EM Presentation (1)

8/8/2019 EM Presentation (1)

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Environmental Monitoring

Considerations

Nancy Roscioli, Ph.D.

Don Hill and Associates, Inc.


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Environmental Monitoring

Components Airborne nonviable particulate monitoring

Airborne viable contaminant monitoring Viable contaminant monitoring of surfaces

Viable contaminant monitoring of personnel

Temperature and humidity monitoring Pressure differential monitoring


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General Environmental

Monitoring Considerations Monitoring frequencies and strategies

Establishment of a meaningful and manageable

program

Sampling and testing procedures

Establishment of effective alert and action

limits

Trending of results


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General Environmental

Monitoring Considerations Investigation and evaluation of trends as

well as excursions from alert and action

limits

Corrective actions to be implemented in

response to environmental monitoring

excursions

Personnel training - sampling, testing,

investigating excursions, aseptic technique


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Scope of Environmental

Monitoring Program Should include monitoring of all

environments where products and their

components are manufactured

All areas where there is a risk of product

contamination

Should include monitoring of all water usedfor product manufacturing as well as feed

water to the final water purification system

(WFI System)


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Regulatory Basis for Environmental

Monitoring Program

CFR GMP regulations

FDA Guidance Documents

USP Informational Chapter


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21CFR

211.4

2

Aseptic processing areas:

Easy to clean and maintain

Temperature and humidity controlled

HEPA filtered air

Environmental monitoring system

Cleaning and disinfecting procedures

Scheduled equipment maintenance and

calibration


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21CFR

211.46

Ventilation, air filtration, air heating and

cooling:

Adequate control over microorganisms, dust,

humidity and temperature.

Air filtration systems including prefilters and

particulate matter air filters for air supplies toproduction areas.


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Guideline on Sterile Drug Products

Produced by Aseptic Processing

Defines critical and controlled

manufacturing areas

Recommends airborne nonviable and viable

contaminant limits

Provides some guidance on monitoring

frequencies for critical areas


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Guideline on Sterile Drug Products

Produced by Aseptic Processing

Recommendations for air pressure

differentials

Includes guidance on aseptic media fills

Note: This guidance document was written

in 1987 and is in need of revision


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Microbial Evaluation and Classification

of Clean Rooms and Clean Zones

USP General Information Chapter

Establishment of clean room classifications

Federal Standard 209E

Importance of EM program

Personnel training in aseptic processing

Establishment of sampling plans and sites

suggested sampling frequencies


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Microbial Evaluation and Classification

of Clean Rooms and Clean Zones

Establishment of alert and action limits

Suggests limits for airborne, surface and

personnel contaminant levels.

Methods and equipment for sampling

Identification of isolates

Aseptic media fills

Emerging technologies - barrier; isolator


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Federal Standard209

E Airborne Particulate Cleanliness Classes in

Clean Rooms and Clean Zones

Approved by the GSA for use by all Federal

Agencies

Frequently referenced for controlled

environment particulate requirements:Classes 100, 10,000 and 100,000 (based on

particles > 0.5)


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Guidance for Industry for Sterile Validation

Process Validation in Applications for Human

and Veterinary Drug Products

Scope limited to final drug product manufacturing

and data required for application submission

(NDA, BLA) Requests information on:

Buildings and facilities

Manufacturing operations for drug product Filter validation

Validation of hold times


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Guidance for Industry for Sterile Validation

Process Validation in Applications for Human

and Veterinary Drug Products

Requests information on:

Sterilization and depyrogenation

Media fills and actions taken when they fail

Microbiological monitoring of the environment

Airborne microorganisms, personnel, surfaces,

water system, product component bioburden

Yeasts, molds, anaerobes

Exceeded EM limits


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Viable and Nonviable Contaminant

Limits

Nonviable (>0.5) Viable (CFU)Classifi-

cation ft3 m3 ft3 m3

Class

100

100 3,530 0.1 3.5

Class

10,000

10,000 353,000 0.5 18

Class

100,000

100,000 3,530,000 2.5 88


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Controlled Area Preparation or manufacturing area where

nonsterile product, in-process materials and

product-contact equipment surfaces,

containers and closures are exposed to the

environment

Control nonviable and viable contaminantsto reduce product /process bioburden

Class 100,000 or Class 10,000


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Controlled Area Capping areas are now considered

controlled manufacturing areas

Should be supplied with HEPA filtered air

Should meet class 100,000 conditions during

static conditions


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Critical Area Aseptic processing area where sterile

products, components or in-process

products are exposed to the environment

and no further processing will occur.

