Goals
When you have completed this training module, you should be able to:
a. Perform an audit of a site utilities system
b. Use a range of tools and information, including the contents of this unit and the Internet, in support of auditing a utilities system
c. Understand and apply applicable GMP standards to an audit of a utilities system recognize compliance or non-compliance of a utility system to applicable regulations
Definitions
Action Levels: A level or a range that, when exceeded, indicate that a process has drifted from its normal operating range. Exceeding an Action Level indicates that corrective action should be taken to bring the process back into its normal operating range.
Air diffuser: A plate in the ceiling where the air is forced through. A diffuser may direct the air throughout the room.
Air handling unit (AHU): An integrated piece of equipment consisting of fans, heating and cooling coils, air-control dampers, filters and silencers.
Alert Levels: A level or a range that, when exceeded, indicate that a process may have drifted from its normal operating condition. Alert levels constitute a warning and do not necessarily require a corrective action.
Deadlegs: Drops in the piping system where water is not circulating.
Dead spots: Lengths of piping where water stays and does not move.
Endotoxin test: A test designed to determine if there are fever producing substances in the drug product. This substance can be produced by the degradation of gram negative bacteria from their cell walls. Endotoxin is harmful to humans.
High efficiency particulate air (HEPA) filter: Retentive matrix designed to remove a defined percentage of particulate matter of a defined size.
Highly Purified Water (HPW): Water produced from Potable Water by methods including, for example, double-pass reverse osmosis coupled with other suitable techniques such as ultrafiltration or deionization. HPW (Highly Purified Water) meets the same quality standards as WFI (Water for Injections) but the production methods are considered less reliable than distillation and thus it is considered unacceptable for use as
WFI. The specification for HPW is defined in the European Pharmacopoeia (EP) and HPW is a consideration only for certain products supplied to the European Union (EU).
Manometer: A device that measures the difference in pressure between two points.
Figure : Manometer
Passivation: The chemical treatment of stainless steel with a mild oxidant, such as a nitric acid solution, for the purpose of enhancing the spontaneous formation of the protective passive film. This process is designed to remove foreign metals, oxides and corrosion from the surface of stainless steel and corrosion resistant steels which allows water to move through the pipes and improves corrosion resistance.
Piping and installation drawings (P &ID): Mechanical drawing or blueprints of the required piping system for installation of equipment. If authorized changes are made, they are indicated as red lines on the drawing.
Potable Water: Water, that as a minimum, meets national standards for water intended for human consumption that have been documented as at least equivalent to World Health Organization (WHO) guidelines, the national standards for the USA, Europe and Japan meet or exceed the WHO guidelines. Potable Water is also known as Drinking Water.
Purified Water: Water produced by a suitable method (e.g., deionization, reverse osmosis, distillation, etc.) from potable water to meet specifications as defined by a compendial monograph.
Pyrogen: A substance that can produce a fever in an animal system.
Ultra low particulate air filter (ULPA): A filter rated at 99.99% efficient in removal of particles to 0.12 microns. Each filter must be labeled with the model number, serial number, efficiency and resistance at tested airflow.
Water for Injection: Water produced by a suitable method (e.g., distillation) from potable water, usually with an intermediate purification step(s), to meet specifications as defined by a compendial monograph.
Explanation of Topic
Introduction
To produce either a finished pharmaceutical, an API, an excipient, a medical device or packaging materials the environment within the plant has to be considered. One of the least noticed but important parts of producing a product free of contamination is the plant utility system. The system includes the heating, ventilation and air conditioning system (HVAC), the water system, the compressed gas system and the steam system, if used in the plant. Each of these systems must be qualified/validated.
HVAC System
Air systems should be designed to prevent contamination and cross-contamination. To achieve this protection the air handling system must be carefully designed with many factors taken into account.
Phases of an air handling system
A conventional air handling system has four different phases.
Figure: Diagram of an air handling system
The first phase manages the incoming/intake air or “fresh” air. This phase may include a coarse filter that eliminates large contaminants such as soot, pollution or large visible particles from the external environment. Some systems may recirculate air to “clean” it.
