GMP and BiosafetyGMP and Biosafety
Vibeke HalkjærVibeke Halkjær--Knudsen, Ph. DKnudsen, Ph. DDirector of Environmental Health and Safety DepartmentDirector of Environmental Health and Safety Department
Statens Serum Institute, DenmarkStatens Serum Institute, Denmark
Synergies and clashesSynergies and clashes
I Plan to Talk About…I Plan to Talk About…
The definition ofThe definition ofBiosafety and GMP
Synergies and clashesSynergies and clashesStrategies for sorting out clashesRisk assessments
ExamplesExamplesGeneral layoutVentilation systemsCleaning flows, e.g. from the IPV facility at SSIKill System, e.g. from the IPV facility at SSI
Biosafety Biosafety
DefinitionDefinitionA combination of procedures, containment systems, and construction technologies with the purpose of minimizing the riskminimizing the risk of infecting laboratories and prevent escapeprevent escape of microbes into the surrounding environment
PurposePurposeTo create a safe environment in which to research infectious diseasesTo prevent escapeprevent escape of infectious agentsTo minimizeminimize staff member’s and other people’s contactcontact with infectious agents both inside and outside the containment zoneTo preventprevent the introductionintroduction of infectious agents into the nature
When is it Relevant to When is it Relevant to ConsiderConsider BiosafetyBiosafety??
ManufacturersVaccine production (in combination with GMP, BSL2 )(in combination with GMP, BSL2 )GMO (Genetically Modified Organisms)
Hospitals/patient care facilitiesIsolation rooms with or without airlocks
Test laboratoriesVaccine productionHospitals/patient care facilitiesBioterrorism
GMPGMP
DefinitionDefinitionThe Good Manufacturing Practices (GMP) are the part of the quality assurance that ensures that pharmaceutical products products areare producedproduced consistentlyconsistently and controlled in accordance with the appropriate quality standardsThese standards depend on the intended use of the product and the requirements issued by the marketing authorisation (MA) or the product specification
GMP applies to both production and quality control
PurposePurposeTo ensure that the product is safethe product is safe for the end user
BiosafetyBiosafety –– GMPGMPSynergiesSynergies
Restricted accessRestricted accessSegregationSegregation of production areasFacility designed for easy cleaningeasy cleaningMinimizeMinimize contaminantscontaminantsValidate processesValidate processes, systems, equipment, and facilitiesJob certificationcertification and mandatory trainingtrainingMandatory personal protective equipment (PPE)(PPE)Written policies and proceduresWritten policies and proceduresDocumentationDocumentation, double signatures, etc.
GMP Requires…GMP Requires…
Large areasLarge areas compared to diagnostic & research labs.
Clean room requirementsClean room requirements, 20 air shifts per hour
Primary containment barrier is thePrimary containment barrier is the fermentorfermentorThe virus willwill be contained, as you are struggling to keep the bugs out!!!
GMP andGMP and BiosafetyBiosafety Design ClashesDesign Clashes
HVAC design
Room pressure
Doors
Cleaning rooms
Kill systems
GMP (keep out)GMP (keep out)Protect the productMinimize cross contaminationProduction flow: Dirty to clean (raw materials to purified product)
BiosafetyBiosafety (keep in)(keep in)Protect the employeesPrevent escape of materialsProduction flow: Clean to dirtyClean to dirty (non-infectious to infectious)
Why doWhy do BiosafetyBiosafety and GMP Clash?and GMP Clash?
Merging GMP and containment Merging GMP and containment
When synergy does NOT exist….When synergy does NOT exist….
….Necessitates a strategy….Necessitates a strategy
GMP andGMP and BiosafetyBiosafety ClashesClashesThen what ?Then what ?
Read the guidelinesUnderstand them
• Not only WHAT they say –•• But alsoBut also WHYWHY they say itthey say it
Is there another way to do it ?
