RABS
RABS
RABS
Francesco Longanesi
Areas segregation
EU_cGMP
Clean areas are classified according to the required characteristics of the environment. Each operation requires an appropriate environmental cleanliness level in the operational state 4 grades can be distinguished: grade A, B, C, D Examples of operations to be carried out in the various grades
Based on airborne particulate (viable and non viable ) classification and recommended limits for microbial contamination
EU_cGMP
In order to reach the B, C and D air grades, the number of air changes should be related to the size of the room and the equipment and personnel present in the room. HEPA terminal filters for grades A,B,C. range of 0.36 0.54m/s (guidance value) of Air speed for unidirectional flows
EU_cGMP
Premises considerations (exposed surfaces, recesses, sealing ,changing rooms lay-out, interlocking systems, pressure cascade ,areas pressure warning systems ) . Comfortably Temperature and relative humidity The clothing and its quality should be appropriate for the process and the grade of the working area.
Clear SOPs and regular training for Aseptic gowning qualification , personal personnel (maximum number, hygiene training (aseptic technique, cleanroom and cleanliness, changing ,clothing behaviour, microbiology, hygiene,gowning) treatments, methodical movements)
EU_cGMP
The utilisation of isolator technology to minimise human interventions in processing areas may result in a significant decrease in the risk of microbiological contamination from the environment. Monitoring should be carried out routinely and should include frequent leak testing of the isolator and glove/sleeve system
EU_cGMP
There are many possible designs of isolators and transfer devices. Laminar air flow may not exist in the working zone of all such devices
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Isolators design
EU_cGMP
air classification required for the background environment for aseptic processing should be at least grade D Transfer of materials into and out of the unit is one of the greatest potential sources of contamination. Transfer devices may vary from a single door to double door designs to fully sealed systems incorporating sterilisation mechanisms Isolators should be introduced only after appropriate validation
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Isolators
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Isolators (1)
ISOLATOR DEFINITION: a Separative Device that provide assured protection by using physical and dynamic barriers to create separation between operation and operator; it is supplied with HEPA filtered air and may be decontaminated in quantifiable and highly reproducible manner TYPES: Closed, Open; flexible wall, rigid wall; positive or negative pressurization DESIGN & OPERATIONAL SPECIFICATIONS [ f ]: Feasible both for aseptic and containment applications Construction materials mechanical and chemical resistant Operator interface:gloves,gauntlets,half suites HEPA/ULPA filtered air supplied Either turbulent (closed) or unidirectional air flow (open) Pressure differentials:from 25Pa to 100Pa (monitoring&alarms)
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DESIGN
Isolators (2)
Air Change rate :dont need to comply with 20V/h minimum (absence of personnel) for unidirectional airflow could reach very high values Airborne Particulate cleanliness classification : ISO 5 for internal environment Recirculation rate: one through or return air system Leak tightness (0,5% of Volume leak rate acceptance criteria).Even for open (dec. safety and health requirements ) Decontamination using a reproducible and validated method Leak testing:pressure decay(closed) & induction leak test(open) Gloves integrity test: oxygen,pressure decay,flow rate methods Monitoring: DP(alarms),T,UR% Environmental controls: viable & non viable,surface&gloves
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DESIGN OPERATIONAL
RABS (1)
(from ISPE Definition paper _August 2005) [ i ]
RABS DEFINITION: A Restricted Access Barrier System is an advanced aseptic processing system that provides an enclosed environment to reduce the risk of contamination to product, containers, closures, and product contact surfaces. RABSs are not closed systems and are suitable for applications where process interventions are needed .A RABS provides a level of separation between operator and product that affords product protection superior to traditional systems. TYPES: Passive , Active [ j ] , [ l ] DESIGN & OPERATIONAL SPECIFICATIONS: Rigid Enclosure Unidirectional filtered (HEPA) airflow (ISO5 environment) Suitable entry&exit materials transfer systems DESIGN
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RABS (2)
Surrounding room classification should be ISO 7 minimum in operation (ACTIVE RABS). When open door interventions are necessary, an ISO 5 (class 100) vertical unidirectional airflow system outside of the RABS reduces risk of a breach in ISO 5 conditions Locked door access or interlocked door access with recorded intervention alarms Positive airflow from the enclosure to the exterior environment while the door is opened. remote or automated sampling for in process control testing (IPC) including monitoring for viable and non-viable particles (design adoptions to prevent door openings)
DESIGN
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RABS (3)
Sterilization-in-place (SIP) is preferred for contact parts such as fluid pathways. Where this cannot be achieved, such parts should be sterilized in an autoclave, transferred to the RABS via a suitable procedure and aseptically assembled before processing. Product contact parts such should be sterilized in an autoclave and aseptically assembled before processing. Gloves and gauntlets attached to glove ports are required to be sterile when installed; thereafter, gloves should be sanitized or changed as appropriate to minimize the risk of contamination High-level disinfection of all non product contact surfaces within the RABS with an appropriate sporicidal agent before batch manufacture Following an open door intervention, appropriate line clearance and disinfection commensurate with the nature of the intervention are required
OPERATIONAL
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(*) (ISO 14644-7) Separation descriptor is a numerical abbreviation summarizing the difference in
cleanliness classification between two areas as ensured by a Separative device : [Aa:Bb]
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CONTAINMENT APPLICATIONS :