When air is recirculated, it passes through filters continuously. During this process some air is “lost”, so some fresh air or “make-up” air needs to be added.
The second phase is the conditioning phase. Air enters the central air handling unit (AHU) and is conditioned here (heated, cooled, humidified or de-humidified and filtered). The cooling system in this phase can be a potential source for mold contamination. In the AHU, fresh air and re-circulated air, if any, will be mixed.
The third phase supplies the air to the actual room or area. The air is blown with a fan/blower through an air diffuser into the specific area. Before the air enters the room it may be pushed through another filtration system (e.g., HEPA or ULPA) and then dispersed through a diffuser.
The fourth phase exhausts air from the area. This system contains the air returns found in a room. An air return allows the air to be drawn back into the duct system. Air returns may be located in the ceiling, or on the wall. The design should take the movement of air as well as how to make the best environmental conditions in the room into account.
Returns on the wall are thus more common in cleanrooms. The return should exhibit negative pressure.
Figure: The fourth phase
General Characteristics of a Good HVAC System
A well-designed air handling system should start with a good design, be installed properly, qualified, and maintained. At a minimum, it should have sealed ducts to prevent unfiltered air from entering the system, and tight filters for the same reason.
Different areas with different air cleanliness requirements should have separate air handling systems. The level of filtration should be appropriate for the level of air cleanliness that is to be achieved. The percentage of recirculation air to make up air will vary depending on the level of cleanliness desired. Risks for cross contamination should also be considered. No recirculation of air minimizes the risk for cross contamination and should be used, when handling some types of substances or products.
Air filtration, dust collection, and exhaust systems should be used in production areas where the product may be exposed and according to regulatory requirements. The filter should be located in the system where it will do the most good. Intake and air returns should not be located next to each other. Dust extractors and bag filters should be located up stream of the final filters. Temperature and humidity requirements should be established to keep the product free from contamination. Depending on the product and the environment to be achieved, air changes should be consistent with industry standard with more air changes for cleaner environments. (See ISO 14644, Cleanrooms and associated controlled environments – Part 1:Classification of air cleanliness for cleanroom standards.)
Pressure differences between cleanrooms and areas of different cleanliness are means of maintaining the environment and the principle is to have higher pressure in cleaner areas.
To minimize the risk for cross contamination, which is important in dust generating activities such as for example in tablet manufacturing and when containment is desirable the principle will be to have the highest pressure in the corridor or in the air locks and a lower pressure in the cleanroom to ensure the air is not spread to the environment.
Pressure differentials should be maintained according to design criteria and tested and/or monitored on a frequent basis. An approved procedure and back up power supply should be in place for responding to HVAC failures or loss of power. Duct work should run in long straight sections which allow the air to flow freely. The ducts should be designed so that they can be easily and effectively cleaned. An alarm system should be in place to notify the site if there are unexpected drops in pressure. Depending on the environment, there should be an established airflow direction. There should be adequate controls and monitoring devices for air pressure, microorganisms, dust, humidity, and temperature in finishing areas. Air handling units for dry processing areas (i.e. drying, milling and packaging areas) should be independent.
Filtration
The HVAC system must be constructed to prevent contamination. This can be achieved by installing filters in the system. These filters should be included on a routine preventive maintenance schedule. There should be established procedures for replacing the filters as well as procedures detailing the testing that should take place after the replacement.
These filters may vary from ULPA high efficiency filters to dust or bag filters. Each should be monitored. It is important to monitor filter pressure drops as an increased pressure drop may lead to a decreased retention rate for the filter. Appropriate limits should be established.
Air intakes/supplies and returns should be separated and designed to not suck in the return air. Exhausts should vent away from the intakes.
Each fan and motor and its ductwork should be labeled and the direction of the airflow indicated. Each should be independently controlled, not interlocked, so if there is a problem it can be isolated.
Air pressure differentials
In areas where air changes and differential pressure are critical, the system must be monitored and documented. Air pressure must be measured and correct pressure differentials maintained. If the pressure differentials are not maintained, there should be a procedure in place defining what action to take.
