Sterilies Flashcards
What are the CQAs of a sterile product?
Absence of micro-organisms, Endotoxin control, absence of particles, isotonic, Pure, labelled correctly, container closure integrity.
What standards are applied for HEPA filter testing, Air velocities and room air change rates?
What grade of filters would you expect for critical areas
HEPA filters- 99.97% DOP at 0.3u
Air velocities - 0.45m/s -+ 20%
Air change rates- 20 per hour minimum, more in grade A/B.
H14 filters in critical areas
Annex 1 viable limits per grade
A- <1 for all samples
B- 10 for AAS, 5 for all other samples
C- 100 for AAS, 50 for SP, 25 for CP
D- 200 for AAS, 100 for SP, 50 for CP
Tell me about Gamma radiation
25Kgray of Cobalt 60
1-3 hours exposure time
Perspex dosimeter (red dot)
Bi- Bacillus Pumilis
What controls are present for freeze drier cycle?
Drop temp, drop pressure, raise temp under pressure = sublimation.
1 and 2 drying phases
Leak rate 0.02 mbar/l/s
Chamber sterilisation per batch
What are the specifications for purified water?
<100cfu/ml
<500PPB TOC
<5.1ms Conductivity- 25degrees
<4.3ms conductivity- 20degree
What are the specifications for WFI?
<10cfu/100ml- 200ml min sample volume
<500PPB TOC
<1.3ms Conductivity 25degrees <1.1ms 20degrees
<0.25 EU/ml endotoxin
What are the steam quality standards?
EN285
>95% dryness fraction for porus loads
3.5% Non condensable gasses
<25Kelvin superheat
What do you understand by D value, Z value and F0?
D value is the time taken at 121 degrees to reduce bacterial count by factor of 10
Z value is the change in temperature required to adjust the D value by a factor of 10 at the same time value
F0 is the total lethality time over a sterilisation cycle- taking into account heat up and cool down. Minimum EU F0 is 8. F0 at 121, Fh at 170
What would you expect to see in autoclave validation?
Assume aseptic
IQ/OQ/PQ
Calibration of thermocouples
Fertility test for BIs + Spore count
Geobacillus stereothermophillus
Empty chamber temperature mapping
Worst case load temperature mapping- TCs and BI in hard to reach areas
Include coldest areas (drain)
Review TC data for cycles performed
Watch for slow temp increase- could be conduction rather than latent heat
Combination of TC data and BI kill data
Post fertility test for BI media and BI batch control sample.
Review Leak rate data (1.3mbar)
Review steam penetration in comply packs colour change.
Tell me about ETO sterilisation
Ethylene oxide- chemical sterilisation
Entry of ETO into area/ isolater
Exhaust system in place
Need to ensure no occluded surfaces
Need to control temp + humidity within environment
How do you validate sterile filters?
HMA/ASTM bacterial challenge test
Product surrogate flow and Brevindimonus dimintua 10 to 7 contamination
Worst case filter conditions- Temp, humidity, flow, pressure, time.
Analytical filter post test filter to incubate and identify any organisms.
What are standards for HVAC qualification?
What are Grade A particle requirements?
ISO 14644
At rest and in operation
Particle counts
3520 0.5u and 29 5.0u for grade A
What standards are there for dry heat serilisation?
160degrees - 2 hours (EP)
250 degrees- 30min depyrogenation, 3 log endotoxin reduction
BI bacillus atropheus.
Pipework requirements
2% orientation
No deadlegs 3x diameter of pipe
Turbulent flow in pipe
1-3m/s movement
What activities would you expect in each area classification?
A- High risk filling
B- Background to Grade A
C- Component wash, preparation. Isolator background
What Grade of filters would you expect in critical areas? What efficiency % would you expect?
H14
99.97% under DOP test with 0.3u size
What is ISO Standard for viable EM?
ISO 17141
What are particle limits for grade A/B at rest and in operation?
Grade A
5u- 29 0.5n 3520
Grade B- At rest
5u- 29 0.5u 3520
Grade B- In operation
5u- 2930 0.5u 352000
What are critical factors for disinfection?
