Pharmaceutical Isolator

Technology
Thinking inside the box
Filling in the Fifties
Isolators
Are environments which are sealed, or
supplied with microbially retentive filtered
air, and are reproducibly decontaminated.
When closed, use only decontaminated
interfaces or transfer devices which
preclude contamination.
Are recognized to be superior for product
and/or operator protection when designed
and operated appropriately.
The Isolation Continuum
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Isolators
Containment
Aseptic
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Positive Pressure
Negative Pressure
Increased sterility assurance Increased worker protection
Conventional Cleanroom Mfg
Heavy requirements for
operator training and
monitoring
Sterile gowning
certification required
Relies on continuous
high airflow for
protection
Entire rooms designed
to be essentially aseptic
Isolator-based Mfg
No requirement for
sterile gowning
Background
classified to ISO8
No direct contact
between people and
product
Drastic reduction in
sterile airflow
requirements
Added flexibility for
multi-product usage
Functions For An Isolator
Operator Interface
Isolator Design Fundamentals
Isolator Instrumentation
Pressure monitoring and control
Modes
Run
Leak-test
Decontaminate
Aerate
Particle monitoring
Temp/Humidity
Airflow
Closed isolators acceptable with turbulent
airflow
May employ localized unidirectional airflow
Open isolators use unidirectional strictly
True unidirectional air, as velocities and
space do not generate any laminarity
May be operated in positive or negative
pressure, dependent upon containment or
aseptic

Closed vs. Open Isolators
Closed
Tightly sealed units
Often turbulent airflow
Ceiling air supply and
exhaust
Simpler to design and
operate
Easier to validate
Lowest risk aseptic
process
Open
Utilize mouseholes
for material ingress
and egress
Use unidirectional air
Rely on adequate
airflow to preclude
contamination
Faster throughput
Larger capacities

Rapid Transfer System
Isolator Designs
Flexible wall
PVC Bag with
support
Lighter
Cheaper
Less puncture
resistant
Longer aeration
times
Isolator Designs
Rigid Wall
More puncture
resistant
Short aeration time
Less Pressure
fluctuation
More customizable


Isolator Mock-up
Key step in
design
Assess
ergonomics
Place
instrumentation
No two
isolators are
the same
Leak Testing
Tested during
assembly
Tested daily in
operation
Set on low, but
measurable rate
Important for
VHP safety and
aseptic
operation
Syringe Filling Isolator Line
Sterility Test Isolator
Integrated Vial Filling Line
Rigid Wall Plastic Isolator
Compounding Isolator
Tank able to attach with
RTP
Allows for contained
compounding of
hazardous materials
Able to provide
pos./neg. pressure
Anaerobic
compounding possible
Isolated Robotics
New, next step in
aseptic technology
Sealed, VHP-
compatible robotics
Eliminates need for
most ergonomics
Removes human
intervention at greater
level

Decontamination
Concept now used to
define isolator
environmental control
Repeatable method to
destroy all likely
contaminating
organisms
Not sterilization
High end, automated
sanitization
Sterilization
Absence of viable microorganisms
Generally regarded as a Probability of Non-
Sterile Unit at one in a million (PNSU 10
-6
)
Inversely, Sterility Assurance Level (SAL 10
6
)
Dependent upon controlled conditions and
defendable data
Sterilization & Decontamination
Measured by Biological Indicator
Destruction
Use Spores as challenge organism
BI use coupons, discs, etc. holding a
population of spores
Most common sterilization to use overkill
approach
A science based upon probability, not
perfection

PNSU/SAL
-6
-4
-2
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2
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6
0 5 10 15 20 25 30
Time (min.)
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Validate
Total Kill
GMP Cycle
Decontamination
GASSING
RETURN
Enclosure








Phase 1 Pre-Conditioning








Phase 2 - Gassing
- Gas dwell








Phase 3 Aeration
VHP - Cycle Stages
VHP Cycle Parameters
Humidity inside the Isolator at the beginning of
gassing
Injection rate of hydrogen peroxide
Switching point from gassing phase to dwell phase
Exposure time
Gas concentration
Temperature of the surface to be decontaminated
Temperature inside the isolator
Gas distribution
Ambient temperature

Reliable Cycle Development
Uniformity of temperature on surface
to be decontaminated.
Especially at beginning of gassing phase
Adequate distribution of VHP
throughout space to be
decontaminated.
Rapid discharge of VHP from system in
aeration
Reproducibility of cycle developed

Isolator Decontamination
Many agents have been employed:
Peroxyacetic acid
Chlorine Dioxide
Steam/Peroxide
Ozone
Formaldehyde
Vapourized Hydrogen Peroxide
VHP most common today
Operating Technique
Not Sterile Processing
Relies upon good, consistent aseptic
technique
Motion as/more important as in cleanroom,
due to small size of space
Cleaning and material compatibility key for
particulate control
Historic Problems
Extreme difficulties in demonstrating
Sterilization and Sterile Processing
Overcomplicated and leaky designs
Perfection set as goal
Zero leak spec
Sterile
Materials and decon agent compatibility
Just equipment in a box
Summary
Now generally accepted
technology
Relies upon solid
design and operation
practices
Widely held as the
superior aseptic
technology
Highly adaptable with
associated devices and
methods