ENVIRONMENTS CONTROLLED MONITORING

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

CRITICAL AREA

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

• Class 100

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

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

BUILDING

• Sufficient space to allow – proper cleaning, maintenance, and manufacturing functions– orderly operations– contamination control

• Sealed windows, flush surfaces

• Changing rooms/washing facilities

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

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

REGULATORY BASIS FOR ENVIRONMENTAL MONITORING

• CFR GMP regulations

• FDA Guidance Documents

• USP Informational Chapter <1116>

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”

ENVIRONMENTAL MONITORING COMPONENTS

• Non-Viable Particles – Air

• Microbial Contamination– Air – Surface

• Pressure Differential• Water quality• Temperature and Humidity

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

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

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

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

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

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

MICROBIAL MONITORING

• Room air• Compressor air• Surfaces

– Equipment– Sanitization containers– Floors– Walls– Personnel garments

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

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

SURFACE MICROBIAL MONITORING METHODS

• Contact Plates

• Flexible Films

• Swabs

• Surface Rinse Methods

PERSONNEL MONITORING

• Garments– Chest – Sleeves– Other areas are sampled for qualification

• Gloves– Finger impressions

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

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

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

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

AIR - ACTION LEVELS

Class CFU/m3 CFU/ft3

100 < 3 < 0.110,000 < 20 < 0.5100,000 < 100 < 2.5

EQUIPMENT/FACILITIES SURFACE – ACTION LEVELS

Class CFU per Contact Plate

100 3 (including floor)10,000 510,000 10 (floor)

PERSONNEL GEAR SURFACE – ACTION LEVELS

ClassGloves

(cfu/plate)Clothing (cfu/plate)

100 3 5

10,000 10 20

ACTION LEVEL INVESTIGATIONS

• Review of:– Maintenance records– Sanitization documentation– Operational parameters

• Identification of microbial contaminants• Training of personnel

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

WATER REQUIREMENTS

Test WFI Purified Potable

TOC 500 ppb 500 ppb NoneConductivity See USP See USP NoneMicrobial 10 CFU/100mL 100 CFU/mL 500 CFU/mLEndotoxin 0.25 EU/mL None None

WATER SYSTEMMONITORING FREQUENCY

Test WFI System Purified Water

Endotoxin Daily * NoneMicrobial Daily * Weekly

TOC Weekly WeeklyConductivity Weekly Weekly

ENVIRONMENTAL MONITORINGSURVEILLANCE SUPPORT

• Alert and Action Levels• Data Management

– Collection, trend analysis and interpretation• Isolates Characterization• Investigation/Corrective Actions• Documentation

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).

THANK YOU