Fundamentals of an Environmental Monitoring Program

7/25/2019 Fundamentals of an Environmental Monitoring Program

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Global Aseptic Seminar

Kalamazoo

June 2014


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Instructor Bio

Over 30 years of academic and industrial experience inmicrobiology labs and mfg support

Currently in Microbiology and Aseptic Support group,Global Quality Operations at Pfizer, assessing asepticprocessing facilities, investigations, policy documents,and network aseptic processing training

Directs the MicroNet, Pfizer's microbiology network,sterile and non sterile manufacturing support

Dona Reber, MS, SM (NCRM)

PDA member, working on TR Disinfection, member for recently completed TR

Objectionable Organisms

Provided training for new FDA Inspectors on EM

PMEDG Chair

Publications/presentations: environmental monitoring, microbial identifications and

microbiology risk assessments. PDA book: Microbial Identifications: The Keys to a

Successful Program, October 2012

NOTE: Presentation is PDAs and my own work and opinion, does not necessarily reflect Pfizer

policy.

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Question:Why is environmental monitoring performed?

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Why is Environmental Monitoring performed?

TO:

- Demonstrate control of aseptic processing

- Identify problems in facility or process

- Identify trends more than individual events

- Gather data to support root cause analysis

and/ or follow-up on CAPAs of contamination

events


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What Environmental Monitoring is not. . .

A release test

An analytical test

Highly recoverable

Always repeatable

Always linked to direct cause and effect

The total picture for control of the APA


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PDA Technical Report #13

Key Revisions and Changes

Rev1 (2001) EM Classifications (US

FDA/USP/EU/ISO) Surveillance Support

Cleaning and Disinfection Sampling Selection and

Frequency Alert and Action levels Data Management IDs Investigations

System Surveillance Types of Monitoring

Validation

Rev 2 (2014) EM Classifications (US

FDA/EU/JP/WHO/ISO) Environmental Monitoring

Site selection and frequency Alert and action levels, USP shift

to Excursion Rates recommended scheme for IDs Investigations Elements Data Management/EM

documentation records

EM by application Types of Monitoring Terminal Sterilization Aseptic Processing Isolation Technology


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Environmental Monitoring:

Key Regulations and Guidelines

Excerpt from FDA Aseptic GuidelinesIn aseptic processing, one of the most important laboratory controls is theenvironmental monitoring program. This program provides meaningful information on

the quality of the aseptic processing environment (e.g., when a given batch is beingmanufactured) as well as environmental trends of ancillary clean areas. Environmentalmonitoring should promptly identify potential routes of contamination, allowing forimplementation of corrections before product contamination occurs (211.42 and 211.113).

Excerpt from EU Annex1


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Types of Environmental Monitoring

Total Airborne (Non-Viable) Particulate Monitoring

Active Viable Air Monitoring

Passive Viable Air Monitoring

Surface Monitoring

Personnel Monitoring

Water Testing

Room Temperature and Relative Humidity

Room Differential Air Pressure

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FDA Aseptic Guidelines Limits


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EU Annex 1 Limits


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EU Action Limits

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What is meant by

average value?


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EU Annex 1 non viable limits


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ParticleSize

ISO 14644

US FDA(Aseptic

Processing

Guidance)

USP

EU Annex 1and WHO Annex 4

Japan(Aseptic

Processing

Guidance)

JP XVI

ISO 5 ISO 5 /Class 100, ISO 5/Class 100Grade A

Grade B (at rest)Grade A

Grade B (at rest)Grade A

Grade B (at rest)

0.5 m 3520 3520 3520 3500 3520 3520

5 m 29 Not specified Not specified 20 20 Not specified

ISO 6 ISO 6/Class 1000 ISO 6/Class 1000 NA NA NA

0.5 m 35,200 35,200 35,200 NA NA NA

5 m 290 Not specified Not specified NA NA NA

ISO 7 ISO 7/Class 10,000 ISO 7/Class 10,000Grade B (operation)

Grade C (at rest)

Grade B (operation)Grade C (at rest)

Grade B (operation)Grade C (at rest)

0.5 m 352,000 352,000 352,000 350,000 352,000 352,000

5 m 2,900 Not specified Not specified 2,900 2,900 Not specified

ISO 8 Class 100,000 ISO 8/Class 100,000Grade C(operation)

Grade D (at rest)Grade C (operation)

Grade D (at rest)Grade C(operation)

Grade D (at rest)

0.5 m

3,520,000 3,520,000 3,520,000 3,500,000 3,520,000 3,520,000

5 m

29,000 Not specified Not specified 29,000 29,000 Not specified

[1]Class 100 and Grade A are defined as requiring unidirectional flow by all applicable guidelines[2]Obsolete U.S. Federal Standard 209E classification added for continuity[3]Class titles for US FDA and USP indicate equivalent particle counts per ft3[4]ISO 4.8 based upon reduced limit for particles 5 m[5]Grade D operational particulate counts are dependent upon the operation and are not defined by any guideline

Reference PDA Technical Report #13:Fundamentals of an Environmental Monitoring Program

Why are 0 5um and 5 0 um


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Why are 0.5um and 5.0 um

size particles important?

