Integrated process equipment into high containment system Presented by Stefano Butti Technical Sales Manager
Mobile: +39 331 6819414 F.P.S. Food and Pharma Systems Srl Via Vandelli 20 I-22100 Como (Italy) e-mail:
[email protected] website: www.foodpharmasystems.com
Containment in the pharmaceutical industry: Overview Containment system JETMILL
Process
Localsuction arms
Reactor
Cleanroom
Filters
LAF
Dryers
Downcross booth
Milling
Charging system
Micronisation
Packing –off system
Blending
flexibleisolator
Rigid isolator
Tablet pressing
Capsule filling
Final packaging
Dispensing and IPC test
ISOLATOR
QMILL
LAF CLEAN ROOM
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Glove-boxes
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Half-Suite boxes
RABS
Containment in the pharmaceutical industry: Project activities
On-site preliminary discussion
Front-end design
Detail engineering
Manufacturing
Document review
FAT
Transport & installation SAT validation (IQ/OQ) Maintenance and operator training Containmentt performance verification Containmen
Containment in the pharmaceutical industry: applicable standard and literature 1.
EN 14175 Biosafety cabinet (Part 1,2,3 and 6)
2.
ISO 14644-7 Separative devices (clean air hoods, glove boxes, isolators, and minienvironments)
3.
4.
5.
6.
ISO 10648-1 Containment enclosure – Part 1 Design principles ISO 10648-2 Containment enclosure – Part 2 Classification according to leak tightness and associated checking method AGS-G001-2007 Containment Systems a design guide (IchemE editor)
Hazard group definition: Nomenclature TLV (Threshold Limit Value) ppm or mg/m 3 8h TWA Referred to a chemical substance in gas form, is a level to which it is believed a worker can be exposed day after day for a working lifetime without adverse health effects TLV Example: Starch TLV 10’000 mg/m 3 8h TWA Testosterone (ormon) TLV 4 mg/m 3 8h TWA Dexamethone (steroid) TLV 0.02 mg/m 3 8h TWA
OEL (Occupational Exposure Limit) mg/m3 8h TWA Referred to a chemical substance in dry form is an upper limit on the acceptable concentration of a hazardous substance in workplace air for a particular material or class of materials OEL Example: Citric Acid OEL 2500 mg/m3 8h TWA Salbutamol OEL 0.1 mg/m3 8h TWA
Hazard group definition: OEL Example…. OEL (Occupational Exposure Limit) 1 mg of lactose in a volume of 1m3 correspondent to…
N° 2 Casinò dice compared to…
Empire State Building NY, approx. volume: 1’000’000 m3
Hazard group definition:
Table from: Containment Systems a design guide (IchemE editor)
Containment in the pharmaceutical industry : Occupational Exposure Band (OEB) definition OEB
Range of OEL (µg/m3)
Toxicological/Pharmacological proprieties
OEB 1
> 1.000
Harmful, and/or low pharmacological activity
OEB 2
100 – 1.000
Harmful, and/or moderate pharmacological activity
OEB 3
10 - 100
Moderate toxic and/or high pharmacological activity
OEB 4
1 - 10
Toxic and/or very high pharmacological activity
OEB 5
<1
Extremely toxic and/or extremely high pharmacological activity
Containment strategy description: Strategy 1: Controlled general ventilation Strategy 2: Local exhaust ventilation Strategy 3: Local exhaust ventilation with barriers Strategy 4: Open handling within simple isolator (also flexible) or high-integrity coupling between closed containers Strategy 5: Open handling within high containment isolator or closed handling within isolator
Strategy 1: Strategy 1 : Controlled general ventilation
No special engineering requirements; adequate control is achieved by general ventilation of the process area.
CLEAN ROOM installation
Strategy 2: Strategy 2 : Local exhaust ventilation
LAF booth
A Local Exhaust Ventilation (LEV) system is used to contain the contaminants within a defined area and draw airborne contaminants away from the operator breathing zone. This can involve either: • a good point exhaust ventilation • a unidirectional air-flow booth This can achieve significant reduction in operator exposures to the concentration of airborne dusts and vapours generated
Downcross booth
Biosafety Cabinet
Strategy 3: Strategy 3 : Local exhaust ventilation with barriers
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A down-cross booth or unidirectional air-flow booth system is used in combination with an extra barrier to contain the contaminants within a defined area, this could typically involve: • Glove tent • Glove bag with flexible isolators • Continuous liner systems
Class II Biosafety cabinet for small Laboratory activities
Strategy 4: Strategy 4 : Open handling within isolator
Open transfer or handling of hazardous materials takes place within an isolator. Typically this might involve surrounding the transfer operation with a fixed or flexible air-tight barrier. Containers of process material may be placed in or removed from the isolator only in a way that does not compromise the integrity of the containment it provides. The operator uses glove ports for transfer and cleaning operations.
High-integrity closed coupling without external containment
This containment strategy can also cover transfers effected by high integrity coupling systems within closed containers.
Isolator with cont. liner technology
Split valve with rigid containers
Strategy 5: Strategy 5 : Closed handling within isolator
Closed transfer or handling of hazardous materials takes place within an isolator. This is similar to previous strategy with exception that open transfer is not permitted even within the enclosure. The operator using glove ports attaches the closed container directly to the access port for the process and then opens the valve to effect the transfer of material.
