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