ENVIRONMENTAL MONITORING

November 2012

Sreenath Sreenath

QC Micro

WelcomeWelcomeMicrobial Microbial

Monitoring of Monitoring of Manufacturing areaManufacturing area

The Purpose of an Environmental Monitoring Program

The cGMP Notes states that the purpose is to:

Provides crucial information on the quality of the asepticprocessing environment during manufacturing

Prevents the release of potentially contaminated batch ifappropriate standards are not fulfilled

Prevents future contamination by detecting adverse trends

Microbial Monitoring is a program designed to demonstrate the control of viable (living microorganisms) and non-viable particles in critical areas.  These areas include clean-rooms for drug fill/finish, formulation tank rooms, laminar flow hoods, biological safety hoods, isolators, Intravenous (IV) compounding areas and sterile packaging. 

Viable monitoring -Testing for the detection and enumeration of bacteria, yeast and mold.  It includes the monitoring of personnel, air and area surfaces for microbial contamination. 

Non-viable monitoring –A reference for particle counts measured by a laser counter

Environmental monitoring describes the processes and activities that need to take place to characterise and monitor the quality of the environment.

Environmental Monitoring is a surveillance system for microbiological control of cleanrooms and other controlled environments. It is a process which provides monitoring, testing and feedback to the microbiological quality levels in aseptic environments.

Sources of contamination :can come from air, personnel, equipment, cleaning agents, containers, water and compressed gases amongst other things.

Sound monitoring required understanding the various stringent regulatory specifications by various organizations such as the Food and Drug Administration (FDA), International Standards Organization (ISO), Parenteral Drug Associates (PDA), European Union (EU) and United States Pharmacopeia (USP).

4W1H …………………….!!!!

WHERE?WHEN..?WHAT...?WHO….?HOW ....?

4W1H can solve any issues!!!!

4W1H

WHERE: ……?MFG AREA/Dedicated Location

WHEN:……?The air and Surface monitoring should be conducted actively during the aseptic processing/operation.

Personnel monitoring when the operator leaves the process area.

Product contact surfaces would be monitored at the end of the filling operation

4W1H

WHAT:…….?The testing/Accuracy conclusion of the particular area

WHO:……?The trained personnel/Microbiologist

HOW:……?As per the current practice/SOP/GMP/GLP/Protocols /Docs

Get familiar to …………….,

What is a clean room????A room or environment in which you move the air by way of supply and return locations to control the airborne particle levels and temperature and humidity.

What is Federal Standard 209E: The Federal government's basic design and performance requirements for clean rooms. Some of the information sets minimum and maximum levels, but in general it gives recommended guidelines.

What is a Class: Defines the limit or measurement that a room will perform to particles per cubic foot at 0.5 micron or larger.

Get familiar to …………….,

What is a HEPA Filter???? Class of air filters which meet a minimum performance level of 99.97% on 0.3 microns efficiency. (This is only an efficiency test and may not show small pin holes or leaks.) In the cleanroom market HEPA is normally rated at 99.99% and an additional face scan test is performed to assure no pin holes or leaks are found.

Get familiar to …………….,

What is a particulate matter????Contamination found in the air or which is generated within a room from a process.

What is Recovery ??? : How quickly the room or area will clean up and return to normal.

Monitoring Criteria ….,

Daily Monitoring: (Micro Area-LAF/UV Passbox /Room)

Monthly Monitoring: (MFG Area/Equipments/Drain Points)

Quarterly Monitoring: (Compressed Air)

Half Yearly Monitoring: (Operators/Personnel Hygiene monitoring)

Yearly Monitoring: (HVAC/AHU System Validations)

Occasional Monitoring: (As and When required-During Technical issues with filters/ on maintenance/Filter change)

Specimens to be covered

Air (For Both viable & Non-viable & compressed air) Surfaces ( Floors, Walls, Equipment, etc.)

Personnel (Operators/Working personnel's)

Drains (In the MFG Areas)

Air Quality

Air Sampling

Passive Air Sampling

(Plate Exposure)

Active AirSampling

(Volumetric)

For a known Q

ty

(1000L) of A

ir/cubic

meter

Open pre-incubated

media plates (90mm)

keep exposed for 4 hrs

224 areas- Settle plate/SAS

GP-130BP-94

Surface monitoring in a Clean Room

Surface monitoring

By contact plates(RODAC)

By Swab sampling

55 mm Plates to be fixed on a flat

surface

Swabs are rubbed over the test

surface & tested for microbial

contamination

Swabs are used for the surfaces that are not flat

64 areas-By RODAC

GP-43BP-21

Personnel Monitoring….!!