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13

10.10.01 10 100 1000

0.050.03 0.50.3 3 5 30 50 300 500

Limit of

Human Vision

Limit of Light

Microscopy

Rhinovirus

E. coli Red Blood Cells

Ragweed

Pollen

Bakers Yeast

Human Hair

Pin Head

Most Bacteria


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Total Airborne Particulate Monitoring

Discrete laser particle counting technology

Monitor 0.5 m and 5.0 m particles (EU only)

Grade A frequent or continuous monitoring

Fixed sampling rates (cfm)

Varying sampling volumes. (0.5 or 1 cu meter)

Fixed or portable equipment

Isokinetic heads

Additional considerations for manifolds

Lasair III Portable Air Sampler

Manifold Air Sampler

Climet Fixed Remote Air Sampler

MetOne Air Fixed Sampler


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Active Viable Air Monitoring

Impaction of organisms onsolid growth media

Slit to agar

Sieve

Centrifugal

Delay timers

Fixed volume sampled cubicfoot or cubic meter.

Fixed or portable equipment

SMA-1

RCS Plus

MAS 100

R2S Slit to Agar

AirIdeal 3

SAS


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Passive Viable Air Monitoring

Settle Plates, continuous

Exposure limit per 4 hours in Annex 1

Qualify organism recovery at >maximum exposure time

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Volumetric SMA-1 and settle plate

What if theprocess is

less than

four hours.

Do I adjust

the limits?


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Surface Monitoring: Plates

Replicate Organism Detection and Counting(RODAC)

plates and swabs

Fixed area sampled ~20 cm2

Qualify recovery, including disinfectantexposure

Soybean Casein Digest Agar

with polysorbate and tween

Day Engley (D/E)

Neutralizing Agar


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Surface Monitoring - Swabs Used for areas that are hard to sample with a RODAC plate:

lumens, small items, stopper bowl, filling needles

Usually wetted with buffer solution (e.g., Ringers solution) or

directly with broth.

Samples may be:

placed immediately in broth (presence/absence testing) for Grade A,

or

taken to lab for f ilt ration and plating (quantitation, Grades B, C, D)

Qualify recovery, including surface disinfectant exposure

AES ChemunexBecton Dickenson


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Personnel Monitoring

Typical sites: gloves forearms and chest

Sample upon exit from APA

Self sampling only on exception, discouraged by

regulators!

Assure all finger pads and thumb

are sampled , one plate per glove


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Water Testing: WFI Assures microbiological and chemical quality of the water

TOC (on or off line meters)

Conductivity (on or off line meters)

Endotoxin

Total Heterotrophic Plate Count

DI, purified, Feed water also tested


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WaterSamplingRepresentative locations appropriately labeled and monitored on routine basis

Frequency may vary depending on usage.

Containers used for Microbiological sampling must be sterile.

The water sampling is the same as routine use, including use of hoses.

Excerpt from Water and Wastewater, USP

IF IT IS NOT POSSIBLE TO TEST THE SAMPLE WITHIN ABOUT 2 HRS OF

COLLECTION, THE SAMPLE SHOULD BE HELD AT REFRIGERATED

TEMPERATURES (2-8C) FOR A MAXIMUM OF ABOUT 12 HRS TO

MAINTAIN THE MICROBIAL ATTRIBUTES UNTIL ANALYSIS. IN SITUATIONS

WHERE EVEN THIS IS NOT POSSIBLE (SUCH AS WHEN USING OFF-SITE

CONTRACT LABS), TESTING OF THESE REFRIGERATED SAMPLES

SHOULD BE PERFORMEDWITHIN 48 HRS AFTER SAMPLE COLLECTION.



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Calibration, Qualification and Training

Instrument calibration generally performed by vendor

(volume and time).

Method qualification for viables based on recovery studies ofbroad range of microorganisms, including representativeenvironmental isolates-FDA Aseptic Guidance, ISO 14698(AnnexA)

Analysts trained on methods including cGLP and aseptictechnique, plate counting.

Operators or quality samplers trained on aseptic samplingtechnique, equipment. Quality oversight.


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New Technologies for EM

Technology How it Works EM ApplicationBioVigilant IMD-Air

350/350A

Real time particle

monitoring, detects

biological fluorescence and

size.

