What is environmental monitoring in pharmaceutical industry
- Published on: Dec 29, 2022
What are the benefits of environmental monitoring?
A robust environmental monitoring program will usually provide you an early notice of a breakdown in control measures if it is managed correctly.
Monitoring is however a passive reading of the environment. It cannot be used to justify bad practice with supposedly good data. In such case all that is indicated is that the environmental program is also poor.
There should be a clear policy on when and to what level to identify microorganisms.
To sum it up the environmental monitoring program:
– Provides you with crucial information on the quality of the processing environment during manufacturing.
– Helps you to aid the release decision and determine if a batch could potentially be contaminated.
– Helps your firm to react on changes in the environment and thus allowing better control of the environment, which in turn will make the likelihood of contamination less
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What are other factors to consider during monitoring?
In addition to air, surfaces and people monitoring, you should assess factors that can potentially contribute to contamination of the product during environmental monitoring plan. You should implement on-going monitoring of the factors such as:
– Temperature
– Humidity
– Pressure differentials
– Air within the classified and critical areas
– Utilities that may contact open product or components
– Equipment and critical surfaces within a classified or critical area
– Sanitization
– Operating personnel
What is an environmental monitoring plan?
It is necessary that you establish what to look for when designing an environmental monitoring plan, e.g. common aerobic bacteria, molds and/or anaerobic bacteria.
It is equally important that you set the objectives of the environmental monitoring plan. Normally the plan should provide supporting data to demonstrate the adequacy/performance of the contamination/environmental control measures taken.
Environmental monitoring plan should include:
– People who will be working at different zones
– Monitoring people while exiting the area
– Monitoring aseptic practice e.g. filling
– Your controlled processing areas
– Monitoring airborne contamination
– Surface monitoring
– Materials you will be using
– Components that are in the controlled areas
– Pre-filtration/pre-sterilization bioburden
You can use techniques such as Hazard Analysis and Critical Control Point (HACCP) in order to focus a monitoring plan on where the product is at greatest risk of contamination.
Product as well as process characteristics should be taken into account such as:
Product characteristics:
– Terminal sterilization versus Aseptic Processing
– Microbiological vulnerability
Process characteristics:
– Process design
– Product flow
– Personnel flow and numbers
– Working patterns (shifts?)
– Plant occupancy and levels of activity
– Points in process where the product is at greatest risk
Generally, your environmental monitoring plan should constitute in two parts.
Firstly, prepare a general monitoring scheme that aims to demonstrate the effectiveness of maintenance, housekeeping, operator discipline and compliance with established standards.
For the general monitoring schemes, you will choose sampling locations which can adequately provide data on such parameters. The locations should provide good coverage of the whole cleanroom and associated areas such as
– Changing rooms,
– Air locks
– Transfer hatches
– Preparation areas etc.
Secondly, prepare a batch/process specific scheme that aims to take account of individual processes and to provide batch specific information on the potential for product contamination. You can use these data as evidence in batch disposition process as well as for demonstrating compliance with established standards.
For batch/process specific monitoring schemes you will choose sampling locations to reveal potential problems with process and/or product integrity.
Your sampling points should reflect the process flow pattern and environmental monitoring should follow the product flow through the manufacturing area.
In particular points in the process where the products and components are exposed to the environment should be taken into account.
Your sampling should generally include:
– Air sampling (active and passive),
– Hard surface sampling (at or adjacent to critical areas),
– Operators gown and gloves
– Liquid sampling (e.g. bioburden).
What are the cleanroom classifications and particulate limits?
Cleanroom classifications:
When you will attempt to classify your cleanrooms and corresponding limits for non-viable airborne particulate counts, you may observe there are some degree of misunderstanding and confusion exists between “2004 US Food and Drug Administration” (USFDA) environmental cleanliness requirements for sterile product manufacture and those of the “European Medicines Agency” (EMA) EudraLex Volume 4, Annex 1.
USFDA environmental cleanliness requirements are named “Federal Standard 209”.
The confusion has since been exacerbated by the adoption of ISO cleanliness classification system standards ISO 14644-1:2015 by the USFDA.
Eudralex, Federal Standard 209 and ISO 14644-1 differ in detail but follow very similar number for maximum permitted number of particles (limits) for respective particle size. Eudralex and Federal Standard 209 make reference to alert as well as action levels.
For your ease of understanding we have constructed the below table to demonstrate the difference and similarities between the three major regulatory requirements.
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Please note:
i. FDA classifies cleanrooms from ISO 5 to ISO 8
ii. Eudralex classifies cleanrooms from grade A to D
iii. ISO 14644-1 specifies classes of air cleanliness in terms of the number of particles expressed as a concentration of air volume.
Particulate limits:
Alert Limit: established microbial or airborne particle level giving early warning of potential drift from normal operating conditions and triggers appropriate scrutiny and follow-up to address the potential problem. Alert limits are always lower than action limits.
Action Limit: established microbial or airborne particle level that, when exceeded, should trigger appropriate investigation and corrective action based on the investigation.
