Environmental Monitoring
The Irish Industry experience
PDA 11 Dec 14
Prepared by:
Jane Wyatt
FineFocus ltd
Presented by:
Margaret Corduff
AuQuality ltd
Objective: Present a practical and informative overview of the
Irelands experiences with environmental monitoring (EM)
• Environmental Monitoring:
•
Why do we do it?
• 2013 / 2014 – EM regulatory hot topics
• Overview of the top occurring issues:
•
Problems & recommended solutions
EM – Why we do it…
Environmental Monitoring – Why we do it?
Regulatory requirement (Annex 1, FDA sterile guidance):
• Monitor classified areas which support key production stages
But……
That is not why we do it…..
…We do it for the patient…
• To detect trends;
• To detect contamination
• To protect the patient…..
Even in the most regulated industries and facilities, with GMP controls in
place….things can & will still go wrong.
For this reason, our continuous improvement of the
EM program is critical.
EM – Regulatory Hot Topics
EM Regulatory Hot Topics
Topic
Audit Body
Detail
BSC
Monitoring
FDA
•
•
Definition of working height for total particulate monitoring;
Documented evidence that validated agents were used for
every clean of the BSC (incl. contact time)
Water
testing
HPRA
•
Expectation for a biofilm strategy to be in place for API site.
Incubation
HPRA
•
Concerns over industry is moving away from dual incubation
Media
selection
HPRA
•
•
HPRA reviewed a study at one site which demonstrated that
70% IPA is not neutralised by Lecithin & tween.
Following this, they brought it up for discussion during an
audit at another company & queried which neutralisers
worked best against which disinfectants.
Plate
reading
FDA
•
•
•
•
Dual peer review at plate reading & Real Time Review;
Logbooks;
Chain of custody;
Micro plate as raw data
Mould
Korean
•
Mould strategy
Trending
HPRA
FDA
•
•
Analysis of trends – method & conclusions
Results / numbers below alert levels
Rapid
methods
HPRA
•
Interested to "drive" the use of rapid methods
EM Common Problems across
sites in Ireland
Problem 1 – EM Location Selection
Background:
Expectation to perform a documented quality risk management
assessment to identify monitoring locations.
But which tool is appropriate?
Recommended Solution:
Design the model in line with ICH Q9 risk management principles.
For Example:
Step 1: Process map
Step 2: Identify all potential contamination hazards
Step 3: Rate the hazard for high, medium or low based on the severity & likelihood
of occurrence
Step 4: Implement additional controls where required (prioritise high risks) &
implement a level of detection for all medium & high hazards.
Problem 2 – Disinfectant Qualification
Background:
Disinfectant qualification in line with EN standards can give results where
facility isolates do not meet acceptance criteria for some contact
times
Recommended Solution:
Build your cleaning & disinfection program based on results from a
disinfectant study to achieve bactericidal, fungicidal & sporidical
activity
Problem 2 – Disinfectant Qualification cont.
For Example:
Company MML have a disinfectant A and sporicidal B.
Disinfectant A:
• Failed to achieve 2 log reduction for spores/mould at 5 min contact time;
• Can achieve this criteria at 15 min;
• 15 min is not practical on a daily basis.
Sporicidal B:
• Can achieve spore & mould 2 log reduction at 5 min
• Has EHS issues if used in excess.
Solution:
Do not complete further testing. Data achieved is sufficient to provide a full
compliment of kill.
Revise cleaning procedure to include the following cleaning regime:
• Use 5 min contact time with Disinfectant A daily to achieve bactericial activity;
• Use Sporicidal B (5 min contact time) to eliminate introduction of spores &
mould on material & personnel transfer;
• If observation of an adverse trend of spores or mould occurs, use Disinfectant A
to implement a response clean with an increased contact time of 15 min.
Problem 3 – Trends
Background:
How often should we trend and what are the minimum requirements?
Recommended Solution:
Reports should be:
• Easy to read;
• Inclusive of all classified areas;
• Assess hot topics month to month;
• Assess effectiveness of root causes;
• Be visual.
Problem 3 – Trends cont.
For Example:
EM Reporting minimum requirements:
1. Defined frequency
Monthly / quarterly / annually
2. Monthly summary
Document # samples, OOS, alerts, number of batches, activity
3. Rolling trend
12 months
4. ID Review
Types of organisms identified? Is there a drift from last period?
5. Numerical Review
How many counts over the period below alert? Any adverse trend?
