selection off conttaiinmentt for fill-finish operations
TRANSCRIPT
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 Forum - Milano November 15th-16th, 2006
INDEX
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
Containment Forum - Milano November 15th-16th, 2006
Pharma scenario
isolationisolation
isolation & containmentisolation & containment
containmentcontainment
Containment Forum - Milano November 15th-16th, 2006
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
Containment Forum - Milano November 15th-16th, 2006
Possible solutions
Separation between
PRODUCT / PERSONNEL / ENVIRONMENT
Proper combination of:
Working area containmentWorking area containment
&Personnel gowningPersonnel gowning
Containment Forum - Milano November 15th-16th, 2006
Possible solutions: personnel
GowningGowning: proper barrier between operator and exposed product
standard uniformstandard uniform “PPPS”“PPPS”sterile suitesterile suite
Containment Forum - Milano November 15th-16th, 2006
Possible solutions: working area
ContainmentContainment : : proper confining of activties
with exposed productexposed product
critical operation identification
proper containment device choice
Containment Forum - Milano November 15th-16th, 2006
Possible solutions: working area
Typical critical critical operations in fill&finish:
Injectables Facility
OSD Facility
liquid
solid
aerosol
non aerosol
powder
freeze-dried
• Dispensing&formulation
• Filling
• Dispensing&formulation
• Dispensing&formulation
• Filling
• Dispensing&formulation
• Lyo unloading
• Dispensing
• Product transfer
• Tabletting/capsule filling
• Blistering/Bottle filling
(cont’d)
Containment Forum - Milano November 15th-16th, 2006
Possible solutions: working area
Typical critical working area “enclosure”
Dispensing
Formulation
Filling
Lyo unloading
(cont’d)
Injectables Facility
Clean RoomClean Room
Barrier TechnologyBarrier Technology
RABS
Isolator
Containment Forum - Milano November 15th-16th, 2006
Possible solutions: working area
Typical critical working area “enclosure”
OSD Facility
Dispensing
Tabletting/capsule filling
Blistering/Bottle Filling
(cont’d)
Clean RoomClean Room
Barrier TechnologyBarrier Technology
RABS
Isolator
Down crossDown cross
Containment Forum - Milano November 15th-16th, 2006
Possible solutions: working area
Typical critical working area “enclosure”
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 Forum - Milano November 15th-16th, 2006
Main containment devices
� Containment connections
� Containment isolator
� C-RABS
Containment Forum - Milano November 15th-16th, 2006
Containment connections
� Split valve
� High containment split valve
� RTP port
� Liner
Containment Forum - Milano November 15th-16th, 2006
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 Forum - Milano November 15th-16th, 2006
Containment connections: split valves
couplingdocking dischargingactive part
(cont’d)
passive part
Containment Forum - Milano November 15th-16th, 2006
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 Forum - Milano November 15th-16th, 2006
Containment connections: high containment split valves (cont’d)
Containment Forum - Milano November 15th-16th, 2006
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 Forum - Milano November 15th-16th, 2006
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 Forum - Milano November 15th-16th, 2006
Containment connections: RTP ports(cont’d)
� Wide range of products
� β container � β bag
Containment Forum - Milano November 15th-16th, 2006
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 Forum - Milano November 15th-16th, 2006
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 Forum - Milano November 15th-16th, 2006
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 Forum - Milano November 15th-16th, 2006
Containment isolator: cleaning
�Spray Guns
� Automatic
� Manual
� Spray Balls
� only fixed positions
� not fixed
Containment Forum - Milano November 15th-16th, 2006
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
2005
Containment Forum - Milano November 15th-16th, 2006
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
Containment Forum - Milano November 15th-16th, 2006
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
Containment Forum - Milano November 15th-16th, 2006
Passive RABS
�air handling unit integrated with
room HVAC
� possibility to additionally protect
an area outside
Containment Forum - Milano November 15th-16th, 2006
Active RABS
� air handling unit independent
from room HVAC
� outside area protection possible
as option
� possibility to specifically treat the
air in the RABS
Containment Forum - Milano November 15th-16th, 2006
Air inlet
ventilatore ventilatore + +
filtro HEPAfiltro HEPA
“Filter Fan Unit”“Filter Fan Unit”
da HVAC + filtro HEPAda HVAC + filtro HEPA
Containment Forum - Milano November 15th-16th, 2006
Open RABS
� air exhausted in the room
� no possibility to create
differential pressure (+ or -)
AIR FROM THE ROOM
Containment Forum - Milano November 15th-16th, 2006
Closed RABS
� air not exhausted into the
production room but
recirculated and exhausted
outside (return duct and exhaust
duct)
� proper for powder handling
(depending on OEL)
� possibility to create differential
pressure (+ or -)
� possibility to specifically treat the
air in the RABS
Containment Forum - Milano November 15th-16th, 2006
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 Forum - Milano November 15th-16th, 2006
INDEX
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
Containment Forum - Milano November 15th-16th, 2006
Possible combinations
Injectables Facility
&
C
&
&
-Dispensing
Formulation
Filling
Lyo unloading
Containment Forum - Milano November 15th-16th, 2006
Possible combinations
OSD Facility
Dispensing
Tabletting/capsule filling
Blistering/Bottle Filling
&
&
&
&
(cont’d)
Containment Forum - Milano November 15th-16th, 2006
Possible combinations
OSD Facility
Product transfer
& &
&&
&&
(cont’d)
Containment Forum - Milano November 15th-16th, 2006
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
Containment Forum - Milano November 15th-16th, 2006
Selection criteria: GMP & HSE
GMPGMP HSEHSEGMPGMP
++HSEHSE
Containment Forum - Milano November 15th-16th, 2006
Selection criteria: decision tree
Working area protection
LIQUIDLIQUID
aerosol?
