Establishing EnvironmentalMonitoring Programs Utilizing

A Risk Based Approach

Kelly Thomas– Atlantic Technical and Validation Services

1Copyright 2016 by

Atlantic Technical and Validation Services

Agenda• Review Regulatory & Industry Guidance governing EM programs

• How to Establish Base-Line EM data for facilities

• Discuss Risk Analysis Methods

• The Importance of Trend Reports

– Frequency / Content

• Regulatory Trends– PAT

• Case Studies

– Real-life inspection stories related to EM programs

– Review of 483 findings2

What is Environmental Monitoring?• QC analyst sample controlled environments for:

– non-viable particulates

– viable air

– surface

• Assesses the effectiveness of cleaning /disinfection program

• Trending EM data provides very insightfulinformation

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Non-Viable Particle Levels GovernRoom Classification (ISO 14644)

• ISO 5

– Used in Aseptic Processing, rooms where sterile productsor packing components are exposed to the environment

• Limit: > 0.5 um = 3,520 particles / m3

> 5.0 um = 29 particles / m3**

• ISO 6

– Starting to see more of this room classification. Usuallynext to ISO 5 areas

• Limit: > 0.5 um = 35,200 particles / m3

> 5.0 um = 293 particles / m3**

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Non-Viable Particle Levels GovernRoom Classification (ISO 14644)

• ISO 7

– Commonly seen adjacent to ISO 5 rooms

• Limit: > 0.5 um = 352,000 particles / m3

> 5.0 um = 2,930 particles / m3**

• ISO 8

– Non-Sterile Areas

– Used for terminally sterilized products

• Limit: > 0.5 um = 3,520,000 particles / m3

> 5.0 um = 29,300 particles / m3****EU and Japan set limits for 5 micron particulates

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Regulatory & Industry Guidance governing EM

• USP <1116>

– Chapter was revised in 2012 with MAJORchanges governing EM of aseptic operations

– Risk-based thinking now REQUIRED forroutine sample location and frequencydetermination

• Sample locations / frequency based on risk toproduct.

• NO LONGER based on area of room!!!6

Regulatory & Industry Guidance governing EM

• USP <1116>

– Data reporting requirement change: Must showthe percentage of plates that displayed ANYmicrobial growth even if the alert or action limitwas NOT exceeded.

– Alert and Action levels are defined by data

• USP <1115>

– Governs Environmental Monitoring of Non-SterileProducts

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Elements of a Robust EM program

• Trained personnel– Adherence to good sampling techniques

• Approved Procedures– Sampling maps detailing frequency

• Area Qualifications– Static and Dynamic Conditions

• Qualified and Calibrated equipment– Particle counters, viable air samplers, incubators

• Trending– Add / Remove sites based off data

– Alter sampling frequency based off data 8

3 Phase Life Cycle for EM Programs

• Phase One:

– Room qualifications

• Phase Two:

– Establishing Base-line data

• Optimization / Continuous Improvement

– Trend reports

– Modify site number, locations, and frequency basedoff data

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Phase One: Room Qualification

• Utilize formula provided in ISO 14644 to determinenumber of sites needed in each room.

• Based on square footage of the room

NL = √A

NL: # of locations

A: area of the room in square meters

• Specific to non-viable particulate sample locations;however, I recommend also doing viable and surfacesampling at the sample locations.

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Phase Two: Base-Line Data

• Post room qualification, routine EM sites andfrequencies must be set.

– DO NOT continue to monitor all the same sites from theroom qualification

– Utilize Risk Based Methodologies to determine sitesand document rationale / justification for site selection(and for sites not selected).

• Maintain sites for one year to obtain data for ALL 4seasons.

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Overview of Risk-Based Methodology

• Step 1: Planning

• Step 2: Determine Activities that could impact the ControlledArea

• Step 3: Perform Risk Assessment

– Several tools exist: FMEA, PHA, Risk Priority Number

• Step 4: Selection of Sample Locations and Frequencies

• Step 5: Optimization / Continuous Improvement

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Step One: Planning• Utilize a cross-functional team to ensure all

aspects are considered

– Micro

– QA

– Manufacturing

– Facilities / Engineering

• Select the Risk Management Tool that will beused.

