MONITORING CONTROLLED ENVIRONMENTS

Pacific BioLabs Inc.(510) 964-9000

info@PacificBioLabs.com

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CONTROLLED AREA

Manufacturing area where non-sterile product and in process material contact equipment surfaces or are exposed to the environment

Viable and nonviable contaminants are controlled to specific levels

Class 100,000 and Class 10,000

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CRITICAL AREA

Aseptic processing area where sterile products/components are exposed to the environment and no further processing will occur

Class 100

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ROOM CLASSIFICATION(CLASS NAMES)

ISO US FS 209E USP SI

3 1 M 1.5

4 10 M 2.5

5 100 M 3.5

6 1,000 M 4.5

7 10,000 M 5.6

8 100,000 M 6.5

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ROOM CLASSIFICATIONLIMITS IN PARTICLES > 0.5µm

ISO US FS 209E ISO (m3) FS 209E (ft3)

3 1 35.2 1

4 10 352 10

5 100 3,520 100

6 1,000 35,200 1,000

7 10,000 352,000 10,000

8 100,000 3,520,000 100,000

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BUILDING

Sufficient space to allow proper cleaning, maintenance, and

manufacturing functions orderly operations contamination control

Sealed windows, flush surfaces

Changing rooms/washing facilities

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BUILDING (cont.)

Clean utilities such as gasses, water

HVAC system

Filtration of air – HEPA’s

Airflow from critical to less critical areas

Air lock to maintain positive pressure

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ENVIRONMENT/HVAC SYSTEM VALIDATION

HVAC air velocity, airflow patterns

HEPA filter integrity and efficiency

Air pressure differentials 0.04 to 0.06 inches of water gauge

Cleaning and sanitization/disinfection studies

Airborne non-viable particle counts

Airborne viable particle counts

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EXAMPLE (www.fda.gov/cdrh/qsr/06bldng.html)

Specifications for a medical device assembly facility

Class 10,000

Particles > 0.5µm Guess ??

Air Pressure 0.05 inches of water

Temperature 72 + 2.5°F

Air Velocity 90 feet/minute

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REGULATORY BASIS FOR ENVIRONMENTAL MONITORING

CFR GMP regulations

FDA Guidance Documents

USP Informational Chapter <1116>

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ENVIRONMENTAL CONTROL21 CFR 820.70 (c)

“Where environmental conditions could reasonable be expected to have an adverse effect on product quality, the manufacturer shall establish and maintain procedures to adequately control these environmental conditions”

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ENVIRONMENTAL MONITORING COMPONENTS

Non-Viable Particles Air

Microbial Contamination Air Surface

Pressure Differential

Water quality

Temperature and Humidity

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PRODUCT BIOBURDEN

Does not have to be part of an environmental monitoring program

Test performed on a non-sterile product to determine its microbial load

Reflects the quality control of manufacturing process and raw materials

Needed to verify adequacy of sterilization process

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ENVIRONMENTAL CONTROL21 CFR 820.70 (c)

An uncontrolled environment may result in inconsistent bioburden levels

Bioburden spikes may exceed the sterilization process capability to achieve the desired SAL

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MICROBIAL IDENTIFICATION

USP <1116> An environmental monitoring program should

include identification of the flora obtained from sampling.

ANSI/AAMI/ISO TIR 15843:2000 Characterization of bioburden is required to

reduce the frequency of dose audits

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ENVIRONMENTAL MONITORING PROGRAM

Documented in SOP

Details procedures used for monitoring

Includes sampling sites

Specifies sampling frequency

Describe investigation when Alert or Action levels are exceeded

Describes methods for trend analysis

Training

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AIRBORNE PARTICULATE COUNT

AKA total particulate count

Detection of particles > 0.5 µm (outside of US particles > 5.0 µm are counted)

Monitoring is recommended during operations

Optical particle counting equipment is commonly used

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MICROBIAL MONITORING

Assess the effectiveness of sanitization practices and of personnel

Provides sufficient information to ascertain that the environment is controlled

Is conducted during normal operations

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MICROBIAL MONITORING

Room air

Compressor air

Surfaces Equipment Sanitization containers Floors Walls Personnel garments

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Airborne Viable Particulate Count- Methods