RTP technology isolators and rescricted access barrier system, “double containment”
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Extra containment level:
FPS containment strategy selection chart : L o w
C o n t a i n m e n t l e v e l
H i g h
Containment in the pharmaceutical industry: Rigid isolators (Design Criteria & Working principle)
Technic al Features
Full StainlessSteel construction following cGMP requirements
FDA approved materials for not Stainless Steel parts
Configuration for HAPI or Sterile products activities
Constant negative (positive) pressure working condition
Transfer system available : Airlock / RTP / Endless Liner / Split Valve
Full CIP / SIP available ATEX configuration
Internal class below to ISO5 / Class A / Class 100 / Class M3.5
OEL < 0.1 μ g/m3 8h TWA (OEB5)
Leak test following ISO10648-2 below to class 1 or AGS-2007 with 0.5% of Volume leakrate
Sterility level below to 6log (SAL 10 -6 ) by VHP generator
Containment in the pharmaceutical industry: material inlet pass-box
Containment in the pharmaceutical industry: RTP’s
Containment in the pharmaceutical industry: Split Valves
Containment in the pharmaceutical industry: Continuous liner
Containment in the pharmaceutical industry: transfer system - Hicoflex ®
Containment in the pharmaceutical industry: transfer system – Ezi-Dock TM
Containment in the pharmaceutical industry: Design phase – project development
Project development Individuate the requirements and create 3D models of the final design following provided URS
Ergonomic test with moke up and design review
Manufacture
FAT and installation
Containment in the pharmaceutical industry: Design phase – ergonomic evaluation & manufacture
D o t t . B o n a p a c e t a b l et p r e s s a n d capsule filling machine integration
Containment in the pharmaceutical industry: Flexible containment
F P S f l ex i b l e c o n t a i n m e n t
Flexible isolator with integrated gloves
Glove Bags for maintenance activities
Glove bag for cleaning activities
Glove bag for process operations
Seal tight zip for safe access
Antistatic materials for flexible media Taylor made solution to meet specific requirements
Containment in the pharmaceutical industry: barrier isolators S t ai n l e s s S t e e l i s o l a t o r s f o r laboratory activities of: weig hting , IPC, sam plin g, dispensin g, charging,
discharging, sieving….
Containment in the pharmaceutical industry: integrated system – reactors charging (pilot plant) Different size and type of pilot reactors in glass or SS could be integrated in different way to respect process step
Containment in the pharmaceutical industry: integrated system – reactors charging (production plant)
Small and large production reactors could be interfaced with isolator for safe charging by gravity or by VTS
Containment in the pharmaceutical industry: integrated system – filter and tray dryers (pilot plant)
Filter and tray dryer for pilot plant are fully integrated with complete automation control
Containment in the pharmaceutical industry: integrated system – filter dryers and tray dryers (pilot plant)
ANFD for pilot plant with milling and dispensing isolator are fully integrated with complete automation control
Containment in the pharmaceutical industry: integrated system – filter dryers (production) ANFD for production plant are fully integrated with sampling, heel push product discharging and packingoff contained system
Containment in the pharmaceutical industry: integrated system – Milling & micronisation (pilot plant)
F P S M u l t i -m i l l i n g p a t f o r m
Cone-mill
Pin-mill
Q-mill
Spiral Jet-mill
Cryo-milling
Containment in the pharmaceutical industry: integrated system – Milling & micronisation (production plant) M i l l i n g & M i c r o n i s a t i o n production Half suit isolators (8” - 12” J e t m i l l s )
Containment in the pharmaceutical industry: integrated system – packaging pilot plant Semi-automatic capping machine
Weighting chamber
Sieving and multiblending chamber
Capsule-filling and capsuleorienting chamber
Semi-automatic counting machine
Containment in the pharmaceutical industry Integrated Systems: Oral Solid Forms processing Pan Coating machine
Dispensing In Process Control
Containment in the pharmaceutical industry Integrated Systems: Oral Solid Forms processing Capsule filling machine Overview
Tablet press machine
Capsule filling machine – Internal View
Containment in the pharmaceutical industry Integrated Systems: Oral Solid Forms processing OEB5 Marchesini Blistering machine
OEB4 Marchesini Blistering machine
Containment in the pharmaceutical industry: integrated system – ISPE SMEPAC Test
Containment performance v e r i f i c a t io n f o l l o w i n g IS P E guideline during FAT and at end user site from appro ved third party
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Isolation and containment systems: R.A.B.S.
Restricted Access Barrier System – ISPE definition (August 2005)
A 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 clean room operations.
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Isolation and containment systems: R.A.B.S. Active open RABS for dosing machine
Integrated air treatment system
Horizontal air flow in the dosing machine area
Vertical air flow on the transportation belt and an horizontal air flow for the docking station
Air recirculation and de-humidifier system
PLC control
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Isolation and containment systems: R.A.B.S. Passive open RABS application for filling line
Upgrading of existing filling lines
Barrier with glove ports where needed
Packing materials introduction devices
Integration with existing filling line control system
Glove tester
Containment in the pharmaceutical industry Integrated Systems: Glove tester Automatic / Manual Glove tester:
Efficient
Fast response
Easy to use
Available for different flange size/shape