• Determine scoring

– Highly recommend to procedularize this13

Step 2: Activity Impact Assessment• Team members should evaluate ALL activities

that occur in the controlled area that couldhave an impact on the environment.– Gowning

– Personnel flow

– Material / equipment / waste flow

– Cleaning

– Equipment / Materials

• Visual tools aid in completing this activity– (Fishbones, Cause & Effect, Process Maps)

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Fishbone Example

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ControlledEnvironment

Man Mother NatureMachine

Behavior

Process Knowledge

Gowning

Training Airlocks

Sinks

Floor Drains

Production equipment Outside temp

APIs / Raw materials

Floods

Packaging materials

Hoses

MethodMaterials

Carts

Equipment Operating SOPs

Cleaning Supplies (mop heads, disinfectants)

Cleaning SOPs

Step 2: Activity Impact Assessment

• Have the team walk through each room soeveryone can clearly visualize the area lay-outand flow of activity. Talk to the operators inthe room. They know BEST!!

• Ensure team members understand whatprocess will be occurring in the room

– Wet operations

– Open or closed processes

– Type of product

Copyright 2012 by East Coast ValidationServices, LLC.

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Step 3: Perform Risk Assessment• Different tools are available to determine Risk

levels.

– Failure Modes and Effects Analysis (FMEA)

– Preliminary Hazard Analysis (PHA)

• Use the tool the team is most comfortable with

• Highly suggest having a SOP governing RiskAssessments and provide templates for thetools.

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Risk Assessment Tools: FMEA• Identify Failure Modes

– Ex: Surface sample exceeds limit

• Identify Harms

– Ex: Environmental contamination in the clean room

• Identify Hazardous Conditions

– Floors, walls and equipment surface contamination

– Personnel contaminated

• Score the Severity, Occurrence and Detection18

Risk Assessment Tools: FMEA• Tips on Scoring

– Ensure enough separation between Low, Medium, Highscoring numbers to give adequate Risk priority numberresults. DO NOT USE 1, 2, 3

• To help eliminate subjectivity, define categories as best youcan.

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Severity Level Scoring

Low 1

Medium 3

High 9

Severity Level Description Scoring

Low No harm to patient 1

Medium Potential health risk 3

High Death 10

Risk Assessment Tools: FMEA

• Determine Risk Priority Number (RPN) for eachfailure mode. (Multiply scores: S x O x D = RPN)

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Failure Mode Severity Occurrence Detection RPN

ImproperGowning

3 1 10 30

MissedCleaning

1 6 8 48

Air HandlerUnit shutdown

9 1 10 90

Risk Assessment Tools: FMEA

• Determine EXISTING Control Measures

– Ex: Gowning, cleaning

• Determine if ADDITIONAL Controls neededto Mitigate Risk

– Ex: Increased cleaning frequency, more stringentgowning requirements.

• RESCORE Risk with the additional controls inplace to see if RPN is reduced.

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Example of a FMEA Record

Another Risk Assessment Tool:Risk Block Assessment

• Utilizes the following categories todetermine risk level:

– Duration of activity in the room (Use batchrecords or logbooks to determine thisinformation)

– Number of people in the room

– Proximity

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Risk Block Method Example

• Room Description: Dispensing

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Risk Factor Room Data Risk Level

Number of People 3 Medium

Duration of Activity > 1 hour but < 3 hours Medium

Proximity Located AT the potentialcontamination source (openprocessing)

