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Microbiological Validation
Mark OldcorneWrexham Maelor Hospital
What is Validation?
The QA of any preparation activity is reliant on the satisfactory validation of the procedures
Validation should demonstrate that the overall process will reproducibly provide a product that complies with its specification
What is validation? Action of proving, in accordance
with the principles of GMP, that any procedure, process, equipment, material, activity or system leads to the expected results
Action of proving (and documenting) that something ‘works’
5 Pillars of GMP Premises People Processes Products Procedures
Profit!!!
Overview
Microbiological validation of Premises
environmental monitoring cleaning and disinfection
People operator broth transfer tests hand cleaning and disinfection
Overview Processes
process broth tests transfer spraying validation gassing processes
Products sterility tests
Underpinned by Procedures(parametric release!)
Validation Master Plan Part of
QA programme Site Master File
Schedules Methods Responsibilities
MicrobiologicalValidation Methods
Physical - AHU\filtrationPhysical - AHU\filtration
Microbiological - Personnel Microbiological - Personnel activityactivity
Microbiological ValidationGeneral Considerations 1 Biological systems
biological variability imprecision of methods low levels of contamination
Stressed / damaged organisms
Microbiological ValidationGeneral Considerations 2
Growth requirements of organisms require universal growth media TSA + Sabs Dex
Sequential temperature monitoring vs use of multiple media
Microbiological ValidationGeneral Considerations 3
Incubation times
5-7 days
but must read after day 1
Recovery Rates for TSA and SAB platesCherwell plates (irradiated)
Exposed for 3 hours in dispensary
0
10
20
30
40
50
60
0 1 2 3 4 5 6 7
Incubation Time - Days
cfu
TSA 32oC SAB 25oC
Microbiological ValidationGeneral Considerations 3 Incubation times
5-7 days but must read after day 1
Incubation temperatures Bacteria - 30-32oC Fungi 20-25oC
Microbiological ValidationGeneral Considerations 4 Sterile media
Aseptically prepared plates Pre-incubation
Irradiated plates less risk of false positives growth characteristics altered
Fertility assessment
Microbiological ValidationGeneral Considerations 5
Viable but non-culturable organisms (VBNC) Presence of non-recoverable organisms
Results are Retrospective Prospective release Retrospective release
Interpretation of Results
Facilities management Investigational threshold (Alert limits) Action limit
Counts ID of Organisms
source of organism consequences of contamination presence of new organisms failure of control measures
Trend analysis 1
Identify progressive and gross changes
variables
Workspace
Room
Product
Operator (not just aseptic processing)
Operator – spraying in
Trend Analysis 2
Methods available visualisation by charting and graphical methods statistical analysis population study software exception reporting
follow up of problems limitation of variables number of exceptions (investigational or action limits)
used as a measure of cleanliness
Microbiological Environmental Methods Random Methods
Settle plates
Contact sampling
Finger dabs
Organised Methods Active air sampling
*Assumptions**Assumptions*
Settle Plates
method of collection sampling area sampling time positioning
trend analysis representative sample
laminar air flow consideration 0o, 45o and 90o
Surface Counts
methods Rodac Plates Swabs Proprietary systems
sampling area and location pickup efficiency neutralisation post sampling removal of media application pressure validation of disinfection processes
Finger Dabs
sampling technique
what does it assess?
holes in gloves
poor transfer disinfection
Active Air Sampling
methods impingement filtration
sampling efficiency - recovery rates particle size sampling method
disruption of air flow - isokinetic probes
quantitative comparison accessibility sensitivity
Sterility Testing Ideal test? - product Test lacks sensitivity Retest only available under certain
conditions Prospective vs retrospective Appropriate levels of control SAL of testing process
Broth Transfer Testing 1 Process transfer tests
worst case scenario >batch size x3 initially 6 monthly repeat
Operator transfer tests Universal Broth Transfer Test Adapted operator tests or process tests
Broth Transfer Tests 2
Ideal test? - QA of process
Statistical considerations to reach AQL
1 in 1000
or 1 in 10,000
Frequency?
Sensitivity - do we challenge the test?
Conclusions Microbiological validation indicates
personnel involvement All microbiological validation
methods have limitations Microbiological validation methods
cannot be used in isolation and should be used holistically to gain a true picture of product assurance
The future Where does the validation cult go?
Next stage is validating the validation
Next stage to that is validating the validation of the primary validation and so on……….
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