ISO 14698 also requires the establishment of a target value. This is value indicates the normal controlled performance of a location.
Sampling frequency examples:
You plan for sampling frequency of environmental monitoring should depend on historical performance as well as changes to processes, plant and procedures. Normally general sampling schemes are executed weekly and specific sampling schemes at each work session.
You can use the following example of sampling frequency of environmental monitoring in aseptic processing.
– Settle plate monitoring of the filling rooms will be completed for each session of each fill operation, maximum of 4-hour exposure.
– Glove prints and contact plate sampling of operator gowns will be performed by each filling operator in the Grade A (ISO 5) area prior to leaving the room.
– Glove prints and contact plates will be performed by any other staff in the filling room prior to each exit.
NB: Glove prints or contact plates for gowns are not required on exit when the room is opened e.g. for cleaning, maintenance and certification activities.
– Viable air sampling will be completed daily using suitable equipment (e.g. Merck MAS-100). Class A (ISO 5) areas will not be sampled during operation of the filling machine.
– Non-viable particle counts will be completed continuously for each fill operation.
– RODAC plate sampling other than gown samples will be performed at the end of each fill day.
– At Rest Environmental Monitoring will be completed one (1) day per 6 months and after major maintenance operations e.g. preventative maintenance, certification activities etc.
Your sampling plans should be approved, justified and contain clear schematics showing sample locations. Sampling procedures should contain information regarding when testing should be performed, by whom, under what activity and method to use.
Samplers should be appropriately trained (e.g. sampling may require excellent aseptic technique in order to avoid false positives).
Other key elements to consider in environmental monitoring plan
Temperature and Relative Humidity Monitoring
You should control and monitor the temperature and relative humidity of your facilities as appropriate. For the processing area, both of these factors should be connected to an alarm system.
If the temperature and humidity are elevated, personnel may begin to shed increasing numbers of skin cells and sweat causing more potential contamination. An approved SOP or procedure should be in place explaining what actions should be taken if a temperature or humidity excursion occurs.
Pressure Differentials
Appropriate pressure differentials from room to room and area-to-area is necessary to prevent contamination of the drug product.
You should maintain positive pressure differential between the most critical area and the next critical area. Pressure differentials should be monitored and alarmed continuously.
A typical pressure and airflow for the area should look something like that shown below:
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The flow of air should be out of the critical areas into the adjacent areas, unless the opposite is required due to safety or cross-contamination reasons.
The critical areas, where product is exposed, should also be the cleanest areas, with the fewest numbers of particles and microbes.
Utilities:
You should monitor utilities including the HVAC system, the water system, and compressed gases that may come in contact with either the exposed product itself or the air that the product is exposed to.
– Monitor compressed gases by testing for viable and non-viable particulates.
– The Water for Injection (WFI) system should be monitored on a routine basis. Tests that should be performed include microbial quality and endotoxin tests as well as USP chemical tests. The reason for testing this water is that it may be used as a solvent for preparation of parenteral solutions and also for final product formulation.
– You should also test the potable water, purified water, the feed water for WFI and component rinse water on a regular basis. Results of the tests should be analyzed for trends that might be developing.
What environmental monitoring testing are performed in pharmaceutical industry?
You need to divide the environmental monitoring testing into two major categories. Those are
1. Non-viable contaminants testing, and
2. Viable contaminants testing.
What is non-viable contaminant testing?
You should test the count of non-living particulates or particles that may contaminate a sterile product. This would include dust particles, dirt, rust, tiny metal shavings, lint from a garment, human particulates and other sub-visible particles that can still contaminate a sterile product if they are present in the environment.
Factors that are tested for this category of contaminant include:
1. Air in the processing and support area
2. Compressed gases
Be aware that the most critical processing areas where sterile product or components are exposed to the air during processing should be monitored for non-viable particulates.
Non-viable air sampling should routinely be conducted during aseptic processing.
You should place the sampling devices in grade A areas within one foot and directly upstream of the working zone where exposure of critical items or materials take place.
Place the sampling device to sample the HEPA filtered air just before it reaches the areas where critical items or materials are exposed.
Placement of the sampling devices in other areas of the processing suite is less prescriptive since these areas are usually subject to turbulent flow.
The frequency of the air testing should be every time the aseptic processing area is in use. Support areas may be tested less frequently.
Refer to table for particulate limits for alert and action limits for non-viable monitoring.
What is viable contaminant testing?
You are required to perform viable or microbiological particulates/microorganisms in your processing environment.
Develop a microbiological isolate identification program. The extent and frequency of identification should be risk based with the greatest emphasis on any isolates from critical zones being identified.
In order for you to determine if microorganisms are present, number of methods are in use. Some of the most common are:
Surfaces testing
1. Contact plate method
2. Swab method
Air Testing
1. Settling Plate method
2. Impaction/Impinger methods
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How to monitor surfaces for viable contaminants?
Ideally, you should monitor surfaces while the cleanrooms are in operation mode.
You should give considerations on the type and level of activities that represent actual filling processes. Some surfaces may be tested during operations or before operations. Monitoring the surfaces every time, the aseptic processing area is used.
