

Grade A

Grade B

Filer C-RABS

Lyoloading/unloading system

isolator

buffer

+ -/+++

optionaloptional

differential pressure during filling

depyrogenatingtunnel

Case 1: RABS for aseptic filling

� working area

� production room

� personnel access

� material transfer

� closed enclosure with unidirectional flow and air

extraction

� Grade A (ISO 5)

� Grade B (ISO 7 in operation)

� sterile uniform for Grade B

� interlocked closed doors during production

� use of gloves

� mouse hole

� RTP ports

� airlock chambers

Case 1: RABS for aseptic filling(cont’d)

� personnel with PPE

� doors opening after phase of additional air extraction and wetting

� sanitization and aseptic condition recovery

� intervention

� cleaning � doors opening after phase of additional air extraction

and wetting

� personnel with PPE till inactivation complition

� decontamination (inactivation) and sanitization of

surfaces

� decontamination (inactivation) and sterilization of

product contact parts

Case 1: Isolator for aseptic loading /

unlaoding of freeze-driers� working area

� production room

� tight enclosure with unidirectional flow

� Grade A (ISO 5)

� positive pressure during FD loading

� negative pressure during FD unloading

� Grade B (ISO 7 in operation)

� sterile uniform for Grade B

� use of gloves

� mouse hole

� RTP ports

Case 1: Isolator for aseptic loading /

unlaoding of freeze-driers (cont’d)

� doors opening after WIP with spray guns

� personnel with PPE (depending on inactivation capability of WIP)

� VHP decontamination before batch re-start

� intervention

� cleaning � doors opening after WIP with spray guns

� personnel with PPE (depending on inactivation capability of WIP)

� VHP decontamination of surfaces

� inactivation and sterilization of product contact parts

Case 2: RABS for cross-contamination

� Tablets blistering machine with low potent product with cross-

contamination risk

C-RABSC-RABS

blisteringmachine

boxingmachine

check weigher

casing machine

labeller

C-RABSblistering m. boxing m.

C-RABSblistering m.

boxing m.

� working area

� closed enclosure with air extraction

� local extraction on opening

� standard pharmaceutical uniform

(could be opened only after phase of

additional air extraction)

� use of gloves

� mouse hole with local air extraction

� tight connections

(cont’d)

Case 2 : RABS for cross-contamination

� intervention

� cleaning

� personnel with standard pharmaceutical uniform, no PPE

� wetting

� doors opening after phase of additional air extraction

(cont’d)

� manual cleaning

� personnel with standard pharmaceutical uniform, no PPE

� wetting

� doors opening after phase of additional air extraction

Case 2 : RABS for cross-contamination

Case 3: RABS for medium potent containment

� Tablets blistering machine with medium potent product

C-RABSC-RABS

C-RABSblistering m.

boxing m.

blisteringmachine

boxingmachine

check weigher

casing machine

labeller

Case 3: RABS for medium potent containment

� secondary containmnet

� working area

� production room

� closed enclosure with air extraction

� negative pressure

� local extraction on openings (optional)

� standard pharmaceutical uniform

� use of gloves

� mouse hole

� containment connections

� airlock chambers

(cont’d)

Case 3: RABS for medium potent containment(cont’d)

� intervention

� cleaning � surface decontamination

Case 4: High potent OSD plant

� Capsule department for an high potent product

� dispensing in a containment isolator with double chamber

� wet granulation and drying in one step processor (including sieving)

� blending in IBC tumbler

� capsule filling (containment isolator)

� bottle filling (containment isolator)

� material transfer by IBCs

� connections with containment split valves

� process equipment with CIP

� secondary containment in the room

Case 4: High potent OSD plant

granulation-drying-sizing blending capsule filling

ISO valve

Push-push system for filters

Pre-chamber

(cont’d)

bottle filling linedispensing

Conclusion

Restricted

Access

Barrier

SystemIntegral systems: hardware to be associated to proper

procedures and operational modes

Isolation

Connection

Thank you for attendance!

For any question:

FOSTER WHEELER ITALIANA FOSTER WHEELER ITALIANA

Pharmaceutical DivisionPharmaceutical Division

Germana Molinari+39 02 4517 6733

germana_molinari@fwceu.com

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