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© PharmOut 2016
• History & perspective
• Advanced aseptic processing concept
• Evolution
• Expectations
Overview
© PharmOut 2016
Photo Courtesy of Bosch Packaging
1989 – ampoule filling isolator with softwall isolator
© PharmOut 2016
In2001 lots of debate about killing microbes
What I love is that we are still
debating it today, > 15 years on!
© PharmOut 2016
We still try to put cleanroom equipment
and processes in a small box; operate
like we do in a cleanroom; and use
open cleanroom monitoring techniques
to monitor how well we’re doing !
How can we get better?
© PharmOut 2016
Increasing system integrity
Increased sterility assurance
RABS2000s
Isolators1990s
Evolution - The aseptic processing integrity spectrum”
Advanced aseptic processing2000s
Blow-fill-seal1970s
© PharmOut 2016
Advanced aseptic processing
• This US FDA initiative started the whole RABS debate.
• US FDA suggested that they would favour firms that used ”advanced aseptic processing”.
• Isolators.
• Properly managed “blow fill seal”.
• A number of big pharma and generic firms got grumpy because they didn’t want to be pushed into using isolators because they were unsuitable:
• Dry powder fill.
• Excessive change-over time - Multiple product generic and CMOs.
• The concept of the RABs emerged (restricted access barrier system):
• ISPE got in on the act and agreed a definition with US FDA in 2006.
© PharmOut 2016
Maturing technology in EU/PIC-S GMPs – Isolators & RABS
21. The utilization of isolator technology to minimize human interventions in processing areas
may result in a significant decrease in the risk of microbiological contamination of aseptically
manufactured products from the environment. There are many possible designs of isolators
and transfer devices. The isolator and the background environment should be designed so
that the required air quality for the respective zones can be realised. Isolators are
constructed of various materials more or less prone to puncture and leakage. Transfer
devices may vary from a single door to double door designs to fully sealed systems
incorporating sterilization mechanisms.
• Today, we should see Isolators and RABS as essential technology that should at least be considered –improved separation of personnel from process.
• Perhaps the revised Annex 1 (2016/17) will say??????
• “The utilisation of barrier technologies, RABS and Isolators can improve the sterility assurance during open aseptic processing, and should be considered when selecting the most appropriate environmental control solution.”
© PharmOut 2016
Traditional cleanroom(our GMPs are written around this approach)
© Critical Systems Ltd 201621
© PharmOut 2016
Traditional cleanroom – characteristics
• Grade B/ISO7 Room scale critical environment contains operators
• Critical Grade A/ISO5 Aseptic process Core located in the
Grade B/ISO7 room
• Operators access equipment from surrounding Grade B/ISO7 room
to load the process and intervene using defined SOPs. High reliance
on operator garments
• Bio-decontamination…
‒ Autoclave sterilisation of product contact parts, followed by
aseptic assembly.
‒ Topical disinfection of surfaces
‒ Room fumigation in some cases (rare these days)
• Separation between operators and aseptic process core
‒ Polycarbonate doors
‒ Screens
‒ Curtains
© PharmOut 2016
Conveyor
Vial
Nozzle
Filling
Mechanism
Conventional Clean Room
HEPA Filters
Class 100
(ISO 5)
Grade B
non-UDF
Room
Grade A
UDF Zone
Traditional cleanroom – principles
© PharmOut 2016
Conveyor
Vial
Nozzle
FillingMechanism
HEPA Filters
HVAC - Fans
Grade A
UDF Zone
Grade B
non-UDF
Room
Minimum open cleanroom – principles (limited access)
© PharmOut 2016
The minimum acceptable cleanroom practice todayRigid screens separate personnel from the aseptic process.
Highly controlled access to the machine enclosure.
© PharmOut 2016
Definitions (ISPE) – just be aware of thisA barrier system is:
• “A system of physical partitions that affords Grade A protection
by partially separating its interior from the surrounding
environment utilizing airflow.”
Restricted Access Barrier System (RABS) is:
• “An aseptic processing system that provides an enclosed, but
not closed, environment meeting Grade A conditions utilizing a
rigid-wall enclosure and air overspill to separate its interior from
the surrounding environment.”
