Environmental monitoring in a pharmaceutical manufacturing facility
Environmental monitoring in a pharmaceutical manufacturing facility
1.0 Purpose
This procedure defines the requirements for conducting viable and non-viable environmental monitoring in classified areas of the pharmaceutical manufacturing facility. Environmental monitoring assesses the microbial quality of the cleanroom and identifies potential sources of contamination
2.0 Scope
This procedure applies to all clean rooms and controlled areas involved in the manufacture of non-sterile and sterile drug products. It covers monitoring requirements for ISO 5-8 cleanrooms and controlled areas.
3.0 Responsibilities
3.1 The Quality Control (QC) microbiologist is responsible for performing all environmental monitoring testing according to this procedure, as well as recording results. They are also responsible for proper storage, handling, and use of growth media and equipment.
3.2 The QC manager is responsible for reviewing all completed environmental monitoring data, reports, trend analysis, and determining appropriate actions based on the results.
3.3 The Maintenance/Eng. manager is responsible for ensuring proper maintenance, certification, and operating conditions of HEPA filtered areas per engineering controls procedures.
3.4 The Production manager is responsible for ensuring all manufacturing personnel follow proper gowning and aseptic practices in clean rooms.
4.0 Procedure
4.1 Environmental Monitoring Locations
4.1.1 Viable air sampling locations are designated by gridding out each clean room into equal sectors based on the square footage.
4.1.2 The formula for determining the number (n) of environmental monitoring locations in a cleanroom is: n = √A
Where: n = Minimum recommended number of sampling locations A = Surface area of the cleanroom in square meters
4.1.3 This formula provides a rough guideline for selecting an appropriate number of environmental monitoring locations based on the size of the cleanroom. It assumes that larger cleanrooms require more sampling locations to adequately represent the entire area.
4.1.4 Surface monitoring locations include all product contact surfaces, hand contact surfaces, cleaning tools, and general room surfaces. At minimum, samples are taken on the ISO 5 workstation, ante room floor, and machine surface contact points.
4.1.5 Non-viable air particulate monitoring is conducted in all classified rooms with certification performed semi-annually.
4.2 Environmental Monitoring Schedules
4.2.1 For an operational cleanroom during active manufacturing operations (aseptic manufacturing area):
– Viable air monitoring is conducted at the beginning of operations after cleaning, every 4 hours during operations, and at the end of operations.
– Surface monitoring is performed at the beginning before operations, every 2 hours during operations, and at the end after cleaning.
– Non-viable air monitoring is done at the beginning, every 2 hours, and end of operations.
4.2.2 For a cleanroom not in operation:
– Viable air and surface monitoring is performed weekly at minimum.
– Non-viable air monitoring is performed monthly at minimum.
4.2.3 For non-classified controlled areas such as corridors and gowning rooms:
– Viable air and surface monitoring is performed monthly at minimum.
4.2.4 For non-sterile manufacturing perform viable environmental monitoring once in a month and nonviable monitoring once in 6 months.
4.3 Environmental Monitoring Methods
4.3.1 Viable Air Monitoring (Passive air sampling & Active air sampling)
4.3.1.1 For Settle plate monitoring expose the SCDA plate at required location by opening the lid of the petri plates and expose the media plates for Not less than 4 hours. After exposure collect the plates and send for incubation.
4.3.1.2 Use an impaction air sampler calibrated per manufacturer instructions to pull a known volume of air across nutrient agar plates contained within the sampler head.
4.3.1.3 For each viable air sample location, use one agar plate with Soyabean casein digest agar with 0.5% Glycerol.
4.3.1.4 After sampling, transfer the exposed plates to an incubator within 2 hours.
4.3.1.5 Incubate the exposed plates at 30-35°C for 48hrs and transfer them to another incubator, incubate at 20-25°C. Examine and record results after days incubation.
4.3.2 Surface Monitoring
4.3.2.1 Use contact plates containing tryptic soy agar for surface sampling. Contact plates are used for flat, regular surfaces.
