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Risk Based Approaches to Setting Environmental Monitoring Programs
Fergus O’ConnellQA Manager
AMS Laboratories
Purpose of Environmental Monitoring• To demonstrate effectiveness of:
– Housekeeping activities– Production and maintenance activities– Operator discipline– Compliance to standards.
Also,– An environments suitability for planned activities.
• Need to establish microbial risks involved– Facility– Equipment– Processes– People
• Risk Assessments should aid in setting up monitoring programs which are:– manageable, – meaningful and – defendable
• Risk Sources– Manufacturing Process– Manufacturing Environment– Human Factors
• Generic risk assessments can cover a number of productsDon’t forget product-specific considerations
EM Program - Design & Qualification• Questions for EM program:
– Locations & number of sites?– Frequency of testing?– Technical type – Active, Passive, Surface?– Clean Status?– Time (in operation/at rest)?– Are there any other important aspects specific to the site?
• Each aspect– Provides data relating to the efficiency of control measures. – Should be tailored to suit an individual site.
Where to Start?• A useful starting point:
– Map the full manufacturing process• Activities e.g. interventions, • equipment & • process parameters.
• Assess the risks for each at different stages of EM Life-cycle– Pre-qualification (theory but no data)
• Oversampling needed.– to determine the most sensitive locations
– Post-qualification (risks help selection of routine sites).– Periodic re-assessment during routine monitoring.– After any process changes.
• Is there a need to adjust the EM program?
Site Selection• EM qualification study:
– provides useful information for selecting the routine EM sites.• sites which give the highest counts
– Most sensitive measure of control status.
• sites appropriately placed to herald a problem in each room.
– Qualification Report/Risk Assessment should define:• Number & location of sampling sites,
– Air » Active» Settle Plate
– Surface» Swab» Rodac
Number of Sites – one suggested approach• Viable & Non-Viable measurements
– Similar numbers of sampling points – Same locations (or as close as possible).
• Settles plates– Similar number of sites as active & particulate monitoring– Different locations
• Surface Monitoring– Guidance is very limited here
» “Square root of the area” method difficult to apply to equipment
– Individual facilities should justify the number of surface sites.
Note: Monitoring during production should be considered in the initial risk assessment.
PDA Technical Report #13 (Revised 2001) considerations for site selection:
– Where would microbial contamination adversely affect product quality?
– Which would most likely demonstrate heaviest micro proliferationduring production?
– Which would represent those most inaccessible or difficult to clean, sanitize or disinfect?
– What activities in the area present risks and contribute to the spread of contamination?
– Would the act of sampling at a site contaminate the product or cause erroneous data to be collected?
• PIC/S – for aseptic operations “sampling methods used in operation should not interfere with zone protection”.
• FDA – “It is important that locations posing the most microbiological risk to the product be a part of the program”.
• USP – “Microbiological sampling sites are best selected when human activity during manufacturing operations are considered”.
– recommends observing & mapping of cleanroom activities• Movement & positioning of personnel.• Identify the most frequent interventions.
Site Selection
Site Selection• Monitor sites with a greater opportunity to contribute
bioburden.
High Risk Areas– Product contact: vibratory trays, gloved hands etc
Lower Risk Areas– Non-product contact: pass-through hatches, floors etc
• Note: Factors important to site selection may be unique to a facility.
• Most critical sites are not always practical– Risk: monitoring these might result in product contamination
– Identify indicator sites • near, but not in contact with, the product.
What to Monitor
• Consider anywhere contamination can be transferred– Some examples include:
• Pooling of water,• The act of cleaning & storage,• Contamination transfer by equipment wheels or by foot,
– E.g. from a lower class to higher class area.
Identify worst case areas and activities (Risk Assess)
Some examples:– Areas/Activities with proximity to product and product
contact– Human Factor – high activity and/or traffic (e.g. door
handles)– Areas with poor air flow (dead zones)– Personnel Flow– Material Flow– Waste Flow– HVAC returns– Interventions & Manipulations– Drains present
Method Risks • Active-air sampling risks
– consider air flow patterns for critical locations– impact of EM personnel & equipment
• Risk to product and the sample.– variability of upto tenfold possible between commonly used
devices – USP<1116>
• Settle Plates risks– Prone to dessication
• long periods of exposure• high airflows• qualitative/semi-quantitative
• Contact Plate Risks– If no disinfectant neutralizer present,– Not suitable for irregular surfaces,– Microorganism confluence (if media is wet),– Media residue must be removed.
• Swab Risks– Results impacted by poor technique and sampling,– Manipulations required to culture the sample,– Poor transfer efficiency,– qualitative/semi-quantitative,– <50% recovery,
• Less where organisms are stressed i.e. in production environments.
Manufacturing Process Risk Considerations
• Solvents– Water-based processes more favorable for microorganisms,– Alternative solvents might decrease the risk.
• pH– Values below 2 and above 10 detrimental to microbes.
• Drying– Water Activity (Aw) <0.6 suppresses microbial growth,
Scale 0.0 -1.0 (completely dry - pure water)Tablets ~0.36
– Some organisms may remain viable and pathogenic at low numbers (e.g. Salmonella spp.).
Manufacturing Process Risk Considerations
• Temperature
– 25-350C promotes growth.
