MICROBIAL DATA

DEVIATIONS
EDEL FITZMAURICE

BEST PRACTICES IN ENVIRONMENTAL MONITORING

PHARMIG 13 FEB 2019
WHAT IS IN NAME
MDD Microbiological Data Deviations
Microbiological excursions
OOL Out of Action
WHAT IS NOT IN NAME
OOS Out-of-Specification (OOS) Results

Out-of-Expectation (OOE) Results

Out of Trend (OOT) Results

as defined by: FDA Guidance for Industry Investigating Out-of-

Specification (OOS) Test Results for Pharmaceutical Production

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PROGRAMME
Investigations
Repeat samples
CAPAs
Case Studies

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PHARMIG BEST PRACTICES IN ENVIRONMENTAL
MONITORING

HOW TO INVESTIGATE
OUT OF LIMITS RESULTS

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EXCURSIONS OR
DEVIATIONS
Very difficult to identify the root cause of an investigation
99% of all murders investigated with 8 hours of the murder
are solved
6 days before notice of above action or alert levels

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TIME LAPSE BETWEEN
SAMPLING AND RESULTS

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CRIME SCENE
We need to preserve the crime scene –
How best to do that

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CRIME SCENE
Use of camera may be useful in aseptic processing
Not commensurate with the risk in most non- steriles
Notes to document during sampling

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WHAT TO NOTICE
WHEN SAMPLING
How many people in
the area
Fast moving people
Adherence to
gowning regulations
Interventions
New Personnel
Filling hoppers/
Transferring
activities
Production activity

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WHAT TO NOTICE
DURING SAMPLING

Differential
pressure
Temperature and
RH
Impeded airflow
Packaging
materials
Paperwork
Water

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RECORDS
If it is not documented, it didn’t occur.
Did I have a problem with aseptic technique during sampling
?

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RECORDS
If it is not documented, it didn’t occur.
Did I have a problem with aseptic technique during sampling
?

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 THE MENTALIST V CSI
THE MENTALIST CSI LAS VEGAS
MICROBIOLOGY CHEMISTRY

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 CHALLENGES
ANALYTICAL OOS MDD

Result within hours Result available in

Can reanalysis test days
samples Cannot rerun
Can rerun standards samples

Can redilute Cannot recreate the

event
Can investigate the
data on Empower etc

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MICROBIOLOGICAL
DATA DEVIATIONS
NEIGHBOURHOOD
WATCH MULTIDISCIPLINARY

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THE TEAM
• Engineering Personnel
• Manufacturing Personnel
• Supply Chain
• Microbiology
• Quality Assurance
• QP
• An Oldie

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MICROBIOLOGICAL
DATA DEVIATIONS
No documented Regulatory guidance
OOS procedures – Analytical
Require SOP outlining actions
All actions including informing all relevant personnel must
be documented
Look at the organisms identified
• Staph /Micrococci – personnel
• Gram negatives – water
• Moulds – packaging materials

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MICROBIOLOGICAL
DATA DEVIATIONS

Act in a timely manner

Need to evaluate immediate impact on product
Need to act if repeated above alert
Root cause

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RISK ANALYSIS
TOOLS

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LAB BASED
INVESTIGATIONS
Was the correct sample size taken? Correct volume/ dilution of
sample?
Was the sample stored correctly before incubation?
Were the samples incubated within the allocated times?
Were the cultures OK?
Was there contamination present in other tests (or related tests)
performed at the same time, including environmental controls?
Was the correct Media used?
Was the media/reagent stored correctly before use?
What are the results of the Growth promotion and sterility testing?

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LAB BASED
INVESTIGATIONS
Was the sample media integral – i.e. no cracks in plates?
Was the Sample OK? Was it integral and secure (not leaking)?
Were the incubation conditions satisfactory?
Was the sampling and Lab equipment cleaned and sanitised correctly ?
Any issues with any equipment in the chain and command of the sample?
Were negative and positive controls satisfactory?
Personnel OK? Trained ? Qualified in Aseptic procedures?
Was the correct Aseptic technique employed in the lab?
Are the isolates located as expected – on glove dab marks, SAS ‘dimples’,
filter membrane etc.
Is the isolate part of the Culture Collection?
Take photographs to document the samples at time of reading (include
plates, gram stains and any thing else that may be relevant).