Once in 6months

-By Contact plates (Finger Dab Testing)

-By Swabs

Near mouth, Arm pits, Tips of finger & palm (with gloves), Upper Surface of footwear

-By swabs-Monthly to cover all the critical / non critical drains 29 Drain points 10 Non Critical & 19 Critical Drains

Drain monitoring….!

Compressed Air monitoring….!

55mm RODAC plates Drawing of 1000L of Air Quarterly -15 Points 4 points in BP/11 points in GP/ 1 in utility

Particle Counting…..!!

Useful in detecting significant deviations in air cleanliness from qualified processing classifications

Immediate understanding of air quality can be realized

Useful as a tool for qualification and monitoring before /during and after operations

Used To Identify Sensitive Locations For Continuous Monitoring

HVAC Validation….!!

-Yearly by external party

Parameters-Temperature/ RH/ DP-Air velocity-Air Changes-Filter integrity-Non-viable Air borne particles-Viable Air borne particles

HVAC Validation….!!

Parameters1.Temperature/RH/DP

Check the Temperature/RH/DP of the rooms with calibrated thermometer (For

Temp)/ Hygrometer (For RH) and record every two hours (5 readings per day)

consecutively for three days.

Acceptance Criteria: The temperature should be within 23º 2ºC

The relative humidity should be within 45 5% and the low RH should be within 20 5%.

The pressure differential in the area should be more than 10 Pascal across the

room.

HVAC Validation….!!

Parameters2. Air velocityCheck the air velocity at the four corners & center of HEPA filter-using anemometer. Calculate the average velocity of filterAcceptance Criteria: Average velocity should be 90 feet/minute ± 20%. (0.45m/sec)

3. Air ChangesCalculate the number of air changes per hour in the area using the formula:

Average Air velocity (ft/min) x Area of the filter (Sq.ft) x 60 Volume of the room (Cu.ft)

Acceptance Criteria: NLT 20 air changes/Hr

4. Filter integrity For the efficiency of HEPA Using DOP (Di Octyl Pthalate )/PAO (poly Alfa Olefin)

Acceptance Criteria: The efficiency of all the terminal HEPA filters should not be less than 99.97% (For Class 100,000) & for LAF- 99.99% (Class100)

HVAC Validation….!!

Anemometer

Filter integrity

HVAC Validation….!!

Parameters5. Non-viable Airborne particle Count:

Derive the minimum number of sampling point locations (NL) from the following equation. NL = √AA = Area of clean room in square meters.

Check the particle counts in the locations using a calibrated particle counter. EX: For Secondary gowning- NL is 02, Where as in Blister Pkg room, NL is 05

Acceptance Criteria: For Class 100,000Particles of >0.5 should not be more than 3520000Particles of >1.0 should not be more than 832000 Particles of >5.0 should not be more than 29300 per Cubic Meter of air.

Acceptance Criteria: For Class 100Particles of >0.5 should not be more than 3520 Particles of >1.0 should not be more than 832 Particles of >5.0 should not be more than 29 per Cubic Meter of air.

HVAC Validation….!!

Airborne particle Counter SAS sampler

Settle plate methodExposed plate after

incubation

HVAC Validation….!!

Parameters6. Viable Airborne particles:-After the HVAC Validation-By Settle plate method & Volumetric Air sampling

LIMITS:

Test Alert Limit

Action Limit

Settle Plate Exposure (CFU/90mmPlate/4 Hrs)Under Dispensing and Sampling BoothOther locations

NMT 1 NMT 75

NMT 1 NMT 100

Active Air Sampling (CFU/Cubic Meter of air)Under Dispensing and Sampling BoothOther locations

NMT 3 NMT 100

NMT 5NMT 200

Surface Monitoring (CFU/55 mm Plate)Surface of Dispensing and Sampling BoothOther locations

NMT 10NMT 25

NMT 25NMT 50

OOS….!! And Action

Alert Limit: (Non Pathogen)

If microbial count exceeds the alert limit in environmental monitoring inform the same to Quality Assurance, Production head and continue monitoring on next day.

If the contaminant levels are seen consistent or increase, advise to increase the frequency of cleaning.

Monitor the area frequently till the environment count comes below alert limit. During this period production activity will be continued

Action Limit: (Non Pathogen)

If microbial count exceeds the action limit in environmental monitoring stop all production activity of particular area and carry out the investigation. Quarantine all the products which are manufactured during that period.

Recheck the bioload of all products, which were manufactured during the last two weeks by drawing extra samples in order to evaluate the effect on product.