Investigations, area

qualifications, training

Milliflex Rapid ATP Bioluminescence Water bioburdenscreening

Growth Direct Automated incubator / plate

reader/non destructive

Viable environmental

monitoring screening

Charles River EndosafePTS MTS

Kinetic chromogenic, colorintensity measurement,

early endotoxin detection

Automated WFI testing

Precautions When Conducting


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Precautions When Conducting

Environmental Monitoring

Sampling of water same as manufacturing usage

More Precautions When Conducting


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More Precautions When Conducting

Environmental Monitoring

Is it okay to refrigerate plates before incubation?

EM Program:


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EM Program:

Elements and Rationale


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EM Program: Location Considerations

Critical product or sterile component exposure examples:

Filling needles

Stopper bowls

Vial Turntable

High potential for microbial/particle presence

Elevated recoveries observed during qualification or f romhistorical trend analysis

Difficult to clean or sanitize

High traffic (e.g. doors, RABS door handles, intercom)

Smoke studies indicate areas of eddies or turbulence

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EM Excursions and Limits

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Limits are defined as when exceeded

Investigation


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When to identify organisms in an EM Program

All isolates found in Grade A and B are identified to the specieslevel where possible.

All isolates found in Grades C and D with results above the act ion

level should be identif ied to the species level.

Periodically, isolates found in Grades C and D should be identif ied

to at least the genus level to develop trending of common isolates.

Lets look at some examples of EM sampling of

common items. . .

Trending of EM Data


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Trending of EM Data

Purpose: To provide assurance that a continued stateof control is being maintained. Knowledge for

response to adverse trends before control is lost.

Observe changes in both numbers and types of

organisms.

Develop Trending Rules: By Grade and Location (room

or sampling site)

Reviewed periodically (e.g. monthly, quarterly,

annually)


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Trending of EM Data, Examples


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Is this data in control?

A running pattern, suggests short episodic trends that should beinvestigated before becoming problematic.

Action level

Alert level


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A trending pattern is when there is a continued increase or

decrease in the results, a problem that is not being addressed

Alert level

Action level


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A cyclic pattern is when a series of data points show the same trend at

periodic time intervals. This could be an indicator of some systematic

error. Perhaps it is temperature fluctuation in the room, humidity issues

or seasonal variations

Action level

Alert level


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What comment might an inspector make about this data?

Action level

Alert level

Alert level does not reflect real data, difficult to identify trends


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Trending by Genus and species

Staphylococcus

luteus, 9.6%

Staphylococcus

epidermidis, 8.7%

Staphylococcus

hominis, 5.6%

Bacillus cereus,

4.3%

Corynebacterium

tuberculostearicum2.9%

Staphylococcus

capitis, 2.8% Bacillus pumilus,2.7%

Staphylococcus

warneri, 2.5%

Bacillus subtilis,

2.4%

Staphylococcus

haemolyticus, 2.2%

Ralstonia pikettii,

1.7%Paenubacillus

glucanolyticus,

1.5%Bacillus

megaterium, 1.5%

Proprionibacterium

acnes, 1.0%

Bacillus

licheniformis, 0.9%

Bacteria Most Often Submitted for Identif ication Testing During 2010, Barry A. Fri edman, posted May 17, 2011

T di b T f Mi i


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Trending by Types of Microorganisms

15-20% air/soilsource

Organisms suchas large Grampositive rods,

spore formers,Bacillus andfungi

5-10% water/liquid source

Gram negative rod Organisms such asPseudomonasandAcinetobactorspecies

Data from previousslide shows a similar

distribution:

Common APA Bacteria

People: 35.3%Air soil: 13.3%

Liquid water: 1.7%

70+% PeopleOrganisms, such as,Staphylococcus,

MicrococcusandPropionibacteriumspp.

S f C t i ti PEER


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Sources of Contamination: PEER

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Investigation: Examples, What to Look for


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Some Inspection Observations

Questions Asked/Comments During


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FDA Inspector Training, 2013-2014

How to get to the issuesSo much data and so little time!

How do I know if locations/samples are adequate?

How are environmental monitoring methods qualified?

What are factors to consider for investigations?

What is expected for trending?

Are some air samplers/swabs/em equipment better than others?

Help! Incubation temperatures/times are not always the same!


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EM INVESTIGATION Study:

What Would YOU Do?

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While reading plates, the analyst realizes that the agarlot used for EM sampling was expired prior to use for EM

sampling

Invalidate the results???????


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Discussion Points for Case Study

QUESTION: Should counts be invalidated on expired media for samples inGrade A during filling? WHY or WHY NOT?