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DOCUMENT AREAS OF
INVESTIGATION
LOOK AT THE TREND DATA FOR SAMPLE POINT AND
ADJOINING AREAS
HVAC
Doors open , differential Pressure
Air returns impeded
Equipment layout
Adjacent areas
Materials airlock
Personnel airlocks

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DOCUMENT AREAS OF
INVESTIGATION
No. of Personnel in the area
Gowning: gloves; frequency of garment change
Packaging materials in the area
Raw materials in the air
Cleaning Validations
Cleaning schedule
Cleaning agents; suitable, expired ?

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PEOPLE

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ON THE BEAT
Only place to solve the
crime is at the scene
 Observe
 Observe
o Observe
Get into the “mind” of a
microbe

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PHARMIG BEST PRACTICES IN ENVIRONMENTAL
MONITORING

HOW MANY REPEAT

SAMPLES TO TAKE?

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THE QUANDRY
Do you repeat ?
Do you test first and then do additional cleaning and then
retest again?
Do you just want passing results ?
Test, test clean?
If you are continuously monitoring, what is the benefit in
resampling ?
Define in SOP what the resampling programme in different
rooms and grade areas

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CREATE IN-HOUSE
POLICY
What if you get two above alert within a set period of time
Do you treat as above action?
What is you get two above actions within a set period of
time?
Do you treat these events any differently ?

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CREATE POLICY
If in production, test at least twice within a given period?
Do you take additional sample locations as part of the
investigation
Do you take additional sample types ?
Does the same person or different person take the additional
samples

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PHARMIG BEST PRACTICES IN ENVIRONMENTAL
MONITORING

CASE STUDIES FOR OUT

OF TREND SITUATIONS
SOLVED CRIMES

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CHANGES IN ROOM
LAYOUT

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CHANGE THE
SAMPLER!
Some people are
persistent
shedders

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IMPEDED AIRFLOW –
DEAD SPOTS
Equipment layout
impeded airflow

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FUNGAL
CONTAMINATION IN
CHANGE AREA
Eventual source
was a water leak
behind wall and
floor seal

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MICROBIOLOGY LABORATORY &
OOS RESULTS
Intermittent high
fungal counts

Issue Contract
cleaners
Benches and
surfaces were last
to be cleaned
It was not on their
schedule !

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UNSOLVED CRIME
Gram Negatives in a grade D clean room air samples

If revisited – Human Microbiome ??

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THE DIFFICULTIES
You rarely know if you have solved an excursion or deviation
Did the issue go away of its own accord?- the homeopathic
effect
You can never recreate the crime scene
Chemists and engineers like solved solutions
Educating the QPs

The Mentalist v CSI

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PHARMIG BEST PRACTICES IN ENVIRONMENTAL
MONITORING

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 DON’T PROMISE WORLD PEACE

Don’t be aspirational
If you commit to additional testing – don’t forget about it and
3 years later wonder why you are using MCA in Air samples
May need inclusions in the change control procedures

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SOME COMMON CAPAS
Review action and alert levels are they appropriate
Change in Cleaning frequencies / techniques/ dilutions
Additional of a sporicidal clean
Retraining of personnel
• Including Laboratory/ Microbiologists/Engineering
Gowning Techniques
Relocation of equipment
Repairs to Equipment
Changes in Manufacturing
Change in the Purified Water or WFI management

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MAY NEED INCLUSIONS IN THE
CHANGE CONTROL PROCEDURES

If any construction work – informed, make recommendations,

additional cleaning, additional sampling using SDA
Changes in cleaning and disinfection materials
Cleaning and disinfection procedures
Cleaning Contractors

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THE CHALLENGE
Microbiology personnel have to investigate the issue and
may not be in possession of the full facts
Does Microbiology become the owner of the problem ?

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FUTURE
PDA and Microbial Data Deviations
Annex 1
Contamination Control Strategy

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QUESTIONS AND
THANK YOU
Edel@EFA.ie

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