© PharmOut 2016
It is considered to qualify as RABS that complywith the PHSS monograph the following design and
contamination control attributes should becombined in a system design:
RABS disinfection method andprocess application
manual or automatic
RABS environmental &
contamination control
attributes + monitoring
The RABS –‘System’
RABS access control for
barrier process transfers and
operator access
Sterilisation processes for
direct and indirect product
contact parts
© PharmOut 2016
Annex 1 Grade B
RABS Background
‘Open’ ‘Closed’
RABS with air over spill tothe ISO7 surrounding Area.Photograph courtesy of Boehringer Ingelheim Germany.
Possible HPV high level disinfection
together with the Clean room.
Closed RABS for HPV
gassing with integral air returnpaths and part recirculationPhotograph courtesy of Franz Ziel, Germany for a Pharma project in Ireland.
© PharmOut 2016
Open RABS – characteristics
• The Grade B/ISO7 Room scale critical environment contains operators
• Critical Grade A/ISO5 Aseptic process Core sits in Grade B/ISO7 room
• Operators use glove ports for intervention, and closed component handling from the surrounding Grade B/ISO7 room
• Bio-decontamination…generally as open room
‒ Autoclave sterilisation of product contact parts, followed by aseptic assembly.
‒ Topical disinfection of secondary surfaces
‒ Room fumigation in some cases
• Separation between operators and Grade A/ISO5 Aseptic process core
‒ Polycarbonate doors
‒ Screens
With glove ports and transfer
ports for components
© PharmOut 2016
Conveyor
Vial
Nozzle
Filling
Mechanism
HEPA Filters
Class 100
(ISO 5)
HVAC
Class10,000(ISO 7)
Grade B
Grade A
Locally increased
UDAF zone to protect door opening for very limited
interventions
Grade B
Room
Passive RABS
In passive RABS
resistance to airflow can
cause lateral flows.
RABS – principles
7-Feb-18 © Critical Systems Ltd 2016
34
© PharmOut 2016
Conveyor
Vial
Nozzle
Filling
Mechanism
HEPA Filters
Class 100
(ISO 5)
HVAC
Class10,000(ISO 7)
Grade A
Locally increased UDAF zone to protect door opening
for very limited interventionsGrade B
Room
Active RABS
RABS – principles
© Critical Systems Ltd 2016
© PharmOut 2016
Conveyor
Vial
Nozzle
Filling
Mechanism
HEPA Filters
Class 100
(ISO 5)
HVAC
Class10,000(ISO 7)
Grade BGrade A
This variation has the ability to close a valve to allow a closed system gassing, fumigation or bio-decontamination or surface sterilisation.
HEPA Filters
HVAC
HEPA Filters
HVAC
Closed RABS – principles
© PharmOut 2016
Conveyor
Vial
Nozzle
Filling
Mechanism
HEPA Filters
Class 100
(ISO 5)
HVAC
Class
10,000
(ISO 7)
Grade B Grade A
Closed RABS – principles
This variation has the ability to close a valve to allow a closed system gassing, fumigation or bio-decontamination or surface sterilisation.
© PharmOut 2016
Isolator – characteristics
• Small contained enclosure excludes process operators
• Critical Grade A Aseptic process Core sits in Grade C or D “at rest” room
• Operators only open equipment when off-line. Human access via glove ports, and closed process loading
• Bio-decontamination…
• Sporicidal gas bio-decontamination of product contact parts.
• Steam sterilisation of fluid pathway.
• Separation between operators and aseptic process core
• Isolator shell
• Windows
• Glove ports
• Transfer ports sterilised change-parts & components
© PharmOut 2016
Conveyor
Vial
Nozzle
Filling
Mechanism
Isolator
HEPA Filters
Class 100
(ISO 5)
AirReturn
Class
100,000
(ISO 8)
Isolator – principles
Grade A
Grade C
or min Grade D
© PharmOut 2016
www.pharmsystems.com/ LabServices/LabFacility_...
Half suit (a sterile API application)
© PharmOut 2016
Barrier technology - the future
1. GMPs will expect that we consider the use of RABs and Isolators.
2. We need to get better at the technology.
3. Personal view –
• We need to find a better agent that HPV for bio-decontamination. ClO2, O3, and NO2 seem to offer some exciting opportunities.
4. For many isolators, traditional microbial monitoring presents the greatest aseptic processing risk:
• Getting media IN & OUT.
• Managing the false negative risk of the gassing agent.
5. Technologies we should consider:
• Rapid and instant microbial detectors.
• Take the environment to the detectors, not place the detector in the isolator or RABs.
6. Design the process to be more barrier sympathetic.