% plates 0 – 5 cfu, % plates 5 – 10 cfu etc
6. Deviation review
Summary of OOS, re-occurrence, corrective actions
7. Conclusion
Constructive review & status of environmental control
Problem 4 – Media Selection
Background:
Commercial media available with a range of neutralisers, packaging, fill
volume. Which should you use?
Recommended Solution:
Process map the life of the plate and exposure conditions to design
media selection criteria. Use this criteria to best assess which media to
use.
Questions to ask:
1.
2.
3.
4.
What residual cleaning agents (if any) exist?
Is IPA sprayed in the vicinity?
Any chlorine based materials?
How is the media transferred into the critical zone? Any potential VHP or UV
ingress?
5. How long is the media exposed? Any impact from air changes and proximity to
HVAC exhausts which may cause dehydration?
Once selected, in additional to the vendor qualification documentation,
complete a site exposure validation to verify selection & demonstrate
capability
Problem 5 – EM Investigations
Background:
Re-occurring environmental monitoring investigations
Recommended Solution:
Make environmental excursions visual, high priority and not just your
problem
1. A0 communication posters – Bring the science back to basics!!
2. Hot spot maps
Problem 6 – EM Incubation
Background:
Incubation regime – Recent HPRA comment that they did not like the
single incubation regime.
Recommended Solution:
Maintain the use of single incubation
For Example:
1. Initially introduce dual temperature monitoring using USP guidance of the higher
temp first.
2. 7 days incubation
3. in larger organisations & where chain of custody, movement of plates, etc may
cause an issue – assess moving to single temp
4. Demonstrate that environmental isolates typically grown at lower temperatures
will flourish at the higher temperature
5. Isolate all moulds & yeasts and inoculate onto TSA at a low number (< 100 cfu);
evaluate to demonstrate that recovery between single and double regime is
within 50 – 200 % recovery
6. Annually complete dual temperature monitoring to detect potentially new
lower temperature organisms
Problem 7 – EM Frequency
Background:
What is the best frequency of monitoring in Grade C/D areas?
Recommended Solution:
Use risk management principles to determine the level of risk associated
with each room based on the process stage (with current GMP
controls in place) against historical occurrence & base the frequency
on this
For Example- Grade C Filling (Background to Isolator):
Controls:
• Rapid transfer of autoclaved materials into the decontaminated isolator;
• Hook up of product vessel using closed aseptic process;
• Daily cleaning & sanitisation, gowned personnel;
• Sterile filtered product.
Historical data – 12 months:
• On average 1 contamination event weekly.
Outcome:
Severity = Moderate
Occurrence = Intermittent
Monitoring frequency = Weekly
Risk
Rating
Frequency of
monitoring
Grade C
High
Every monitor
Weekly
Medium
Every 2nd monitor
Fortnightly
Low
Every 4th monitor
Monthly
Problem 8 – Facility isolates
Background:
How do you select facility isolates and do you select every category?
Recommended Solution:
Assess annually and select different categories (despite the fact that >
80% of organisms are typically Gram +ve cocci)
1. Trend all isolates identified through alert / action investigations
2. Select morphologically distinct isolates from all areas quarterly (below alert)
3. Trend all together and choose the top occurring:
1. Gram positive cocci
2. Gram negative rod
3. Mould
4. Gram +ve sporeformer
Even through 2, 3 & 4 will be present at a much lower level, they are critical &
must be used to qualify test methods to show that we can detect them in our:
a. EM media growth promotion
b. Bioburden and sterility method qualification
c. Disinfectant qualification
Problem 9 – Anaerobic Monitoring
Background:
Is there a requirement to perform monitoring for anaerobes
Recommended Solution:
No, unless you have a process that has oxygen depletion steps there is no
requirement.
In addition, it is difficult to apply a truly anaerobic EM method.
USP <1116>: monitoring for strict anaerobes should only be considered if
the process has oxygen depletion steps or if a strict anaerobe has
been detected from a sterility failure.
1.
2.
3.
4.
Assess all compounding, filtration and filling stages for the use of nitrogen
Identify potential areas where oxygen depletion steps may occur
Determine for these steps the risk of contamination (anaerobic or aerobic)
Assess the benefit of introducing a monitoring method into these steps over the
risk
5. In the event of a sterility failure due to the presence of anaerobic organism –
develop anaerobic monitoring processes including testing of gases and media
fills.
Summary
Summary
•
•
Top occurring EM issues are the same across the industry In Ireland
Approaches to problems include risk based, scientific approaches
which should be continually assessed and trended.
•
Keep sharing and networking within your industry
Thank You.
Irish Sterile Manufacturing network will meet again to discuss
more experiences in May 2015
Questions?
Thank you
[email protected]