Risk assessments
Decide on a solution
Brace yourself to face the authorities
”WHO’s: IPV Guideline””WHO’s: IPV Guideline”
The first guideline that tries to merge the two aspects
“Guidelines for Safe Production and Quality Control of IPV Manufactures from Wild Polioviruses”
Polio: BSL2 BSL3/Polio
http://www.who.int/biologicals/publications/trs/areas/vaccines/polio/Annex%202%20(65-89)TRS926Polio2003.pdf
Biosafety Biosafety -- Risk Risk AssesmentAssesment
EvaluateReservoirVolumeConcentrationPossible ways of escapeRoute of transmissionInfectious doseSusceptible hostsIncubation periodDecontamination principles
Along with Along with all other all other
aspects of aspects of product product safetysafety
Production Production -- Risk AssessmentRisk AssessmentIn different situations
During productionPlanned start up/shut downUnplanned start up/shut downFire/power failure CIP/SIP
For different aspects of the productionTemperature (high, low)Pressure (high, low)Flow (fast, slow, reverse)Volume/level (high, low)Mixing/surface tension/bubblespH, redox/densityLeakage/breakageTanks/pumps/pipes/valvesComputer/alarms/communication
Key wordsNone/too much/forgotten More/lessPart ofAddedReversed/wrong directionWrong component/objectLeaking/lostToo fast/slow/lateToo hard/softToo long/shortToo hot/cold
LargeLarge--Scale ProductionScale ProductionCan create a spillCan create a spill
Largest vessel on the floor (IPV 2,500 l)•• DilutionDilution leading to larger spill volume ?
• Pipes with water/growth media•• High pressureHigh pressure,
• Steam, gasses, pumps (3-7 Bar)
Can create a fireCan create a fire•• High temperatureHigh temperature
• Heating mantels, pumps, etc.
Special design considerations Special design considerations HEPA filters
• Testing, decontaminating, bagging out, etc.Floor drains, sloped floors, suction devicesPPE, waste handling, etc.
Special ongoing training and retrainingSpecial ongoing training and retrainingSlide slightly modified in handouts, pictures deleted
LargeLarge--Scale ProductionScale ProductionRisk AssessmentRisk Assessment
Due to GMP – we already have…Closed systemsClosed systems – a process requirement
Double filters & steam trapsDouble filters & steam traps on tanks etc. to keep all contaminating elements outout
• Thereby keeping the infectious agents withinwithin the tanks
Sterile tube weldersSterile tube welders for inoculation and sampling
Adequate monitoring and alarmsalarmsAutomatic shut downAutomatic shut down in response to critical alarms
cGMP procedures• Batch records, GMP trained employees, SOPs, log books, etc.
Which Guideline Wins ?Which Guideline Wins ?
After the risk assessment:
GMP takes precedence at a lowat a low biosafetybiosafety riskrisk
GLSP, BSL-1, or BSL-2
Biosafety should take precedence at a high biosafety risk
BSL-2, BSL-3, or BSL-4
In reality you need to comply with both
But “standard” technical solutions donot necessarily apply !
Examples of Possible ClashesExamples of Possible Clashes
Building layoutBuilding layoutGeneral aspectsGeneral aspects
Ventilation systemsVentilation systemsDesign considerationsDesign considerations
Cleaning flowsCleaning flowsClean versus dirtyClean versus dirty
Kill systemKill systemDesigned ”backwards”Designed ”backwards”
Production Rooms Production Rooms -- TightnessTightness
ContainmentAs few penetrations as possibleAs few penetrations as possible
•• Glue instead of nails/screwsGlue instead of nails/screws•• Sealed penetrationsSealed penetrations•• Pressure decay test, smoke testPressure decay test, smoke test
GMP (if run at a negative pressure)As few penetrations as possibleAs few penetrations as possible
•• Glue instead of nails/screwsGlue instead of nails/screws•• Sealed penetrationsSealed penetrations•• Smoke testSmoke test
•• Perfect view Perfect view •• Personnel safety Personnel safety •• Makes it visible to the Makes it visible to the
employees when the employees when the sealant must be renewed !sealant must be renewed !