High

Risk Class Determination

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LOW MEDIUM HIGH

HIGH

MEDIUM

LOWRisk Class

3

Risk Class2

Risk Class2

Risk Class1

Risk Class1

Risk Class1

Risk Class3

Risk Class3

Risk Class2

# of People in the Room

Duration of Activity

• Risk Classification for the Dispensing Room is Class 2

Sample Location Risk Determination

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LOW MEDIUM HIGH

HIGH

MEDIUM

LOWRisk Class

3

Risk Class2

Risk Class2

Risk Class1

Risk Class1

Risk Class1

Risk Class3

Risk Class3

Risk Class2

Risk Class

Proximity of Sample

• Sample location is deemed High Risk

Step 4: Sample Location and Frequency Selection

• NO LONGER based on room size. Selectionsare based on ALL the data that has beenobtained

– Room Qualifications

– Room walk-thrus

– Process / People / Material Flow Maps

– Equipment layout

• Ensure adequate rotation of sample frequencyto capture all activities (shift changes, off shifts)

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Step 4: Sample Location and Frequency Selection

• Document rationale / justification for EACH selected.

– I suggest also documenting the justification for the sitesexcluded after the room qualification. Why is this sitenon-value added?

• Select sites based on microbial risk to the product.

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Step 4: Sample Location and Frequency Selection

• Select sites that assess the effectiveness of the cleaningprogram (wall, floors).

• Document in a controlled document approved by QA (suggestprotocol summary report).

• Maintain this routine sampling plan for a year. Covers all 4seasons.

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Risk Level Sample Location Rationale

Low Sample site located in low traffic areaFew people in the room (0-1)Short activity duration

Medium Few people in the room (2-5)

High Sample site located in high traffic areaSample site located in a hard to clean area (under a tank)Sample site located in a room with long activities

Example of Sample Selection

SampleLocation

SampleID

# ofPeople

Duration RiskClass

Proximity RiskPriority #

Rationale

Floor 1 L L 3 L 3 Low trafficarea. Areadeemedhard toclean

Tank 1 2 M M 2 M 2 Close toopenprocess

Entrydoor

3 M H 1 H 1 Highactivity

Floor byentryway

4 H H 1 L 1 High trafficarea

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Optimizing EM sites• Risk Based, data driven EM programs provide

additional benefits to the business:

– Cost savings

– Efficiency / Time savings

– Improved training for operators

• After a year of data collection, review thetrend report and optimize the locationsselected and the frequencies.

– Same location has never had a failure = Removal

– Increase or decrease cleaning frequency31

Trend Reports• Trend monthly, quarterly and yearly

• Monthly summary report

– # of alert and action level excursions

– Microbial identification summary

• Quarterly

– Include trend charts

– Ensure alert and action limits are clear on the graph

• Yearly

– Summarize entire year’s data

– Document any change controls

– Make a statement that system is operating within validated ranges ORrevalidation is needed

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Regulatory Trends• PAT: Process Analytical Technology

– Ex: Online Particle Counters for Continuous Monitoring

• Real time particle monitoring involves the use ofparticle sensors at specific locations

• Uses external vacuum source, can be installed wherespace is at a premium. Integrates into facilitymonitoring and management systems

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FDA 483 categories for EM Programs

• Site Selection

• Site identification

• Growth Promotion

• Setting alert and action limits

• Incubation periods

• Microbial Identification

• Objectionable organisms

• Data Review

• Inadequacy of investigations

• Lack of trending

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Mylan Laboratories Limited 8/6/15• There is a lack of assurance that you maintain your manufacturing environment in

a state of control suitable for aseptic processing.

Environmental Monitoring

• For example, you did not utilize environmental monitoring data to identifyenvironmental control issues and identify appropriate follow-up actions. Therewere repeated out-of-action-level (OAL) results from microbial testing, but you didnot examine the data for trends or take appropriate follow-up action.

• In 2014, you reported 375 OAL results in your ISO 6 area. Then, on January 31,2015, you obtained OAL results during the manufacture of Injection in Suite. Youalso obtained OAL levels from the settle plates inside the RABS were recoveredfrom the air sampling point.

