Goals
When you have completed this unit, you should be able to:
Ø Perform an Environmental Monitoring Audit.
Ø Use a range of tools and information, including the contents of this unit and the Intranet, to support an Environmental Monitoring Audit.
Ø Apply worldwide regulatory agency requirements to Environmental Monitoring
Ø Recognize compliance or non-compliance of regulations regarding Environmental Monitoring requirements.
Definitions
Air changes: The frequency (minutes, hours, etc) with which the air in a controlled environment (classified area) is replaced. The air can be recirculated partially or totally replaced.
Air classifications: Classification of processing rooms or areas based on the allowed number of particles per cubic foot of air (USA) e.g. class 100, or particles per cubic meter (EU) depending on level of activity in the processing room. The EU refers to these air classifications as Grades A through D, with A being the cleanest during normal activity.
Air Lock: A small room with interlocked doors, constructed to maintain air pressure control between adjoined rooms (generally with different air cleanliness standards). The intent of the air lock is to preclude ingress of particulate matter and microorganism contamination from a lesser controlled area.
Air samplers: A calibrated piece of equipment that samples air by impacting a calculated amount of air onto a solid or semi-solid microbial growth media over a specified period of time. These samplers are used to determine the viable (microbiological) content of the air in the processing room. Some accepted samplers are Slit-To-Agar (STA) samplers, Centrifugal Samplers (CS), and Sieve Microbial Atrium (SMA) samplers.
Action levels: Established microbial or particle levels that, when exceeded, should trigger an appropriate investigation and corrective action based on the investigation.
Alert levels: Established static and operational microbial or particulate levels giving early warning of potential drift from normal operating conditions which are not necessarily grounds for definitive corrective action but which require follow-up investigation.
Classified area: This is an area that is qualified and monitored against a defined particulate level (e.g. ISO 5-8 and EU Grade A-D).
Clean Area: An area with defined environmental control of particulate and microbial contamination constructed and used in such a way as to reduce the introduction, generation, and retention of contamination within the area.
Colony forming unit (cfu): A microbiological term that describes the formation of a single macroscopic colony after the introduction of one or more microorganisms to microbiological growth media. One colony forming unit is expressed as 1 CFU.
Contact plates: Usually a plastic plate that has a raised surface composed of microbiological solid media. The media is then pressed or rolled upon a surface, transferring the content of the surface to the media. RODACs (Replicate Organism Direct Agar Contact) plates are one example.
Continuous monitoring: Ongoing sampling of environmental conditions throughout the period of operations, ensuring that update of data occurs constantly.
Controlled environment: Any area in an aseptic process system for which airborne particulate and microorganism levels are controlled to specific levels that are appropriate to the activities conducted within that environment.
Critical surfaces: Surfaces that may come into contact with or directly affect a sterilized product or its containers or closures. Critical surfaces are rendered sterile prior to the start of the manufacturing operation, and sterility is maintained throughout the process.
Dynamic / “in-operation” testing: Testing performed during processing operations or within an active shift (as applicable) with personnel present to confirm that the environment remains under control during these conditions.
Excursion: A testing result that deviates from normal expectations defined by the firm.
Incident rates: The rate or frequency at which contamination is observed in an environment. Typically expressed as a percentage of samples in which contamination is observed per unit time.
Laminar flow: An airflow moving in a single direction and in parallel layers at a constant velocity from the beginning to the end of a straight-line vector. However, true laminarity is not achievable in clean room applications. “Unidirectional flow” is the more accurate description fro clean room applications and is defined as; an airflow moving in a single direction, in a robust and uniform manner and at sufficient speed to reproducibly sweep particles away from the critical processing or testing areas.
Particulate monitoring: Testing of the processing air for various sizes of viable and non- viable particles. Continuous monitoring is required in grade A and recommended for grade B by EU. FDA is less prescriptive and only state that such monitoring be frequent.
Sanitization Schedules: Schedules established by the firm to sanitize the cleanroom facility surfaces, e.g. walls, ceilings, floors. Schedules may vary depending on the use and condition of the room. The schedule is to be part of an approved procedure for housekeeping and cleaning of the aseptic area.
Settling or settle plates: Usually petri dishes containing a microbial growth media, like agar, which are distributed throughout an area, media side up, to measure the viable content of the air over a specified period of time. This is a passive system that catches microorganisms as they fall onto plates.
Static /“at rest” testing: Testing performed with equipment installed but no personnel present to ensure that the facility environment continues to perform as designed and is compliant during normal operation.
Trend analysis: A periodic review and analysis of the Environmental Monitoring Program results that can be related to time, shift, facility, etc. for patterns that may suggest underlying or developing problems.