– Significantly higher/lower temperatures suppress growth.• Note: different microbes thrive across a broad range of
temperatures– Cryophiles– Mesophiles– Thermophiles (>450C)– Hyperthermophiles (>800C).
• Campaign Lengths and Hold Times– Opportunities for microbial proliferation should be considered.
• A lower risk if conditions are detrimental to growth.
Manufacturing Process Risk Considerations
The Human Factor• Heavy physical labour/Increased numbers of personnel
– Increases risk of contamination• Enhanced sweating• Shedding of skin particles
• Aseptic technique may deteriorate with passage of time– Also with the time of day - day shift versus night shift.– Consider
• longest period of time an operator must perform a repetitive task
• fatigue at the end of a normal days production.
Production Environment• The degree of monitoring should be aligned with risks
associated with the – product, – process– patient.
• Low Risk Areas e.g. tablet manufacturing– policy should focus on
• Bioburden control measure• Targeted monitoring of
higher risk areas– e.g. aqueous coating solutions.
– A lower monitoring frequency may be justified for production areas.
• Highest Risk Areas– batch by batch monitoring may be appropriate.– Focus on Bioburden/Endotoxin control.
Note: Periodic ID to the species level:• provides knowledge of
site-specific flora,• helps to detect changes in
the facility.
System SurveillanceDifferent processes – different risks
• Terminal Sterilization – EM Focus: Microbial flora contributing bioburden & endotoxins
prior to sterilization.
• Aseptic Filling– EM Focus: Number and type of microorganisms in direct contact
with product prior to sealing containers.
• Isolation Technology– EM program similar to aseptic filling.
• Exception of surface and personnel monitoring.• Monitoring of isolator gloves/half-suits should be considered.
When to Monitor – Frequency & Approach• Classified Areas
• Annex 1 of the PIC/S GMP guide• ISO 14698 (2003)
• Unclassified areas/facilities• Risk Assessment should support frequency.• No clear consensus.• Frequencies range from weekly to annually.
– Different frequencies for different risk areasA non-specific example:• Weekly – Final fill, wash bays• Monthly – Dispensary, unclassified rooms.• Quarterly – Change areas, equipment storage rooms.
Remember“No sampling scheme is appropriate for all environments”
Changes in frequency may be required– development of significant trends– new equipment introductions– nearby construction of rooms/utilities– Following maintenance
• Standard cleaning may not be appropriate
Proposed reduction in sampling frequency– Historical data should be reviewed– A Risk Assessment should be performed
Setting Environmental Limits• A balance between:
unnecessary action & insufficient action.
• Limits for non-sterile manufacturing– Not typically set by regulations– Manufacturer must set appropriate limits– Regulatory expectations
• Risk Assessed• Based on historical data• Deviations from the norm are readily detectable
Setting Environmental Limits• Low counts (e.g. ISO 6, LFUs)
– results approach Poisson Distribution (tailing due to random effects)• Alert Limit: 95th Percentile• Action Limit: 99th Percentile
• Higher Counts (e.g. ISO 7 and higher)– results may approach normal distribution
• Alert Limit: +2σ (2 x Std Deviation)• Action Limit: +3σ (3 x Std Deviation)
Note: Need to critically assess (sanity check) the figures .Ensure the limits are commensurate with the risk.
Example: Non-sterile products are unlikely to require action limits significantly tighter than Grade C limits (100cfu/m3).
Reviewing Limits:– should be reviewed/adjusted periodically
• Remember to remove outliers
– Tightening limits:• Easy to justify
– Increasing limits:• May be necessary e.g. increased activity in area.
– Need to demonstrate the environment and processes are still under control.
– Risk Assessments/Investigations should be used.
InvestigationsAddress:• Need to identify the predominant micro-organisms• Review activities in the area• Functioning & suitability of equipment• Interview personnel• Cleaning records• Trend data of related monitoring sites• Need to increase monitoring frequency
Overall goal – find out what changed.
SummaryA variety of risks challenge each environmental control system.
These risks present at different times & stages of the EM lifecycle.
Risk Assessments are a useful tool to anticipate challenges and justify monitoring strategies.
References• Parenteral Drug Association
Technical report No. 13 (Revised): Fundamentals of an Environmental Monitoring Program, 2001.
• Parenteral Drug AssociationTechnical report No. 62: Recommended Practices for Manual Aseptic Processes, 2013.
• USP General Chapter <1116>Microbiological Control and Monitoring of Aseptic Processing Environments.
• FDA, Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice, 2004.
• Qualification of an Environmental Monitoring Program.Scott Sutton. Ph.D.; Journal of Validation Technology, Spring 2010.
• Microbiological Control for Non-Sterile PharmaceuticalsPharmaceutical Quality Group of The Chartered Quality InstitutePharmig Monograph No. 2, PQG Monograph No.12, November 2008
References• ISO 14698-1:2003 Cleanrooms and associated controlled environments -
Biocontamination control - Part 1: General principles and methods• ISO 14698-2:2003 Cleanrooms and associated controlled environments -
Biocontamination control - Part 2: Evaluation and interpretation of biocontamination data
• PIC/S Guide to Good Manufacturing Practice for Medicinal Products - Part I, PE 009-8 (2009); Chapter 5 Production.
• PIC/S Guide to Good Manufacturing Practice for Medicinal Products PE 009-8 (2009); Annex 1 - Manufacture of sterile medicinal products
Thank You
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