4.3.2.2 Remove the lid from the contact plate being careful not to touch the agar surface. Press the agar surface firmly onto the test area for 10 seconds
4.3.2.3 For irregular shaped surfaces and equipment, use membrane filters wetted with a sterile sampling solution (e.g. peptone water). Pass the moistened membrane over the test surface area in a squeezing/rolling motion to pick up any microorganisms present.
4.3.2.4 After surface sampling, re-lid the contact plates and membrane filters and transfer to an incubator within 2 hours.
4.3.2.5 Incubate the exposed plates at 30-35°C for 48hrs and transfer them to another incubator, incubate at 20-25°C. Examine and record results after days incubation.
4.3.3 Non-Viable Air Monitoring
4.3.3.1 Use a remote particle counter calibrated per manufacturer instructions to sample air and measure particulates ≥0.5um and ≥5.0um per cubic meter of air.
4.3.3.2 For static certification of new HEPA filters and annual re-certification, follow accredited certification procedures per ISO 14644 standards.
4.3.3.3 Perform non-viable air monitoring at the points of greatest risk and across all main airflows in the cleanroom.
4.4 Trending and Data Review
4.4.1 Record all environmental monitoring data in the environmental monitoring log, both in paper form and electronically.
4.4.2 Calculate quarterly and annual facility averages for viable air and surface counts.
4.4.3 Any result exceeding action levels must trigger an investigation per the OOS procedure. Potential root causes examined include personnel gowning issues, HVAC system operation, cleaning processes, etc.
4.4.4 The QC manager reviews all environmental data monthly for any adverse trends, even if individual results pass. Trend analysis examines data by room, operating state, shift, and personnel to detect any potential routes of contamination.
4.4.5 The QC manager provides routine management reports summarizing the environmental data review.
5.0 Alert and Action Levels
5.1 Limits for Passive Air sampling (Settle plate) monitoring:
– ISO 5 areas: <1 CFU/m3
– ISO 7 areas: <50 CFU/m3
– ISO 8 areas: <100 CFU/m3
5.2 Limits for Active Air Sampling:
– ISO 5 areas: <1 CFU/m3
– ISO 7 areas: <100 CFU/m3
– ISO 8 areas: <200 CFU/m3
5.3 Surface Sample Alert Levels:
– Any growth of objectionable microorganisms like Staphylococcus, Pseudomonas, molds, etc.
– >3 CFU/plate for product contact surfaces
– >15 CFU/plate for non-product contact surfaces
5.4 Non-Viable Particle Alert Levels:
– ISO 5 areas: >3,520 particles/m3 (≥0.5um) or >20 particles/m3 (≥5um)
– ISO 7 areas: >352,000 particles/m3 (≥0.5um) or >2,900 particles/m3 (≥5um)
– ISO 8 areas: >3,520,000 particles/m3 (≥0.5um) or >29,000 particles/m3 (≥5um)
6.0 Contingency Plans
6.1 If any sample exceeds the limits, an investigation must begin within 24 hours per the OOS procedure. The QC manager determines the initial scope of the investigation based on the monitoring locations and levels detected.
6.2 If levels present a potential product impact, manufacturing operations in the affected area may need to be put on hold pending completion of the OOS investigation.
6.3 The QC manager and production teams will review personnel gowning practices, cleaning processes, equipment maintenance, HVAC system operation, etc. to determine the most probable root cause.
6.4 Once root cause is determined, a CAPA plan will be initiated to correct the issue and prevent recurrence. This may include revising procedures, retraining personnel, replacing equipment, recertifying controlled spaces, etc.
6.5 The facility will return to a monitoring state upon completion of CAPAs to confirm correction of the issues.
7.0 Reference Documents
8.1 SOP on Out of Specification Investigations
8.2 ISO 14644: Cleanrooms and Associated Controlled Environments
8.3 EU GMP Annex 1: Manufacture of Sterile Medicinal Products
8.4 Guidance on Environmental Monitoring (FDA/ORA)