Critical surfaces within the filling area and personnel testing should be included as part of surface
testing. However, surfaces in critical zones should only be monitored after the completion of operations due to the risk of bringing microbiological culture medium into the environment where critical activities are taking place.
Monitoring of surfaces in surrounding areas during operations also poses the risk of leaving residue of microbiological culture medium on the sampled surface. You should only monitor these areas where absolutely necessary and with strict controls.
You should perform additional surface testing on randomly where personnel frequently come in contact with the processing area in an effort to identify potential contamination sources.
Examples are curtains surrounding the Class 100/grade A area, door plates, phones and tools.
Contact plate method:
The contact plate, or RODAC (Replicate Organism Direct Agar Contact) plate, consists of a solid general nutrient agar media, approximately 25cm in diameter.
The sample is taken by gently rolling the raise surface of the agar plate onto a flat or slightly curved surface for a defined time interval.
After you conduct the test, wipe the area using a lint-free wipe soaked in disinfectant (isopropyl alcohol, IPA) to remove residual agar.
The plate is covered and incubated at an appropriate temperature. The presence and number of microorganisms is detected by the appearance of colonies on the surface of the plate.
USE:
1. Personnel gloves and gowns
2. Filling room surfaces
3. Determining the effectiveness of cleaning and sanitization procedures
Swab testing method:
The swab method is used to obtain a sample from small or irregularly shaped objects or surfaces. Samples are collected by swabbing the surface or object with a moistened sterile swab containing sterile diluent to assure uniform coverage of the sampled area.
The swab is then transferred into a container with growth medium. The swab and container are then incubated at an appropriate temperature.
USE:
– Swabbing small items in the filling room
– Swabbing the interiors of small items
How to monitor air for viable contaminants?
You can sample microbes in air in number of ways. Passive sampling (e.g. settle plates) or dynamic sampling (e.g. impaction sampling) may be used to monitor the air depending on the requirements of the governing regulations and guidelines. Below are brief descriptions of some method.
Settle Plate Method:
An open petri dish of defined size, agar media and fill amount, is placed within the filling area for a defined period of time. This time period is generally determined by the type and size of the settle plate. However, the norm is for exposure of 4 hours.
Particles form the air fall onto the open plate and settle on the agar surface. At the end of the sampling time interval, the plate is then incubated at pre-determined temperatures based on the common flora normally recovered at the local facility.
Impaction method:
You can collect samples using one or combination of three methods described below which are called impaction method. All of these methods are considered dynamic because the air is drawn into a sampling chamber to be collected.
The methods are generally used for critical processing areas
1. Slit-to-agar method:
This is considered an active sampling method. Through use of a vacuum pump, usually 1 Ft. area is pulled in through a slit with a calibrated width and impacted onto a slowly moving agar plate under the slit.
After the sample is taken, the agar plate is incubated and colonies are counted.
2. Centrifugal method:
The sampler consists of a propeller that pulls a known volume of air into the unit and then propels the air outward to impact onto a nutrient agar strip. After the sample is taken, the agar plate is incubated and colonies are counted.
3. Sieve method:
The sampler is attached to a vacuum source that pulls room air, at a defined rate, through a top, perforated with calibrated holes. The air is then impacted directly onto an agar plate and exhausts through the vacuum line. After the sample is taken, the agar plate is incubated and colonies are counted.
How to monitor operational personnel?
The last factor in the environmental monitoring system is personnel who populate the processing area. In an aseptic area (ISO5 / USP 100 /Grade A), it is essential that your personnel know and follow their site’s gowning procedures.
It is important that you prepare a formal, documented gowning training program is in place. This program should include training in how to correctly put on sterile garments and should also include periodic refresher training. This is necessary because each individual brings into the processing area both particulate and microbial contamination.
Your personnel need to be routinely tested in conjunction with activities performed in the aseptic processing area. The EC Guide to Good Manufacturing Practice – Revision to Annex 1 states that surfaces and personnel should be monitored after critical operations.
You can use RODAC (contact) plates during Personnel testing, usually on their gloves and different places on the gown.
You should monitor the personnel as soon as possible upon completion of critical tasks. You are expected to establish limits based on recommendations from worldwide regulatory documents as well as data collected from monitoring.
Summary
All of the factors mentioned above need to be aligned and integrated to produce a clean environment for the processing of sterile drug products.
If any one of them is not within limits or not working properly, it can affect the whole processing environment and jeopardize the sterility, integrity, potency and quality of the final drug product.
The goal of the environmental monitoring program is to control contamination through the rigorous monitoring of all of these factors and prevent loss of control through early detection.
Author: Kazi Hasan
Kazi is a seasoned pharmaceutical industry professional with over 20 years of experience specializing in production operations, quality management, and process validation.
Kazi has worked with several global pharmaceutical companies to streamline production processes, ensure product quality, and validate operations complying with international regulatory standards and best practices.
Kazi holds several pharmaceutical industry certifications including post-graduate degrees in Engineering Management and Business Administration.
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