Explanation of Topic
What is an Environmental Monitoring program?
An environmental monitoring program provides information on the non-viable particulate and microbiological quality of the environment being monitored.
Such data provides an insight into the effectiveness of the control programs (e.g. cleaning, housekeeping, gowning, air handling) that are in place. Controlled environments must be monitored using the appropriate regulatory guideline and industry practices. Areas defined as controlled environments must be monitored as appropriate for that environment.
Monitoring programs must be based on the processing requirements of the area and the risk assessment of the area. In non-classified areas, a level of microbiological monitoring is necessary as part of an ongoing risk assessment to maintain awareness of the microbiological environmental conditions during manufacturing activities.
Even though environmental monitoring is most closely associated with aseptic processing, it should include monitoring of all environments where products and their components are manufactured, especially where there is risk of product contamination. In addition to monitoring air, surfaces and people, all water and gases used in product manufacturing as well as feed water to the final water purification system (WFI System) should be monitored.
Specific factors that can contribute to contamination of the product are monitored. On- going monitoring is performed for the factors below:
Ø Temperature
Ø Humidity
Ø Pressure differentials
Ø HVAC system
Ø Air within the classified and critical areas
Ø Utilities that may contact open product or components
Ø Equipment and critical surfaces within a classified or critical area
Ø Sanitization
Ø Operating personnel
Monitoring practices should include development of room sampling plans to define type of testing, frequency and general location of test sites for air, surface, and personnel monitoring. Room sampling plans should consider the configuration of machinery and equipment in the room, airflow patterns (based on validation studies) as well as personnel and material flows. Rationale statements should be available for room testing as well as for the determination of alert and/or action levels. Each environmental monitoring program is unique to the product, process and plant.
Establishing an environmental monitoring program
It is necessary to establish what to look for when designing a monitoring program, e.g common aerobic bacteria, moulds and/or anaerobic bacteria. Equally important is to set the objectives of the environmental monitoring program. Normally the program should provide supporting data to demonstrate the adequacy/performance of the contamination/environmental control measures taken. Monitoring may include:
People
Ø Exit monitoring
Ø Aseptic practice
Plant
Ø Airborne contamination
Ø Surfaces
Materials
Ø Components
Ø Pre-filtration/pre-sterilization bioburden
Techniques such as Hazard Analysis and Critical Control Point (HACCP) can be used in order to focus a monitoring program on where the product is at greatest risk of contamination. Product as well as process characteristics should be taken into account.
Product characteristics
Ø Terminal sterilization versus Aseptic Processing
Ø Microbiological vulnerability
Process characteristics
Ø Process design
Ø Product flow
Ø Personnel flow and numbers
Ø Working patterns (shifts?)
Ø Plant occupancy and levels of activity
Ø Points in process where the product is at greatest risk
Generally a microbiological monitoring program is constituted by two parts. Firstly a general monitoring scheme that aims to demonstrate the effectiveness of maintenance, housekeeping, operator discipline and compliance with established standards. Secondly a batch/process specific scheme that aims to take account of the specific characteristics of individual processes and to provide batch specific information on the potential for product contamination and thus be used in the batch disposition process as well as also demonstrating compliance with established standards. For the general monitoring schemes (effectiveness of housekeeping, maintenance and operator discipline) sampling locations should be chosen which can adequately provide data on such parameters.
The locations should give good coverage of the whole clean room and associated areas (changing rooms, air locks, transfer hatches and preparation areas).
They should be chosen in order to include “worst case” locations such as high traffic areas, low airflow areas and sinks. Locations should be realistic in order to mirror the overall condition of the manufacturing environment. For the batch/process specific monitoring schemes sampling locations should be chosen to reveal potential problems with process and/or product integrity.
They should thus reflect the process flow pattern and monitoring should follow the product flow through the manufacturing area. In particular points in the process where the product and components are exposed to the environment should be taken into account.
The microbiological cleanliness of the gloves of operators intruding critical zones should also be monitored. Sampling should generally include: air sampling (active and passive), hard surface sampling (at or adjacent to critical areas), operators, liquid sampling (e.g. bioburden).
Sampling frequency and limits
Frequency of monitoring depends 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.
Some official guidance is given in USP (1116). Both the Eudralex and the USP include guidance for environmental levels. They differ in detail but follow very similar numbers. However both of these standards reflect a lowest common denominator. They contain the minimum requirements. Normally a well- controlled clean room ought to achieve average numbers much lower than this. Both the Eudralex and the USP make reference to alert as well as action levels.