Passive monitoring Settling plates Not generally recommended in US

Active monitoring Solid culture medium impaction Testing of known volumes of air that allow

quantification by unit of volume air

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AIRBORNE VIABLE PARTICULATE COUNT - EQUIPMENT

Passive air monitoring Petri dish with agar

Active air monitoring Slit-to-Agar (STA) Sieve Impactors Centrifugal Impactors Filtration Liquid Impingement Gelatin Filter Sampler

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SURFACE MICROBIAL MONITORING METHODS

Contact Plates

Flexible Films

Swabs

Surface Rinse Methods

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PERSONNEL MONITORING

Garments Chest Sleeves Other areas are sampled for qualification

Gloves Finger impressions

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EXAMPLE OF SAMPLING SITES

System Site

Environmental air (filling) Near open containers

Room air Proximal to work areas

Water Point of use

Surface (facility) Floor, door handles, walls

Surface (equipment) Filling line, control panels

Compressed air Farthest from compressor

Laminar air flow Near high activity areas

Operator Finger impressions

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SAMPLING FREQUENCY

Sampling Area Frequency

Class 100 or less Each shift

Class 10,000 Each shift

Some support areas Twice/week

Product/container contact areas Twice/week

Other support areas > Class 100,000

Once/week

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TRAINING PROGRAM

Personal hygiene/habits

Illness

Clothing/gowning practices

Introduction to microbiology

GMPs

Introduction to aseptic techniques

Participation in media fills to demonstrate aseptic skill level

Must be documented

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ALERT AND ACTION LEVELS

Alert Level A level than when exceeded indicates a

process may have drifted from its normal operating condition. Warning that does not warrant a corrective action

Action Level A level than when exceeded indicates a

process has drifted from its normal operating condition. Documented investigation and corrective action required

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AIR - ACTION LEVELS

Class CFU/m3 CFU/ft3

100 < 3 < 0.1

10,000 < 20 < 0.5

100,000 < 100 < 2.5

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EQUIPMENT/FACILITIES SURFACE – ACTION LEVELS

Class CFU per Contact Plate100 3 (including floor)

10,000 5

10,000 10 (floor)

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PERSONNEL GEAR SURFACE – ACTION LEVELS

ClassGloves

(cfu/plate)Clothing (cfu/plate)

100 3 5

10,000 10 20

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ACTION LEVEL INVESTIGATIONS

Review of: Maintenance records Sanitization documentation Operational parameters

Identification of microbial contaminants

Training of personnel

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CORRECTIVE ACTIONS

Training of personnel

Additional sampling

Increased frequency of sampling

Additional sanitization

Additional product testing

Evaluation of the need to revise SOPs

Product impact/disposition documented

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WATER REQUIREMENTS

Test WFI Purified PotableTOC 500 ppb 500 ppb None

Conductivity See USP See USP None

Microbial 10 CFU/100mL 100 CFU/mL 500 CFU/mL

Endotoxin 0.25 EU/mL None None

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WATER SYSTEMMONITORING FREQUENCY

Test WFI System Purified WaterEndotoxin Daily * None

Microbial Daily * Weekly

TOC Weekly Weekly

Conductivity Weekly Weekly

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ENVIRONMENTAL MONITORINGSURVEILLANCE SUPPORT

Alert and Action Levels

Data Management Collection, trend analysis and interpretation

Isolates Characterization

Investigation/Corrective Actions

Documentation

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REFERENCES

“Fundamentals of Environmental Monitoring”, Supplement TR 13, PDA J. Pharm. Sci. & Tech. 55(6), 2001.

United Stated Pharmacopeia 30, <1116> Microbiological Evaluation of Clean Rooms and Other Controlled Environments. The United States Pharmacopeia Convention Inc., Rockville, MD. pp 589-596 (2007).

United Stated Pharmacopeia 30, <797> Pharmaceutical Compunding-Sterile Preparations. The United States Pharmacopeia Convention Inc., Rockville, MD. pp 334-351 (2007).

United States Food and Drug Administration “Medical Device Quality Systems Manual” (January 1997).

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