Air quality must be Class 100 during

processing Local Class 100 areas are often utilized

during open processing steps during drug

substance manufacture.


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Critical Area The area just preceding the sterile core

should be one classification higher than the

core.


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Nonviable Particulate Monitoring Airborne cleanliness classifications should

be met during operations

Nonviable monitoring should occur

routinely during operations

Monitoring during static conditions is done

as part of HVAC qualification and may bedone periodically after that to insure area

meets acceptable conditions before use or

following cleaning


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Nonviable Particulate Monitoring Locations for monitoring should be

established during performance

qualification; probes placed close to worksurface

Monitoring frequencies vary:

For aseptic processing areas, during each use

For other, controlled areas, varies from each

use to weekly or less depending on use of area


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Nonviable Particulate Monitoring HVAC Validation and Maintenance

Considerations:

Air velocity, airflow patterns and turbulence

should be validated; smoke studies to determine

flow patterns during static and dynamic

conditions

HEPA filter integrity testing

HEPA filter efficiency testing

Air pressure differentials


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Microbial Monitoring Airborne viable contaminants

Surface contaminants

walls

equipment surfaces

countertops

floors

Personnel contaminants


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Microbial Monitoring Monitoring methods should be capable of

detecting molds and yeasts

Should also be able to detect anaerobes

Most often, this is an issue associated with

products filled anaerobically (with nitrogen

overlay) All lots of media for EM sampling should

be growth promotion tested


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Microbial Monitoring Routine microbial monitoring should take

place during operations (for airborne

contaminants) and immediately followingoperations (for surfaces and personnel).

Airborne monitoring frequencies:

Each use for aseptic processing areas

Varies from daily to weekly to less frequently

for controlled areas depending on use


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Microbial Monitoring Personnel and surface monitoring

frequencies vary:

Aseptic processing - after every fill

Other controlled areas - varies from daily to

weekly or less for surfaces

Personnel monitoring often restricted to asepticarea personnel and personnel working in Class

100 hoods performing tasks such as inoculation


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Microbial Monitoring Monitoring of surfaces and airborne

contaminants during rest periods (following

cleaning)

Important for confirming adequacy of cleaning

procedures

Indicates whether HVAC system is operatingproperly

NOTE: Disinfectant effectiveness studies also

required for cleaning agents used in the facility


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Microbial Monitoring Monitoring frequencies and procedures are

influenced by a number of factors:

Stage of manufacturing

Open or closed manufacturing step

Single or multiple product manufacturing


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Microbial Monitoring Establishment of monitoring locations

should be based on performance

qualification studies during dynamicconditions

gridding study to determine worst case

locations/most meaningful locations Should also establish common flora - will

aid in investigations


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Setting Alert and Action Limits Action limits (for the most part) have been

established in a variety of guidance

documents

Alert limits

Lower than action limits

Reflect actual historical results under normalprocessing conditions


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Exceeding Limits Alert limits are designed to provide some

warning that environmental quality is

approaching action limit and allow you timeto correct.