The alert level is an 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 levels are always lower than action levels. The action level is an 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. A sensible system to evaluate the environmental conditions of premises can be put together using the three sources of information; target level, alert level and action level.
The QP/QA must be informed of environmental data and generally there is a point where QP/QA will consider whether or not a batch may be released. Environmental monitoring results should be part of the batch record review as this is a way of ensuring that it has been considered as part of batch release.
Other key elements of a monitoring program
Sample 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).
Cultivation and enumeration procedures should be approved and include storage and transfer of samples, date (time received/tested and reference to micro method and media to be used.
There should be a clear policy on when and to what level to identify microorganisms. To sum it up the environmental monitoring program:
Ø Provides crucial information on the quality of the processing environment during manufacturing.
Ø Helps to aid the release decision , and determine if a batch could potentially be contaminated.
Ø Helps the 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.
A robust environmental monitoring program will usually provide 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 programme is also poor.
Temperature and Relative Humidity Monitoring
Temperature and relative humidity should be controlled and monitored 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. A positive pressure differential between the most critical area and the next critical area should be maintained. Pressure differentials should be monitored and alarmed continuously. A typical pressure and airflow for the area should look something like that shown below:
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. How to handle ventilation failures should be described in SOPs. The critical areas, where product is exposed, should also be the cleanest areas, with the fewest numbers of particles and microbes.
Utilities
Utilities that should be monitored include 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. Compressed gases should be tested 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. Potable water, purified water, the feed water for WFI and component rinse water should also be tested on a regular basis. Results of the tests should be analyzed for trends that might be developing.
Types of Air and Surface Monitoring
Within an environmental monitoring program there are various types of testing performed. The testing can be divided into two major categories. These categories are testing for:
Ø Non-viable contaminants and
Ø Viable contaminants.
Non-viable contaminants
This category tests for non-living particulates or particles that 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 product. Factors that are tested for this category of contaminant include:
Ø Air in the processing area and support area
Ø Compressed gases
Expectations of world wide regulatory agencies are 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. The particle load, from an air sample taken under normal processing activity (i.e. dynamic conditions), should be evaluated in accordance with EN ISO 14644-1, EU GMP Annex 1 and FDA requirements as appropriate.
The purpose of particulate monitoring is to demonstrate that the particle load of the air just before it encounters the working plane of concern where there may be product or sterile material/container/closure/equipment surface exposure. It is not to sample, count, and size particles associated with equipment operation. Non-viable air sampling should routinely be conducted during aseptic processing.
Placement of the sampling device in grade A areas should generally be within one foot and directly upstream of the working plane where exposure of critical items or materials take place.
The sampling device should be properly oriented 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, such as component preparation areas in controlled areas.
All testing intervals should be defined within an approved procedure. The acceptable number of particles is based on what the area is used for, what type of air filtration is installed, the activity level, and the design of the area.
Viable Contaminants
The other type of monitoring that is performed is viable/microbiological particulates/microorganisms testing. There should be a microbiological isolate identification program in place. The extent and frequency of identification should be risk based with the greatest emphasis on any isolates from critical zones being identified.
The extent of identification performed in other areas should be based on a written program that seeks to adequately characterize the environment to determine if there are any trends or shifts in isolates observed and whether any atypical isolates are present such as fungal organisms, gram-negative bacteria or spore forming gram-positive bacteria.
To determine if microorganisms are present, there are a number of methods in use to determine if microorganisms are present. Some of the most common are:
Surfaces Air Testing
Ø Contact plate method Ø Settling Plate method
Ø Swab method Ø Impaction/Impinger methods
Monitoring of Surfaces
Ideally, surface monitoring should be performed to represent the area while in production mode. Considerations should include the type and level of activity that represent actual filling processes. Some surfaces may be tested during operations or before operations begin. The frequency should be 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 conclusion 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 and so should only be done where absolutely necessary and with strict controls Additional surface testing should also be performed on random items that personnel frequently come in contact in an effort to identify potential contamination sources. Examples are curtains surrounding the Class 100/grade A area, door plates, phones and tools.
The next paragraphs briefly describe methods used for surface testing.
Contact plate method:
The contact plate, or RODAC (Replicate Organism Direct Agar Contact) plate, consists of a solid general nutrient agar media, approximately 25cm which can withstand being 2, pressed onto a surface or object.
