Environmental Monitoring Considerations

Nancy Roscioli, Ph.D. Don Hill and Associates, Inc.

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

Environmental Monitoring Components
‡ Water monitoring:
± Total organic carbon ± Conductivity ± Microbial Contaminants ± Endotoxin

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

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

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 used for product manufacturing as well as feed water to the final water purification system (WFI System) .

Regulatory Basis for Environmental Monitoring Program ‡ CFR GMP regulations ‡ FDA Guidance Documents ‡ USP Informational Chapter .

42 ‡ 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 .21 CFR 211.

.21 CFR 211. humidity and temperature.46 ‡ Ventilation. ± Air filtration systems including prefilters and particulate matter air filters for air supplies to production areas. dust. air filtration. air heating and cooling: ± Adequate control over microorganisms.

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 .

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 .

Microbial Evaluation and Classification of Clean Rooms and Clean Zones ‡ USP General Information Chapter <1116> ‡ 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 .

isolator . ‡ Methods and equipment for sampling ‡ Identification of isolates ‡ Aseptic media fills ‡ Emerging technologies .barrier.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.

000 and 100. 10.000 (based on particles > 0.Federal Standard 209E ‡ ³Airborne 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 100.5µ) .

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 .

personnel. product component bioburden ± Yeasts. surfaces.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. water system. anaerobes ± Exceeded EM limits . molds.

000 3.000 .000 3.1 0.000 100 10.530 353.5 m3 3.530.000 2.5µ) cation ft3 m3 Class 100 Class 10.Nonviable (>0.5 100.Viable and Nonviable Contaminant Limits Classifi.000 Viable (CFU) ft3 0.5 18 88 Class 100.

000 or Class 10.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 contaminants to reduce product /process bioburden ‡ Class 100.000 .

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 .

components or in-process products are exposed to the environment and no further processing will occur. .Critical Area ‡ Aseptic processing area where sterile products. ‡ Air quality must be Class 100 during processing ‡ Local Class 100 areas are often utilized during open processing steps during drug substance manufacture.

.Critical Area ‡ The area just preceding the sterile core should be one classification higher than the core.

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 be done periodically after that to insure area meets acceptable conditions before use or following cleaning .

during each use ± For other.Nonviable Particulate Monitoring ‡ Locations for monitoring should be established during performance qualification. varies from each use to weekly or less depending on use of area . controlled areas. probes placed close to work surface ‡ Monitoring frequencies vary: ± For aseptic processing areas.

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 .Nonviable Particulate Monitoring ‡ HVAC Validation and Maintenance Considerations: ± Air velocity.

Microbial Monitoring ‡ Airborne viable contaminants ‡ Surface contaminants ± walls ± equipment surfaces ± countertops ± floors ‡ Personnel contaminants .

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 .

‡ Airborne monitoring frequencies: ± Each use for aseptic processing areas ± Varies from daily to weekly to less frequently for controlled areas depending on use .Microbial Monitoring ‡ Routine microbial monitoring should take place during operations (for airborne contaminants) and immediately following operations (for surfaces and personnel).

after every fill ± Other controlled areas .Microbial Monitoring ‡ Personnel and surface monitoring frequencies vary: ± Aseptic processing .varies from daily to weekly or less for surfaces ± Personnel monitoring often restricted to aseptic area personnel and personnel working in Class 100 hoods performing tasks such as inoculation .

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 operating properly ± NOTE: Disinfectant effectiveness studies also required for cleaning agents used in the facility .

Microbial Monitoring ‡ Monitoring frequencies and procedures are influenced by a number of factors: ± Stage of manufacturing ± ³Open´ or ³closed´ manufacturing step ± Single or multiple product manufacturing .

will aid in investigations .Microbial Monitoring ‡ Establishment of monitoring locations should be based on performance qualification studies during dynamic conditions ± gridding study to determine worst case locations/most meaningful locations ‡ Should also establish common flora .

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 normal processing conditions .

i.e. alert affected area personnel ‡ Exceeding multiple alerts .Exceeding Limits ‡ Alert limits are designed to provide some warning that environmental quality is approaching action limit and allow you time to correct.. ‡ Exceeding alert limit triggers a warning response .triggers action level response .

must quarantine until determined .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 .

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 of disinfection procedures. for example ± HVAC maintenance .

corrective actions should be pre-established to the extent possible .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.

Investigations and Corrective Actions ‡ 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 adverse environmental conditions .

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 .

42(c)(10)(ii) ‡ Generally 65°F and 35-50% humidity are average ± Too high .Increases personnel shedding ± Too low .Temperature and Humidity ‡ Control of temperature and humidity required for aseptic processing areas ± 21 CFR 211.Increase static electricity .

need procedure to follow if humidity exceeds limit .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.

Water Requirements Test T onductivity icro. urity ndoToxin otable uri ied W I Water Water none 500 ppb 500 ppb none 500 CFU/ml ee 100 CFU/ml Table 10 CFU/ 100 ml 0.25 U/ml none none .

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 .

Purified Water ‡ Defined in USP ‡ Obtained by a suitable process. usually one of the following: ± deionization ± reverse osmosis ± combination .

Potable Water ‡ Meets National Drinking Water Regulations ‡ 40 CFR Part 141 ‡ Periodic monitoring in-house as well as periodic certificates from municipality (if applicable) .

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) .

Water System Monitoring ‡ Purified Water Systems ± Weekly monitoring of system for: ‡ microbial quality ‡ TOC ‡ conductivity .

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 .

Water Use ‡ Purified Water ± Preparation of terminally sterilized microbiological media ± Initial rinsing/cleaning ± Laboratory use ± Feed for WFI system .

Water Use ‡ Potable Water ± Non-product contact uses ± Feed for purified water system .

Powered by vacuum.Microbial Monitoring Devices ‡ Slit-to-Agar (STA) . 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 .

Microbial Monitoring Devices ‡ Centrifugal Sampler .similar to sieve impactor. vacuum draws in air which is impacted on agar plate . cover contains uniformly spaced orifices.consists of a propeller that pulls a known volume of air into the unit and then propels the air outward to impact on a nutrient agar strip ‡ Sterilizable Microbiological Atrium (SMA).

behind is a motor and turbine that pulls air in through the perforated cover and exhausts it beyond the motor.An integrated unit containing an entry section with an agar contact plate.qualitative.Microbial Monitoring Devices ‡ Surface Air System Sampler . ‡ Settle plates . may be useful in worst case locations .

for regular surfaces ± Swabs . swab placed in suitable diluent and inoculated onto microbiological plate .useful for hard to reach or irregular surfaces.Microbial Monitoring Devices ‡ Surface contaminant monitoring devices: ± Contact Plates .plates filled with nutrient agar.

± 80-100 ft3/min ‡ Must validate growth promotion after exposure of settle plates (or other plates) for prolonged time periods. .Monitoring Considerations ‡ Remote sampling probes .validate use of tubing ‡ Must sample adequate quantity of air to be statistically meaningful.

Sign up to vote on this title
UsefulNot useful