Production Rooms Production Rooms -- SurfacesSurfaces
Containment and GMP
WallsWalls•• Vinyl, stainless steel, laminated glassVinyl, stainless steel, laminated glass
oo SteamableSteamable, easy to clean, easy to clean
FloorsFloors•• VinylVinyl
oo SteamableSteamable, easy to clean, easy to clean
CeilingsCeilings•• Numerous layers of paintNumerous layers of paint
oo SteamableSteamable, easy to clean, easy to clean
Which Way ?Which Way ?
VirusVirus
-+
+
+ Emergency Emergency ExitExit
GMPGMP
BiosafetyBiosafety
CorridorCorridor
Airlocks Airlocks -- SizeSize
VirusVirus
-+
+
+
HandwashingHandwashing sinks, PPE, spill handling kits, emergency showers, etc.sinks, PPE, spill handling kits, emergency showers, etc.
BiosafetyBiosafetywants wants
them close them close at handat hand
GMPGMPwants them wants them outside the outside the productionproduction
Airlocks Airlocks -- Production AreasProduction AreasContainment
A minimum of airlocks and doorsA minimum of airlocks and doors•• Some airlocks used for both materials and personnel to Some airlocks used for both materials and personnel to
minimize the amount of “holes” into the virus areaminimize the amount of “holes” into the virus areaElbow switches for opening airlocksElbow switches for opening airlocksHand washing facilities in production areasHand washing facilities in production areasInterlockedInterlocked
GMPDedicated airlocks for materials and peopleDedicated airlocks for materials and peopleUnidirectional flow of peopleUnidirectional flow of people
•• To ensure that dirty staff do not meet clean staffTo ensure that dirty staff do not meet clean staffHand washing facilities Hand washing facilities within airlockswithin airlocksInterlockedInterlocked
AutoclavesAutoclaves
Containment
DoubleDouble--door decontamination autoclavedoor decontamination autoclave•• In connection with the In connection with the
production areaproduction area•• Condensate led to kill Condensate led to kill
systemsystem
GMPDoubleDouble--door autoclavedoor autoclave
Water and DrainsWater and Drains
ContainmentBackflow devices on water systemBackflow devices on water systemNo cold WFI taps inside the virus areaNo cold WFI taps inside the virus areaNo floor drains to kill systemNo floor drains to kill system
•• We use CIP piping and a local vacuum system to We use CIP piping and a local vacuum system to transfer spill to the kill tankstransfer spill to the kill tanks
GMPNo floor drains to sewer systemsNo floor drains to sewer systemsNo domestic water inside production areasNo domestic water inside production areas
NN22 -- COCO22 -- Pressurized AirPressurized Air
Containment1 extra filter right after the wall leading to the virus area1 extra filter right after the wall leading to the virus area
•• Backflow can only move as far as this wallBackflow can only move as far as this wall
SteamableSteamable•• To be able to decontaminate, if a To be able to decontaminate, if a
backflow occursbackflow occurs
Drainable (2% slope)Drainable (2% slope)
GMP2 sterile filters right after the 2 sterile filters right after the wall leading to the virus areawall leading to the virus areaEnsures high quality gassesEnsures high quality gasses
WFI and Clean SteamWFI and Clean Steam
Containment
WFI still WFI still insideinside the buildingthe building•• SteamableSteamable, drainable, drainable
Clean steam Clean steam insideinside the buildingthe building
Vacuum Vacuum insideinside the buildingthe building
GMP
Hot sanitation of WFI systems is usually considered Hot sanitation of WFI systems is usually considered sufficientsufficient
Examples of Possible ClashesExamples of Possible Clashes
Building layoutBuilding layoutGeneral aspectsGeneral aspects
Ventilation systemsVentilation systemsDesign considerationsDesign considerations
Cleaning flowsCleaning flowsClean versus dirtyClean versus dirty
Kill systemKill systemDesigned ”backwards”Designed ”backwards”
Air flow Air flow -- BiosafetyBiosafety
VirusVirusCreate a directional flow Create a directional flow
towards the towards the contaminated areacontaminated area
Directional Flow Toward the Directional Flow Toward the Contaminated AreaContaminated Area
VirusVirus VirusVirus VirusVirus
-
0 or +
0
+
+
+ +
Directional Flow Toward the Directional Flow Toward the Contaminated AreaContaminated Area
VirusVirus VirusVirus VirusVirus
-
0 or +
0
+
+
+ +
GMPGMPBioBio Yes ! Hmmm ?!?