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 the test is conducted, the area tested should be wiped using a lint-free wipe soaked in disinfectant (isopropyl alcohol, IPA, is most commonly used) to remove residual agar according to the site’s SOP. 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:
Ø Personnel gloves and gowns
Ø Filling room surfaces
Ø Determining the effectiveness of cleaning and sanitization procedures
Swab 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:
Ø Swabbing small items in the filling room
Ø Swabbing the interiors of small items
Air Testing
The microbiological quality of the air surrounding the processing area is also tested in accordance with worldwide guidance documents and regulations. Microbes in the air may be sampled in a 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 firm’s policies 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, determined by the type and size of the settle plate, and the site’s practices and SOPs, may vary. However, the norm is for exposure is 4 hours. Any other exposure time used should be justified. 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:
The three methods described below use the impaction method to collect samples. All of these methods are considered dynamic because the air is drawn into a sampling chamber to be collected. The methods are used for:
Ø Critical processing areas
Slit-to-agar method:
This is considered an active sampling method. Through use of a vacuum pump, usually 1 ft3 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.
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.
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.
Operating personnel
The last factor in the environmental monitoring system is personnel who populate the processing area. In an aseptic area it is essential that the personnel know and follow their site’s gowning procedures. It is important that 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. As mentioned before, 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. Personnel testing, usually using RODAC plates is performed on glove and gown sites.
Monitoring should be performed as soon as possible upon completion of critical tasks. Firms are expected to establish limits based on recommendations from worldwide regulatory documents as well as data collected from monitoring.
Sanitization
Sanitization of the processing area should be assessed. Suitability, efficacy, and limitations of the sanitization agents must be determined based on their ability to inhibit or remove microbial contaminants commonly found in the processing areas and adjacent areas. In the choice of sanitization agent the spectrum of activity, sporicidal effect, inactivation by organics/materials/hard water and residues/corrosion, safety, contact time required, stability and cost must be considered.
The firm should have an approved sanitization program with detailed procedures. Based on different chemical characteristics and mode of action sanitization agents can be grouped. The norm mechanism is destruction bacterial proteins by oxidation.
Ø Alcohols (e.g. IPA, Ethyl Alchol) are normally used in 70% concentration and have broad-spectrum activity, rapid action, leave minimum residue, are generally not affected by organics or materials and provide some cleaning effect. However, they are flammable, costly and not sporicidal.
Ø Quaternary Ammonium Chloride Compounds (e.g. Cetrimide, Benzalkonium Chloride) are very active against gram-positive organisms, stable, soluble, compatible with detergents, fungicidal and are inexpensive. However, they are not sporicidal and may be affected by hard water and organic material.
Ø Phenolic compounds (e.g. Chloroxylenol) are generally fungicidal, broad spectrum biocidial and very soluble. However, they are not sporicidal and hard water, some organic materials and natural soap may reduce their effectiveness. Additionally they are no good cleaning agents and may swell rubber and some plastics.
Ø Iodophors are quick in microbial kill, very active against gram-positive bacteria and generally less skin irritating than other sanitization agents. However, they are not good cleaning agents, may stain plastics, inactivated when exposed to UV- light and may be inactivated by organic material.
Ø Chlorine compounds (e.g. Sodium Hypochlorite) have broad-spectrum activity, are sporicidal and are not affected by hard water nor natural/manmade materials and leave very little residue. However, they are inactivate by organics, loose activity on prolonged storage and exposure to UV-light, are corrosive and not good cleaning agents.
Ø Gluteraldehydes (e.g. Tegodor) are broad spectrum and non-staining/corrosive. However, they are unstable in solution, irritating to skin and inactivated by organics.
Routine sanitization should include all critical areas, walls, ceilings and floors. Particular consideration should be given to change rooms, transfer hatches and other areas frequently used. Rotation of sanitization agents used may be done in order to prevent development of resistant microbiological flora. In any case agents should be chosen in order to achieve a wider spectrum of antibacterial effect.
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 system is to control contamination through the rigorous monitoring of all of these factors and prevent loss of control through early detection.
Key Parameters for Auditing an Environmental Monitoring System
Prior to the audit
Determine what type of environmental monitoring will be required for the products manufactured at the site.
Ø Review previous inspections and audit.
Ø Review listed reference materials found in this unit to familiarize yourself with worldwide regulatory expectations.
During the audit
Inspect the facility utilities.
Ø Compressed gases, water systems, steam, and HVAC systems.
o Determine if all utility systems with product contact and/or aseptic processing components have been qualified.
o Determine what routine testing of these systems is conducted and how often.
o Determine what the microbial action and alert levels are for compressed gases, HVAC systems, water, and steam.
o Determine what the particulate action and alert levels are for compressed gases and HVAC.
o Review action and alert limits to determine if they are appropriate.
o Determine if there is a site procedure listing what actions need to be taken if any of these systems exceed these limits.
o Determine if these procedures for “over limits” are followed.