OOS….!! And Action

Pathogen: If pathogen is found in monitoring, inform the same to Quality Assurance, Production head and stop all production activity of particular area and carry out the investigation. Quarantine all the products which are manufactured during that

period.

Recheck the bioload of all products, which were manufactured during the last two weeks by drawing extra samples in order to evaluate the effect on product.

Proactive action: Clean/Sanitize the Manufacturing facilities as per Standard operating Procedure.

GDP Includes…………….,

1. Standard Operating Procedures (SOPs) 2. E/M Test Procedures 3. Equipment Use, Maintenance and Calibration Procedures and Logs 4. Cleaning and Sanitization Data Sheets 5. Site Maps 6. Alert and Action Levels 7. Test Results, Date of Results, Incubation Temperature, Deviation and Quality Review 8. Microbial Identifications 9. Environmental Trending Spreadsheets, etc. 10. Deviation Reporting and/or CAPA Procedures

Guidelines ……………!!,

The U.S. General Service Administration’s standards (known as FS209E)

Global clean room classifications and standards were adopted by the International Standards Organization (ISO). ISO-14644

The first Federal Standard 209 published in 1963Revised in 1966 (209A), 1973 (B), 1987 (C), 1988 (D) and 1992 (E), and withdrawn in 2001

By law, Federal Standard 209E can be superseded by new international standards. It is expected that 209E will be used in some industries over the next few years, but that eventually it will be replaced internationally by ISO 14644

Airborne Particulate Cleanliness Class Comparison

ISO 14644 FEDERAL STANDARD 209E

EU

ISO Class E M ClassISO 1ISO 2ISO 3 1 M1.5ISO 4 10 M2.5ISO 5 100 M3.5 Grade AISO 6 1,000 M4.5 Grade BISO 7 10,000 M5.5ISO 8 100,000 M6.5 Grade C

Airborne Particulate Cleanliness Classes ): 

CLASS Number of Particles per Cubic Meter by Micrometer Size

0.1 micron 0.2 micron

0.3 micron

0.5 micron

1 micron

5 microns

ISO1 10 2ISO2 100 24 10 4ISO3 1,000 237 102 35 8ISO4 10,000 2,370 1,020 352 83ISO5 100,000 23,700 10,200 3,520 832 29ISO6 1,000,000 237,000102,000 35,200 8,320 293

ISO7 352,000 83,200 2,930

ISO8 3,520,000 832,000 29,300

ISO Documents for Clean room facility….!! 

ISO Document Title

ISO 14644-1 Classification of Air Cleanliness

ISO 14644-2 Cleanroom Testing for Compliance

ISO 14644-3Methods for Evaluating and Measuring Cleanrooms and Associated Controlled Environments

ISO 14644-4 Cleanroom Design and Construction

ISO 14644-5 Cleanroom Operations

ISO 14644-6 Terms, Definitions and Units

ISO 14644-7 Enhanced Clean DevicesISO 14644-8 Molecular Contamination

ISO 14698-1 Biocontamination: Control General Principles

ISO 14698-2 Biocontamination: Evaluation and Interpretation of Data

ISO 14698-3Biocontamination: Methodology for Measuring Efficiency of Cleaning Inert Surfaces

Regulatory Requirements

What are the Regulatory Requirements for Microbial Monitoring in a Pharmaceutical Manufacturing Area?

21 CFR 211.42 Design & Construction Features.211.46 Ventilation, Air Filtration, Air Heating & Cooling.211.113 Control of Microbiological Contamination.211.22 Responsibilities of the quality control unit.FDA Guideline on Sterile Drug Products by Aseptic Processing.FDA Guide to Inspection of Sterile Drug Substance Manufacturers.EU Guide to Good Manufacturing Practice. Annex on the Manufacture of Sterile Medicinal Products.

Regulatory Requirements

Industrial Practices:

PDA(Parenteral Drug Association) Technical Report No. 13 Fundamentals of a Microbiological Environmental Monitoring Program.

PhRMA (Pharmaceutical Research and Manufacturers of America) Task Force Report on Environmental Monitoring inNon-Sterile Manufacturing Areas.

BS 5295 Classification, Design & Commissioning Cleanrooms

US Federal Standard 209E for Cleanrooms.

ISO 14644 for Cleanrooms.

USP ‹1116› Microbial Evaluation of Cleanrooms & Other Controlled Environments.

Post Script....!!!!

The challenge in aseptic processing is always personnel:

•As a source ofmicrobial andparticlecontamination.

•As a brake on theimplementation ofimprovedtechnology.

Screwing UP…………….!!!!???!!!!