• From February 6-7, 2015, you obtained OAL results in three critical ISO 5 areas ofSuite during the manufacture of Injection

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Mylan Laboratories Limited 8/6/15Personnel Monitoring

• Deficiencies in your operators’ practices indicate that your manufacturing personnelmonitoring program is deficient. For example, in your video of batch manufacturing, weobserved an operator entering the RABS and in contact with gloves without sanitizing hisgloved hands. These gloves were later worn for aseptic connections, purging filling needles,and interventions on the filling machine. Furthermore, you do not monitor these operatorswhen they exit the area, so you have no way to determine whether the operators who enterRABS without sanitizing compromise the aseptic environment.

• Additionally, on video and in person, we observed employees sanitizing gloved hands beforeEM checks. Sanitizing gloved hands just before sampling is unacceptable because it canprevent recovery of microorganisms. This undermines the reliability of personnel monitoringdata.

• We are also concerned about your failure to review the results of microbial tests to identifypossible trending problems in environmental control in aseptic processing areas.

• Also provide the improvements you have made to your written procedures to address theseviolations and describe any other actions you have taken or plan to take to correct theproblems and prevent their recurrence.

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• Your environmental monitoring data is not reliable because of the materials you use to conduct EMtests.

• On February 6, 2015, our investigator observed environmental monitoring plates previously incubated atxC being used for surface and personnel monitoring. Three of plates showed signs of desiccation. Mediawas shrinking away from the edge of microbial plates.

• Your firm failed to establish an adequate system for monitoring environmental conditions in asepticprocessing areas (21 CFR 211.42(c)(10)(iv)).

• You do not have a scientific rationale for the environmental monitoring sampling locations in asepticfilling Suites. You did not include factors such as smoke study findings, number and location ofoperators, and historical microbial data in your assessment of hazardous points.

• For example, we found that settling plates are not appropriately placed in critical areas. Your smokestudy showed that during set-up and filling, air flows toward the front or back of the RABS. However,two relevant sampling points were recently eliminated. As a result, these points of increased risk are notmonitored.

• During our inspection, we noted that you have no justification for two different action levels for fingerdab results. While you have an ISO 5 action level of x CFU for set-up personnel, you use an ISO 6 actionlevel of y CFU for operators who do not routinely participate in aseptic processing operations using theRABS.

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Mylan Laboratories Limited 8/6/15

Allergy Laboratories, Inc

• You failed to conduct investigations for microbial action levelexcursions during filling of SEV lots and allergenic extractlots that were released and distributed.

• You failed to adequately maintain a system for monitoringenvironmental conditions in aseptic processing areas [21CFR 211.42(c)(10)(iv). For example:

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Allergy Laboratories, Inc

• There is no data to justify the alert and action limits that have been setfor environmental monitoring of surfaces in the Class 100 fill suites andfor personnel monitoring during and after aseptic operations. This is arepeat observation from the 2013 inspection.

• The corrective action to the 2013 Warning Letter item 2b has not beenfully implemented. Your firm created SOP QC-101.00 entitled “Detectionand Counting of Microbial Colonies on Solid Media” which indicates that acolony counter is to be used to observe environmental monitoring plates;however, the colony counter is not routinely used. This SOP has been inplace since August 28, 2013, for reading all environmental monitoringplates in all product filling areas.

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Triad Isotopes, IncMarch 10, 2016

• Your firm's environmental monitoring program is inadequate to ensure thatthe aseptic manipulations of sterile drugs products and components in theISO 5 hood do not compromise the sterility of the finished product.Specifically, no viable air monitoring was conducted for a period ofapproximately 9 months, and personnel monitoring only occurs everyXXXXX even though aseptic operations occur.

• To address your environmental monitoring program deficiencies, youcommitted to complete viable air monitoring from the date of yourresponse. However, you only use settling plates for air sampling, and noactive air samplers, and this is inadequate.

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Conclusion

• The Methodology for establishing EM programshas changed from area dependent to datadriven / risk assessments.

• Utilizing Risk Assessment tools to understandhigh risk locations is a regulatory expectation.

• Strong Process Understanding equates toGood Process Design and Risk mitigation

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Questions?

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Feel free to contact Kelly Thomas at

(201) 675-3199

or

thomas@atlanticvalidation .com