If the EM sample can be repeated, Resample with unexpired media

If the EM sample cannot be repeated (e.g., time sensitive activity), perform

investigation: Points to consider

If expired media lot is available, perform growth promotion testing todetermine if recovery is satisfactory, demonstrating results are valid

If expired media is not available, hold a subsequent same type of media lot

to expiry and perform growth promotion to demonstrate recovery is

satisfactory



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Group Exercise:

Discuss Potential EM sources think PEER


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Discuss Potential EM sources, think PEER

x

Staphylococcusspecies (people bug) on a water sample plate

Sphingomonasspecies (water bug) on a water sample plate

Same organism on multip le days, multiple

locations, first in Grade C and moving to Grade A

Water organisms on surface RODAC plates

Particle counter exceeding limits when area

not in use

Increase in viable counts in manufacturing area

during construction of adjacent area

Increase in spore formers on EM plates in

raw materials sampling area

Environment, Equipment

People

Environment

Raw Materials, Environment, Equipment

People, Equipment

People, Environment

Equipment

Questions?


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Personnel Behaviors:
http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://montgomerycountypolicereporter.com/its-a-cavity-search-charlie-brown/&ei=Sc6IVPX8K5DvaoLhgKAI&bvm=bv.81456516,d.cWc&psig=AFQjCNF53lGj71FvkKIviQHZP5Iq5Fr_vA&ust=1418338236881737


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Personnel Behaviors:

The Good and the Bad

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Hold Up the Green Card Hold Up the Pink Card
http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://montgomerycountypolicereporter.com/its-a-cavity-search-charlie-brown/&ei=Sc6IVPX8K5DvaoLhgKAI&bvm=bv.81456516,d.cWc&psig=AFQjCNF53lGj71FvkKIviQHZP5Iq5Fr_vA&ust=1418338236881737http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://everydaylife.globalpost.com/reinforce-good-behavior-children-ocd-5715.html&ei=ROZ8VPXoHtPksAT-yoLQCA&bvm=bv.80642063,d.cWc&psig=AFQjCNFJ4c2qbP3dFzTAB4lTAg7-Fg8nRQ&ust=1417557932045161http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.littleheroes.com/wp-blog/parenting-advice/bad-behavior-in-children-are-you-looking-for-it/&ei=t-V8VMK4E83IsASL6ICYAg&bvm=bv.80642063,d.cWc&psig=AFQjCNFOGNHJlggjZ29Gz5_ThOK-d4QQ9Q&ust=1417557800456291


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Operator leans on equipment used for processing

while working in the APA.

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1. Good

2. Bad


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EM sampling locations are clearly defined and

posted.

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1. Good

2. Bad


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Items are picked up from the floor during aseptic

processing.

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1. Good

2. Bad

Gloved hands are sanitized with alcohol


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Gloved hands are sanitized with alcohol

frequently & prior to any intervention during

aseptic processing.

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1. Good

2. Bad


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Operators discuss where to go for lunch while in the

APA.

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1. Good

2. Bad

Alcohol is used for disinfection instead of a


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Alcohol is used for disinfection instead of a

sporicidal agent when transferring materials from

the warehouse to the Grade D area

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1. Good

2. Bad


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Entries and exits to the APA are limited to essential

activities.

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1. Good

2. Bad


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EM Alert levels are set at meaningful levels.

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1. Good

2. Bad


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70% Isopropyl Alcohol containers are changed daily

using sterile containers and fresh sterile alcohol.

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1. Good

2. Bad

Alarms for non viable monitoring are at a central


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Alarms for non viable monitoring are at a central

location, in another room from the APA

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1. Good

2. Bad

Operator needs to reach over open product to


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Operator needs to reach over open product to

perform an intervention.

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1. Good

2. Bad

Sterile equipment is protected and dedicated to the


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Sterile equipment is protected and dedicated to the

Grade A area.

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1. Good

2. Bad

O t tifi t b f t i APA


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Operator notifies co-operator before entering APA

that her gown has a rip in the sleeve

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1. Good

2. Bad


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Cart is blocking the air return.

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1. Good

2. Bad

Sterile tools (e g scissors) used in Grade A are


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Sterile tools (e.g. scissors) used in Grade A are

placed on a non-sterile surface between uses.

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1. Good

2. Bad

Non viable monitoring heads are covered


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Non viable monitoring heads are covered

during cleaning of the APA

1. Good

2. Bad


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Sterile tools/extenders are used to contact

critical surfaces instead of gloved hands.

1. Good

2. Bad

Operator stands with arms folded across


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65

p

chest.

1. Good

2. Bad

h l h h h h


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The sterile connection hose is too short to reach the

equipment through the designated wall orifice, so the

Grade B door is propped open to allow the hose to reach

1. Good

2. Bad

l ( b d l ) d


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Sterile garments (e.g. beard covers, goggles) are removed

during manufacturing process.

1. Good

2. Bad

EM T d l i d i h d


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EM Trend results are reviewed with management and

operators

1. Good

2. Bad

Dancing is practiced when the filling line is running

thl i th ti i


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smoothly in the aseptic processing area

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1. Good

2. Bad


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Thank You and the PDA

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Fundamentals of an Environmental Monitoring Program

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