R Low capability
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To
surrounding dissolution/pre-filtration area ( through mouse hole )
DP (Pascal) 10 30
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Overpressure
Smoke generated Inside RAB close to the doors, access ports and to the mouse hole Outside RAB close to doors, access ports and mouse hole The flow demonstrates that the RAB is in overpressure towards the surrounding and module of the Hood that is connected to the RAB via a mouse hole
Backflow absence
Smoke generated: Inside under the working table Outside in proximity of each door Opening in sequence of each door
Unidirectional flow , without bouncing on the working table, without backflow from adjacent zones
Particle counter positioned inside the RAB does not detect any increase of particles (0.5 m and 5.0 m ) during and after the smoke generation
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References (1)
a. Guidance for Industry_Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice . U.S. Department of Health and Human Services_Food and Drug Administration/ Centre for Drug Evaluation and Research (CDER)/Centre for Biologics Evaluation and Research (CBER)/ Office of Regulatory Affairs (ORA)_September 2004 EU_cGMP-ANNEX 1_MANUFACTURE OF STERILE MEDICINAL PRODUCTS _September 2003 ISPE Pharmaceutical Engineering Guides for New and Renovated Facilities_Volume 3-Sterile Manufacturing Facilities ISO Standards 14644 Cleanrooms and Associated Controlled Environments 14644-1 : Classification of Air Cleanliness 14644-4 : Design, Construction and Start-Up 14644-5 : Operations 14644-7 : Separative devices (clean air hoods, gloveboxes, isolator and minienvironments ) Institute of Environmental Sciences and Technology (IEST) standards IEST-RP-CC006.3 -Testing Cleanrooms IEST-RP-CC-002.1 -Laminar Flow Clean Air Device IEST-RP-CC-034.2 -HEPA and ULPA filter leak test IEST-RP-CC-001.4 -HEPA Filters
b. c. d. e.
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References (2)
f. g. h. f. i. j. k. l. PDA Technical Report No 34 Design and Validation of isolator Systems for the Manufacturing and testing of Health Care Products PIC/S_ PI 014-21 ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING July 2004 ISO Standards 13408 Aseptic processing of health care products Part 5 :General requirements Part 6 :Isolator system ISO Standards 10648 Containment enclosures Part 1 :Design Principles Part 2 :Classification according leak tightness and associated testing methods ISPE definition paper of RABS _August 2005 RABS Definitions and Performance levels - http://www.pharmaceutical-int.com/ ISPE Vienna Conference, 2006_Practical Aspects of Glove Testing for a Production RABS Application ISPE_PHARMACEUTICAL ENGINEERING January/February 2007 :Choosing Technologies for Aseptic Filling .. J.Agalloco,J.Akers,R.Madsen
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Francesco Longanesi
Sources of Contamination
(ISPE Baseline-Vol.3 Sterile Manufacturing Facilities[c])
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10 v ol/h
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30 l/h vo l/h vo 40
vo l/
Class 100
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20
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50
60 Times(min)
Class 100(ISO5) op need dirty air is mixed continuously with clean air to reduce particulate load (Pharmaceutical industry type cleanroom)
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CAPITAL COSTS
Higher than OPERATING COSTS conventional cleanroom Building infrastructure time consuming similar of conventional cleanroom High
Higher than conventional clean room Reduced capital High equipment costs costs with renovation and retrofit application Cost saving in energy Higher than consumption conventional (HVAC) and cleanroom clothing Equipment more Equipment more complex but facility complex but facility simpler simpler High Medium
Cost saving in energy consumption (HVAC) and clothing Equipment more complex but facility simpler Medium
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Low capability Aerodynamic separation is upgrade with a controlled differential pressure Less complex than isolators No open doors are permitted
Good Reliability Complex feasibility (Complex feasibility for sterile toxic) Medium Separation (physic barrier and High Separation (physic barrier and openings overpressure aerodynamic barriers )
Minimal Separation (physic PERSONEL IMPACT barrier and EXTENT restricted air overspill) Less complex than isolators suitable for applications where process interventions are needed ISO 5, class 100 ,GRADE A (gowning, Env.Monitoring commiserate with manned cleanroom)
ERGONOMICS
BACKGROUND ENVIRONMENT
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Regulatory requirements
CLOSED
Unidirectional or Turbulent Independent air system: DP easy to control From 25 Pa to 100Pa typical set range DP monitored continuously (alarms) Suitable transfer system (RTP)
Unidirectional
PRESSURE DIFFERENTIAL
Difficult to control
TRANFER SYSTEMS
Transfer doors / hatches Manual disinfection by gowned personnel Reproducibility and validation uncertain Induction leak testing(ISO146447) or L-R method(PDA TR 34)
ENVIRONMENTAL SANITIZATION
LEACK TESTING
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Independent air system: DP easy to control ISO5 HEPA air Independent air sweep in system: DP easy to conjunction with control Mousehole DP monitored continuously (alarms) Continuous or semi Suitable transfer continuous material system (RTP) ingress/egress Manual disinfection by decontaminated gowned while closed personnel (Sealing need Reproducibility before GSIP ) and validation uncertain Hourly leak rate for GSIP safety&healt Induction leak testing aspect Induction leak testing
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Suspension in Sodium Chloride Solution 0.9% Emulsification by stirring, recirculation & sonication pH adjustment and final sonication
Filling of 2L suspension bottles Using peristaltic pump, aliquots of Sterile bulk suspension is filled into the 2 L bottles. The bottles are blanketed with Nitrogen
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MOCK UP development
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[50,5 : 50,5 ]
open-hatches overhead HEPA downflow protection barrier to improve protection against potential contamination from operators
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Air overspill
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