Blowers and fans should be on a routine preventive maintenance schedule. Ductwork should be checked at an established interval for leaks. Preventive maintenance must be established based on written specifications.
Filters are one of the main components of an HVAC system, since they determine the size of airborne particles that pass through them, and thus the hygiene class. Depending on the type of room air requirements, different filters will be used. In an area where there are powders, often the exhaust will have a bag filter attached to it to catch the escaping powder.
Figure: HVAC System
Potential problems
There can be conditions within the HVAC system that can cause the system to malfunction and increase the risk of contamination. A few of these are listed below.
Figure: Potential Problems
Maintenance
The air system should be on a preventive maintenance (PM) schedule. If HEPA or ULPA filters are replaced, they should be substituted on a “like for like” basis. Testing for both filter integrity (leak testing) and efficiency (filter flow rating) should be performed once the filters are replaced as well as on a regular basis.
The cooling unit or condenser should be placed on a PM schedule. Stagnant water (condensed water) can breed bacteria, which contaminates the filters by passing through them (depending on their retention properties) and contaminating production areas. If the air is not properly desiccated (dried) it can also provide a growth media for mold.
Pressure control can be regulated by automatic air or fixed flow control dampers and/or fan speed control. As filters get dirty, the airflow decreases and pressure differentials change. This could lead to a flow reversal within the area and cross-contamination.
Pressure differentials must be defined, monitored, and alarmed in critical cases. The overpressure of each room is measured against a reference point in the factory (point zero). Variable speed drives for fan motors are also commonly used to control airflow.
Objects in the room can significantly disturb the flow of air, and even block it, so that there might be air pockets without air circulation. Machinery or furniture blocking the outgoing air into the room can create unflushed zones, where particle counts and micro- organisms could increase. It is therefore important to consider the content of a clean room, when planning the HVAC system. One of the main points in the design of production rooms is the pressure differentials concept.
During the qualification phase, the airflow is visualized through smoke studies to ensure correct airflow. Air samples are taken at different point to ensure air quality complies with the design. If deviations are found adjustments to the layout or to the air handling systems must be made.
Cleanroom air requirements
Cleanrooms, because of the desired high level of cleanliness, require HEPA or ULPA filters to prevent microbial and particulate contamination. For manufacturing of injectables and sterile products, it is recommended that the filters be placed in a terminal position. The reasons are that they provide a better product protection (any problem arising from the ducts is eliminated) and it is the preferred method for cleanroom classes with high requirements.
HEPA or ULPA filters may be mounted either vertically or horizontally in the cleanroom, depending on what the room will be used for. For the air exhaust, in the case of a vertical unit, a low return is better, as the air is better distributed in the room.
It is important to monitor airflow velocities for each HEPA filter according to a program of established intervals because significant reductions in velocity can increase the possibility of contamination, and changes in velocity can affect the laminarity of the airflow.
The differential pressure on filters is an indication of the clogging of the filters: With the charging of dust on the filters, the differential pressure will increase.
To keep the volume of air constant, the fan speed may increase, with the following consequences:
Ø Damage to filters, and passage of unfiltered air
Ø Particles and microorganisms will be “pushed” through the filter units.
Once a ventilation system is installed, it is necessary to see how well it performs in comparison to its planned purpose, which is to provide a quality environment of specified parameters for the product. Airflow patterns visualized with smoke studies help to identify zones that do not have proper flushing. Airflow patterns should be tested for turbulence, since this can interfere with the flushing action of the air.
The recovery time for an area (clean-up time) is also an important parameter to be determined. When doors have been opened and people enter and leave a room, the original conditions are disturbed and, for a short time, before recovery, the room condition may not meet the defined parameters. It is important to know how long this period is. Regulations do not have requirements as to how long this clean-up time should
However, the generally accepted time to clean-up from one cleanroom classification to the next higher classification, should be less than 15 minutes.
A room should be qualified “in operation” when it has a defined number people in it.
After qualification, the number of people in that room, as challenged during qualification, cannot be exceeded.
Temperature and relative humidity are also important (comfort in clean areas, stability of products, etc.) Particular attention should be given to temperature and relative humidity detectors, their sitting and calibration etc. where there are special requirements e.g. powders for aerosol manufacture or capsule filling.
