Pharmaceutical Isolator TechnologyThinking inside the box

Filling in the Fifties

IsolatorsAre 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 ContinuumAseptic OpenCytotoxic ClosedBarrier SystemBarrier SystemBiosafety CabinetLaminar Flow HoodClassified RoomClassified RoomUn-classified RoomUn-classified RoomIsolatorsContainmentAsepticIncreasing Reliability of OperationPositive PressureNegative PressureIncreased sterility assuranceIncreased worker protectionAseptic Closed

Conventional Cleanroom MfgHeavy requirements for operator training and monitoringSterile gowning certification requiredRelies on continuous high airflow for protectionEntire rooms designed to be essentially aseptic

Isolator-based MfgNo requirement for sterile gowningBackground classified to ISO8No direct contact between people and productDrastic reduction in sterile airflow requirementsAdded flexibility for multi-product usage

Functions For An Isolator

Operator Interface

Isolator Design Fundamentals

Isolator InstrumentationPressure monitoring and controlModesRunLeak-testDecontaminateAerateParticle monitoringTemp/Humidity

AirflowClosed isolators acceptable with turbulent airflowMay employ localized unidirectional airflowOpen isolators use unidirectional strictlyTrue unidirectional air, as velocities and space do not generate any laminarityMay be operated in positive or negative pressure, dependent upon containment or aseptic

Closed vs. Open IsolatorsClosedTightly sealed unitsOften turbulent airflowCeiling air supply and exhaustSimpler to design and operateEasier to validateLowest risk aseptic processOpenUtilize mouseholes for material ingress and egressUse unidirectional airRely on adequate airflow to preclude contaminationFaster throughputLarger capacities

Rapid Transfer System

Isolator DesignsFlexible wallPVC Bag with supportLighterCheaperLess puncture resistantLonger aeration times

Isolator DesignsRigid WallMore puncture resistantShort aeration timeLess Pressure fluctuationMore customizable

Isolator Mock-upKey step in designAssess ergonomicsPlace instrumentationNo two isolators are the same

Leak TestingTested during assemblyTested daily in operationSet on low, but measurable rateImportant for VHP safety and aseptic operation

Syringe Filling Isolator Line

Sterility Test Isolator

Integrated Vial Filling Line

Rigid Wall Plastic Isolator

Compounding IsolatorTank able to attach with RTPAllows for contained compounding of hazardous materialsAble to provide pos./neg. pressureAnaerobic compounding possible

Isolated RoboticsNew, next step in aseptic technologySealed, VHP-compatible roboticsEliminates need for most ergonomicsRemoves human intervention at greater level

DecontaminationConcept now used to define isolator environmental controlRepeatable method to destroy all likely contaminating organismsNot sterilizationHigh end, automated sanitization

SterilizationAbsence of viable microorganismsGenerally regarded as a Probability of Non-Sterile Unit at one in a million (PNSU 10-6)Inversely, Sterility Assurance Level (SAL 106)Dependent upon controlled conditions and defendable data

Sterilization & DecontaminationMeasured by Biological Indicator DestructionUse Spores as challenge organismBI use coupons, discs, etc. holding a population of sporesMost common sterilization to use overkill approachA science based upon probability, not perfection

PNSU/SALValidate Total Kill GMP CycleDecontamination

Chart1

6

4

2

0

-2

-4

-6

Spore Population (Log)

Time (min.)

Spore Population (Log)

Sheet1

TimeSpore Population (Log)

06

4

2

150

-2

-4

30-6

Sheet2

Sheet3

VHP - Cycle StagesGASSINGRETURNEnclosure

VHP Cycle ParametersHumidity inside the Isolator at the beginning of gassingInjection rate of hydrogen peroxideSwitching point from gassing phase to dwell phaseExposure timeGas concentrationTemperature of the surface to be decontaminatedTemperature inside the isolatorGas distributionAmbient temperature

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

Isolator DecontaminationMany agents have been employed:Peroxyacetic acidChlorine DioxideSteam/Peroxide OzoneFormaldehydeVapourized Hydrogen PeroxideVHP most common today

Operating TechniqueNot Sterile ProcessingRelies upon good, consistent aseptic techniqueMotion as/more important as in cleanroom, due to small size of spaceCleaning and material compatibility key for particulate control

Historic ProblemsExtreme difficulties in demonstrating Sterilization and Sterile ProcessingOvercomplicated and leaky designsPerfection set as goalZero leak specSterileMaterials and decon agent compatibilityJust equipment in a box

SummaryNow generally accepted technologyRelies upon solid design and operation practicesWidely held as the superior aseptic technologyHighly adaptable with associated devices and methods

The application of isolation technology to aseptic processing and containment of potent compounds can be viewed as opposite sides of the same issue. Each involves the separation of 2 environments to prevent the exchange of contamination between them. In aseptic processing the organisms on the operator are the contaminants which must be kept from contact with sterile materials and sterilized surfaces. In containment applications, the potent / toxic materials must be kept away from the operator. In non-isolator situations pressure differentials are used to enhance the separation, with the cleaner environment at a higher pressure than the contaminated environment. In isolation systems, this means a positive internal pressure for aseptic processing and a negative internal pressure for containment. Isolators are the most efficient means of accomplishing this separation.