Exceeding alert limit triggers a warning

response - i.e., alert affected area personnel Exceeding multiple alerts - triggers action

level response


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Exceeding Limits Action limit excursions require

investigations

Speciation of organism(s)

Review batch records from date of excursion

Review other recent EM data (trends)

Review cleaning records Interview personnel

Product impact - must quarantine until

determined


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Exceeding Limits Excursions from action limits require

corrective actions that may include:

More rigorous or additional monitoring

More rigorous cleaning

Retraining of personnel

Procedural changes - change to or addition ofdisinfection procedures, for example

HVAC maintenance


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Investigations and Corrective

Actions The investigation procedures to be followed

should be pre-established and included in

SOPs

Depending on the outcome of the

investigation, corrective actions should be

pre-established to the extent possible


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Imperative that EM results be linked to

product release so that affected products are

not released until investigation completed

Material Review Board or equivalent should

be consulted prior to releasing product that

was potentially affected by adverseenvironmental conditions

Investigations and Corrective

Actions


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Trending Should trend monitoring results

(environmental and water)

Periodic (quarterly or monthly) review by QA

and others

Re-evaluation of action and alert limits on an

annual basis This trending information is generally included

in the Annual Product Review


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Temperature and Humidity Control of temperature and humidity

required for aseptic processing areas

21 CFR211.42(c)(10)(ii)

Generally 65F and 35-50% humidity are

average

Too high - Increases personnel shedding

Too low - Increase static electricity


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Temperature and Humidity Temperature should be controlled

throughout all manufacturing areas

Temperature and humidity should be

monitored and controlled in warehouse

areas where temperature/humidity sensitive

raw materials are stored If not able to control humidity, need procedure

to follow if humidity exceeds limit


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Water RequirementsTest otable

Water

uri ied

Water

W I

T none 500

ppb 500

ppbonduc-

tivitynone ee Table

icro.

urity

500

CFU/ml

100

CFU/ml

10CFU/

100 ml

ndo-

Toxinnone none 0.25

U/ml


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Water For Injection Defined by USP

Water purified by distillation or reverse

osmosis

Prepared from water complying with the

U.S. EPA National Primary Drinking Water

Regulations

Contains no added substance


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Purified Water Defined in USP

Obtained by a suitable process, usually one

of the following:

deionization

reverse osmosis

combination


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Potable Water Meets National Drinking Water Regulations

40 CFR Part 141

Periodic monitoring in-house as well as

periodic certificates from municipality (if

applicable)


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Water System Monitoring WFI Systems

Microbial quality and endotoxin

Daily system monitoring

Each use point at least weekly

TOC and Conductivity

Weekly system monitoring

can be taken from worst case point (end of loop,

return to tank)


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Water System Monitoring Purified Water Systems

Weekly monitoring of system for:

microbial quality

TOC

conductivity


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Water Use WFI

Solvent for preparation of parenteral solutions

Formulation of mammalian cell culture media

Formulation of purification buffers

Final product formulation

Vial and stopper washing Final rinse for product equipment


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Water Use Purified Water

Preparation of terminally sterilized

microbiological media

Initial rinsing/cleaning

Laboratory use

Feed for WFI system


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Water Use

Potable Water

Non-product contact uses

Feed for purified water system


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Microbial Monitoring Devices

Slit-to-Agar (STA) - Powered by vacuum,

air taken in through a slit below which is a

slowly revolving plate.

Sieve impactor - Vacuum draws in air

through perforated cover which is impacted

onto petri dish containing nutrient agar


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Centrifugal Sampler - consists of a

propeller that pulls a known volume of air

into the unit and then propels the airoutward to impact on a nutrient agar strip

Sterilizable Microbiological Atrium

(SMA)- similar to sieve impactor; covercontains uniformly spaced orifices; vacuum

draws in air which is impacted on agar plate


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Surface Air System Sampler - An

integrated unit containing an entry section

with an agar contact plate; behind is a motorand turbine that pulls air in through the

perforated cover and exhausts it beyond the

motor. Settle plates - qualitative; may be useful in

worst case locations


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Surface contaminant monitoring devices:

Contact Plates - plates filled with nutrient

agar; for regular surfaces

Swabs - useful for hard to reach or irregular

surfaces; swab placed in suitable diluent and

inoculated onto microbiological plate


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Monitoring Considerations

Remote sampling probes - validate use of

tubing

Must sample adequate quantity of air to be

statistically meaningful.

80-100 ft3/min

Must validate growth promotion afterexposure of settle plates (or other plates) for

prolonged time periods.

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