Documentation
There should be an SOP that includes what steps to take during a power failure. If the plant’s HVAC system is shut off for longer than a pre-determined time period then the plant must be monitored and cleaned as per SOP.
There should be an SOP for replacing filter units and the testing that should be performed upon replacement. These tests may include, in the case of ULPA and HEPA filters, filter integrity testing, velocity, and leak testing.
Maintenance should have an SOP for the maintenance that needs to be performed on air handling systems. This SOP should include the frequency of maintenance, the activities that should be performed, information on what part should be used, etc.
There should be an SOP that lists the activities that should happen if the HVAC system exceeds its established limits (action limits).
Qualification documents for the air handling system should be complete. Documents that should be reviewed to ensure good GMP operation of an air handling plant should include:
Ø A complete description of installation (drawings, installed elements, description, etc.).
Ø Specification of the requirements: What is the system supposed to do? Which values is it supposed to reach?
Ø Standard Operating Procedures on how to operate the system.
Ø Performance control with information on how to judge if everything is operating perfectly (fan, filters, etc.).
Ø Instructions on how to maintain the system.
Ø Maintenance records showing that the system has been properly maintained.
Ø Personnel training records.
Ø Records of environmental testing.
Water Systems
Water is the most widely used starting ingredient or raw material in the manufacture of active pharmaceutical ingredients and medicinal products. Its uses in the production environment range from starting material to cleaning agent to steam source for sterilization processes. Because of this, controlling the chemical and microbiological quality of water and steam is critical. Special care should be taken in the processing, storage, and distribution of water. The higher the risk to the pharmaceutical product, the purer the water should be.
General considerations for water systems
The rationale for appropriate water quality for each process should be documented.
The water quality depends on the stage of its use in the manufacturing process, and intended route of administration for the finished product. Water used in production must be routinely sampled and tested according to a predefined and approved plan.
Figure: Water Systems
This includes the potable water supply. For any water treated to achieve an established quality level, a validated, qualified, and maintained treatment process and distribution system must be used.
Water should circulate in a closed loop system, not open to the external environment.
Fittings and valves should be of a sanitary type. There should be no threaded pieces where bacteria can enter and multiply. Fittings and valves can be taken apart and sterilized if needed. Water that is held in tanks should either be used within 24 hours of manufacture or circulated.
Validation of water systems
Water systems should take a full year to validate because seasonal environmental conditions will affect the quality of the feed water coming into the plant. Validation should follow the same criteria and produce equivalent documents as other types of validation.
Water processing and purification
Before water can be used in the pharmaceutical industry, it needs to be processed.
Environmental pollutants and microbial contaminants need to be removed. Water used in manufacturing product should start as potable water, meeting WHO and other regulatory agency requirements. This “feed water” may be received from a municipality or supply company or undergo treatment at the plant site. If water is purchased from a supplier, it should be accompanied by analytical reports or Certificates of Analysis.
Once the water is received it may need to be softened or deionized. This removes calcium and magnesium ions, which can cause “scale”, or carbonates to form. Water passes through a mixed resin bed or separate cation and anion exchangers. In this first treatment step, bacteria can grow in the bed or resins. It is important to monitor or regenerate the resins on a frequent basis.
When the water has been deionized, then it is ready to be processed for either purified water or WFI. It may be purified through reverse osmosis, deionization or distillation.
The European Pharmacopoeia requires WFI to be produced through distillation.
If reverse osmosis is used, the water is passed through a membrane, leaving behind undesirable contaminants. Reverse osmosis pushes pure water back through a semi- permeable membrane leaving Ions and particles in the reject water. Water is continuously passed over the membrane with the reject water being recycled or sent to drain.
If the water is distilled, the water is heated and then condensed, leaving behind organics and microbial contaminants. “Clean steam” is also generated using a distillation process.