WHAT ? Hmmm OK
Inflow and Redundancy Inflow and Redundancy -- BiosafetyBiosafety
VirusVirus VirusVirus VirusVirus
-
0 or +
0
+
+
+ +0 0
Possible Possible CleanroomCleanroom Contamination Contamination -- GMPGMP
Virus Virus Virus
-
0 or +
0
+
+
+ +
Unusual GMP Nice GMP
A tight construction
Examples of Possible ClashesExamples of Possible Clashes
Building layoutBuilding layoutGeneral aspectsGeneral aspects
Ventilation systemsVentilation systemsDesign considerationsDesign considerations
Cleaning flowsCleaning flowsClean versus dirtyClean versus dirty
Kill systemKill systemDesigned ”backwards”Designed ”backwards”
Clean Versus Dirty Clean Versus Dirty –– Cleaning CartsCleaning Carts
It is a challenge: It is a challenge: to have the right carts
at the right place
at the right moment
spare carts
and enough people
UpstreamUpstreamvirus growthvirus growth
Media prep.Media prep. TouristTourist corridorcorridor
Upstream cell Upstream cell propagationpropagation DownstreamDownstream
InactivationInactivation
Slide slightly modified in handouts, floorplan deleted
Clean Versus Dirty Clean Versus Dirty –– Cleaning CartsCleaning Carts
It is alsoIt is alsoa challenge:a challenge:To get the carts To get the carts back through the back through the autoclave during autoclave during the nightthe night
Slide slightly modified in handouts, floorplan deleted
Examples of Possible ClashesExamples of Possible Clashes
Building layoutBuilding layoutGeneral aspectsGeneral aspects
Ventilation systemsVentilation systemsDesign considerationsDesign considerations
Cleaning flowsCleaning flowsClean versus dirtyClean versus dirty
Kill systemKill systemDesigned ”backwards”Designed ”backwards”
Slide slightly modified in handouts, PI diagram deleted
Kill System Kill System –– IPV Facility in DenmarkIPV Facility in Denmark
ContainmentContainmentSteam traps ABOVE and BENEATH the tanksSteam traps ABOVE and BENEATH the tanks
• Large volumes of highly concentrated virus harvest
GMPGMPDesigned ”backwards”Designed ”backwards”
• Waste flows directly into the treatment tanks (tank volume)• Buffer tank on the backside of the system
Steam decontamination of all collection pipesSteam decontamination of all collection pipes• Due to the risk of bacterial infections
Kill SystemKill System
Volume, homogenization, and concentrationVolume, homogenization, and concentrationDecontamination of liquid waste from the production
• Up to 2,500 l of concentrated virus harvest2,500 l of concentrated virus harvesto if a microbiological contamination of the batch occurs
Liquid waste – pH range: 2 pH range: 2 –– 11;11; NaOH, HOAc
Discharge to sewer – pH range: 5 pH range: 5 –– 99
Almost no solids – only cell debris• Easier to decontaminate than waste from animal facilities• Pre-homogenization/grinding unnecessary• Steam injection is enough to ensure proper mixing
Steam TrapsSteam Traps
Treatment TanksTreatment Tanks
pH Adjustment LooppH Adjustment LoopSinkSink
AutoclaveAutoclaveCIPCIP
UpstreamUpstream
SIPSIPDownstreamDownstream
BuffertankBuffertank
pH pH –– 22--1111
pH pH –– 55--99
Thank You Thank You Thank YouThank You