What schedule would you expect for an aseptic facility?
Contact time
Application method
Concentration
Temperature
Schedule;
Critical areas and production floors- Daily
Background areas walls and rooms- Weekly
Less critical rooms and ceilings- Monthly
What elements are in a CCS?
Facility design
Utility design and control
Maintenance
Environmental monitoring approach
Personnel training and gowning
Container closure
Sterilisation methods
Control of incoming materials
Control of vendors and outsourced activities
Cleaning
HVAC and air quality
Describe a typical isolator setup and gas cycle.
How would you validate an isolator?
Isolator designed as a total barrier- Grade A
Located in C/D area
Integrity is critical
Sterilant gas cycle is critical
Load, close, gas, setup line, Filling operation, product out of mousehole.
Validating isolator;
Annex 15
HEPA integrity tests
Airflow to ISO 14644
VHP Gas cycle;
- Temp, humidity, loading pattern, BIs, contact time, Concentration.
Describe a typical RABs unit
What controls/tests would you perform?
Remote access barrier
Can be open or closed RABS- designed to provide product protection
Located in grade B
Not a total barrier
Gauntlet integrity test
Material transfer/ manual cleaning controls
What are the main risks with single use systems?
Extractable and leachable contaminants
Heavy reliance on supplier for critical product contact components.
What are quality considerations for pre-filled syringes?
Combination products- subject to medical device regulations
Sterile components which have aseptic fill
Plungers and stoppers have critical dimensions and unique placement mechanisms (Vent/ vacuum).
What are the quality considerations for blow fill seal products?
Aseptic point of fill operations
Thermoplastic granule sterility/ bioburden
Bulk material filtration
System sterilisation
Media fill
Describe a pharmaceutical water system
Potable water> Inlet Tank>Chlorine dosing>Pre-filtration>Carbon Bed>Softener>RO>CEDI>UV>PW Tank + Distribution loop> Multi effect still or RO> WFI tank>WFI loop at 80degres.
Water speed in pipework?
Roughness value of pipework?
Deadleg maximum acceptance?
In line monitoring expectations
1-3m/s turbulent
0.8Ra
6x pipe diameter
Monitor TOC, Conductivity, flow rate, temperature
Describe a de-pyrogenisation tunnel
How would you validate a tunnel?
Incoming vials/ components on conveyor
Subject to 250degrees for 30 mins
Cooled via HEPA filtered air
Exit tunnel into Isolator/ controlled area
Validation using annex 15
Temperature data- TCs across the conveyor (edges)
Airflow data to comply with ISO14644- impact to other controlled areas.
HEPA filter integrity pre-post runs
Biological indicators
Particle monitoring
3 log reduction in spiked sample of endotoxin (recovery efficiency established)
3x runs TC in cold spot
Media fill
What are incubation conditions for media fill?
TSB- 7 days 20-25, 7 days 30-35
Growth promotion for batch of broth used.
Why might you have a failed filter integrity test?
Unlikely the filter
Damaged housing
Incorrectly wetted
O ring failure
Incorrect cycle
Uncontrolled temperature during test
What is the ISO standard for compressed air quality? What are you checking for?
ISO8573
Oil content
Dew point
Particles
Micro
What are the different type of active air samplers?
Slit to agar- air pumped onto agar through slit
Sieve impactor- Air drawn through sieve
Centrifugal Sampler- Turbine pulling calculated volume of air onto agar plate
When do you need to requalify cleanrooms?
What would you measure to requalify?
Post changes/ issues
Grade A/B every 6M
Grade C/D every 12M
Particle count
Terminal HEPA integrity
Airflow/ rate
Pressure differentials
Air velocity
How would you qualify a cleanroom?
ISO 14644, Annex 1 annex 15, ISO 17141.
URS- product, process, capacity etc needs
DQ- review design ensure fit for intended operations
IQ- materials of construction, ducting requirements, tagging, access.
OQ- Meets ISO14644 particle standards
PQ- Meets air change rates, pressure differentials, air velocity and micro requirements. Smoke study to visualise.
Media fill.