Determine if the pressure differential between adjacent production rooms/hallways is monitored.
Ø Determine if rooms are pressurized so that clean and critical areas have positive airflow relative to adjacent rooms/hallways or if other pressure differences are more relevant due to risks for cross contamination/safety
Ø Review the number of room air changes monitored. Air changes should be increased for cleaner classifications and where there is a greater amount of particle generation.
Ø Determine if the air velocity is monitored. The velocity parameters established for each processing line should be justified and appropriate to maintain unidirectional airflow and air quality under dynamic conditions within a defined space.
Ø If air velocity is monitored, review the data. Compare readings with validated conditions.
Ø Ensure that air pressure differentials within controlled areas are continuously monitored and alarmed to indicate when the air pressure is out-of-range.
Ø Determine what the pressure differential alarm delay specifications are and how they were established.
Ø Determine what procedures are followed in response to these types of alarms.
Ensure appropriate and timely actions are taken.
Ø Ensure that the minimum pressure differential between rooms of different classifications is .05” water or 10-15 pascals.
Ø Ensure that the direction of air flow is correct.
Ø Determine if the site has an approved procedure that defines the maximum nsize of patches on air filters and under what conditions the filter must be replaced.
Ø Review smoke studies used to demonstrate air flow in the critical area.
Review map of environmental monitoring sites if available.
Request information regarding sampling points chosen and action and alert level decisions. Verify justification exist for the sampling points chosen Verify that the monitoring of air includes temperature, humidity, particulate count and microbial content.
Ø Determine if the testing frequency has been justified and/or validated.
Ø Review data to ensure that the results consistently support the required particulate and microbial standard.
Ø Determine if there is continuous monitoring of air for non-viable particulates.
Ø Determine if the monitoring system is validated.
Ø Determine if there are an adequate number of points sampled and if there is justification for sampling the established points. This justification can be based on historical data as well as the critical operations performed in the cleanroom. Ask if the site has a formal rationale or justification statement defining the selection of testing points.
Ø Ensure that the sampling time meets worldwide regulatory expectations.
Ø Determine if the site performs a trend analysis on its data, and at what frequency (i.e. on a yearly basis, quarterly, monthly).
Ensure that there is an approved program for monitoring equipment and facility surfaces.
Ø Review the data for monitoring surfaces to ensure that it is comprehensive and includes applicable equipment, walls, curtains, door plates, floors, etc.
Ø Determine what method is used for monitoring surfaces (e.g. contact plate, swab) and evaluate the appropriateness.
Ø Determine if there is sound justification for the number, frequency and location of surfaces that are sampled.
Ø Determine when sampling takes place. Samples should be taken after a period of activity.
Ø Determine if the data consistently support the required microbial limits.
Ø Determine if the site performs trend analysis on its data, and at what frequency (i.e. on a yearly basis, quarterly, monthly).
Review the personnel monitoring program.
Ø Determine if the program includes at a minimum, glove (fingers) and gown (chest and forearms) testing.
Ø Determine when in the operational process the samples are taken and how often.
Ø Determine if the frequency is justified.
Ø Ensure that all personnel involved in aseptic filling operations are sampled.
Ø Ensure that the data consistently support the required microbial levels.
Ø Ensure that there are established and approved action and alert levels.
Ø Determine if the site has an approved documented procedure for qualifying personnel in aseptic gowning.
Ø Ensure that there is an existing approved procedure detailing the actions to be taken when either of the alert or alert levels are reached or exceeded. (e.g. re-training).
Ø Review an excursion report/investigation to determine if the procedure is being followed.
Ø Determine if the site performs a trend analysis on its personnel data, and at what frequency (i.e. on a yearly basis, quarterly, monthly).
Review qualification information regarding HEPA filters installed in laminar or unidirectional hoods.
Ø Determine the frequency of qualification of the hood.
Ø Determine if the following tests are performed on the filters:
o Velocity testing
o Particulate testing
o Leak testing
Review the following controls in the Microbiology Laboratory.
Ø Growth promotion testing, storage and incubation of environmental monitoring media.
Ø Identification of recovered organisms.
Ø Validation of test methods.
Review the sanitization program for the processing areas.
Ø Ensure that the sanitizing agents used are effective against flora found in the processing areas.
Ø Ensure that the frequency and method of application is appropriate for each controlled and critical area.
Ø Ensure that the sanitization program is defined through an approved procedure.
Ø Ensure that there is adequate record keeping and documentation of the sanitization program.