Potency
C-RABS (only for cross-contamination)
Hp: no PPE use Hp: no PPE use
N
Standard approach
Y
C-RABS (for personnel safety)
Containment Isolator
Very High
High
Medium
Low
Containment Forum - Milano November 15th-16th, 2006
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
N
very powdery?
Very High
High
MediumY
Low
N
Hp: no PPE use Hp: no PPE use
Containment Forum - Milano November 15th-16th, 2006
Selection criteria: decision tree(cont’d)
Product transfer
SOLIDSOLIDOpen process allowed
or
Closed process with butterfly valves
Potency
Medium
LowClosed process
with standard split valves
Hp: no PPE use Hp: no PPE use
Tight closed process with
high containment valves
Tight closed process
with RTP ports and glove box
High
Very High
Containment Forum - Milano November 15th-16th, 2006
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 STUDY 2CASE STUDY 2
CASE STUDY 2CASE STUDY 2
CASE STUDY 3CASE STUDY 3
Containment Forum - Milano November 15th-16th, 2006
CASE STUDIES: analysis
batch startbatch start
batch endbatch endstopstop
containmentmaterial
transfer
perso
nnel
acce
ss
clean
ing
intervention
Containment Forum - Milano November 15th-16th, 2006
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
or
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
Containment Forum - Milano November 15th-16th, 2006
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
Containment Forum - Milano November 15th-16th, 2006
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
Containment Forum - Milano November 15th-16th, 2006
Case 1: Isolator for aseptic loading /
unlaoding of freeze-driers� working area
� production room
� personnel access
� material transfer
� 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
� interlocked closed doors during production
� use of gloves
� mouse hole
� RTP ports
Containment Forum - Milano November 15th-16th, 2006
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
Containment Forum - Milano November 15th-16th, 2006
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.
OR
C-RABSblistering m.
boxing m.
- -+
+
0
Containment Forum - Milano November 15th-16th, 2006
� working area
� personnel access
� material transfer
� closed enclosure with air extraction
� local extraction on opening
� standard pharmaceutical uniform
� interlocked closed doors during production
(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
Containment Forum - Milano November 15th-16th, 2006
� 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
Containment Forum - Milano November 15th-16th, 2006
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
Containment Forum - Milano November 15th-16th, 2006
Case 3: RABS for medium potent containment
� secondary containmnet
� working area
� production room
� personnel access
� material transfer
� closed enclosure with air extraction
� negative pressure
� local extraction on openings (optional)
� standard pharmaceutical uniform
� interlocked closed doors during production
� use of gloves
� mouse hole
� containment connections
� airlock chambers
(cont’d)
Containment Forum - Milano November 15th-16th, 2006
� personnel with PPE
� doors opening after phase of additional air extraction and wetting
Case 3: RABS for medium potent containment(cont’d)
� intervention
� cleaning � surface decontamination
� personnel with PPE
� doors opening after phase of additional air extraction and wetting
Containment Forum - Milano November 15th-16th, 2006
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
Containment Forum - Milano November 15th-16th, 2006
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
Containment Forum - Milano November 15th-16th, 2006
Conclusion
Restricted
Access
Barrier
SystemIntegral systems: hardware to be associated to proper
procedures and operational modes
Isolation
Connection
Containment Forum - Milano November 15th-16th, 2006
Thank you for attendance!
For any question:
FOSTER WHEELER ITALIANA FOSTER WHEELER ITALIANA
Pharmaceutical DivisionPharmaceutical Division
Germana Molinari+39 02 4517 6733