Contamination in water
Water can support microbial growth. Water is susceptible to bacterial contamination for many reasons. Causes of contamination in water can be:
Ø Stagnant or non-circulating water
Ø Improperly processed water
Ø Water circulating at too low a temperature
Ø Water circulating too slowly
Ø Dead spots or deadlegs in the system
However, a significant part of good water system design is ensuring that microbial contamination is minimized. Microbial contamination can occur as a result of colonization of surfaces and stagnant areas by aquatic bacteria with the formation of biofilm. If the bacteria can be prevented from sticking to the surfaces, the battle is almost won. Smooth surfaces, high temperatures, moving water and no dead spots, are all good design elements.
Training
All personnel required to maintain, sample, and test the water system should be trained in GMP and the duties of their job function. They should also be trained to respond to alarms in the water system.
Types of Water
The type of water used will depend on the requirements of the product during various stages of production, e.g. purified water for tablets, water for injection (WFI) for sterile products. The way the medicine will be used in the body actually determines which water will be used. Sterile products like injectables need to be produced with the highest quality water (WFI) since these products go directly into the body bypassing the body’s defense system.
Water has unique chemical properties, and is able to dissolve, adsorb, absorb or suspend many compounds. These contaminants need to be removed before water can be used as an ingredient.
Four different categories of water are common. They are:
Ø Potable
Ø Purified
Ø Highly purified water
Ø Water for Injection
Potable water
Potable water is water that, at a minimum, meets national standards for potable water that have been documented as at least equivalent to World Health Organization guidelines.
Potable water is usually the starting material for other waters that may be generated at the plant. In this use it may not receive further treatment or purification.
Sampling and Testing
Testing for the full analytical requirements for potable water is usually outside the scope of the typical pharmaceutical laboratory. The recommended practice is to receive
Analytical Reports and/or Certificates of Analysis from the municipality/supply company providing the water. If borehole (well) water is the source of water it may be possible to arrange for the local municipality or a contract water-testing laboratory to sample and test the water against the appropriate standard. The local site may choose to perform a limited number of analytical monitoring tests. Appropriate test methods and specifications for potable water requiring higher quality attributes should be established. Portable water should contain not more than 500 colony-forming units per milliliter (= 500 cfu/ml). If tighter water standards are necessary then total microbial count, objectionable microorganisms and/or endotoxin limits should be established.
Potable water that is used as source water only (i.e., not used in production) may be tested for total aerobic count on a monthly or quarterly basis. This data should be combined with
Municipal/supply Company testing data. Potable water that is used in manufacturing (e.g., API intermediates) should have a point of use tested weekly with all points of use being tested within a month.
Materials and construction
Potable water is normally kept in a buffer or break tank to provide a uniform flow and working pressure. If it is necessary to hold larger quantities of potable water then an anti- microbial treatment step is likely to be required. UV lights, ozone treatment, or chlorination may be used to prevent microbial growth. If the treatment step includes the addition of chemicals then the added chemicals must be eliminated if the water is going to be converted into Purified Water or Water for Injection.
Uses of Potable Water in Manufacturing
Potable water is used in the synthesis of API intermediates prior to final isolation and purification, initial washing of API and formulated product manufacturing equipment. It may be used for non-sterile dosage products that have no microbial growth promotion concern. Potable water should not be used as final rinse water.
Purified Water
Purified water is water produced by a suitable method (e.g., deionization, reverse osmosis, distillation, etc.) from potable water to meet specifications as defined by a compendial monograph.
Sampling and testing
The tests, methodology, and specifications for Purified Water are described in the relevant Pharmacopoeias.
Purified water should have not more than 100 cfu/ml. The requirement for absence of specific microbes should be based on the use of the water. Ingredient water may require the absence of selected Gram-negative microorganisms (e.g.. E. coli, Pseudomonas) based on the product formulation, microbial growth promotion capability and use, e.g., topical application versus a liquid oral dosage form.
Analytical testing of a validated, well controlled purified water system may be performed as infrequently as once a month. However, it is becoming more typical to install in-line monitors (e.g., Conductivity and Total Organic Carbon) to continuously monitor the chemical purity of the water system. The exact nature of the testing is determined by the specification claimed for the water system. Microbiological testing is typically performed at least weekly using a rotation schedule of sampling points.
Storage conditions
Purified water is usually held and distributed in stainless steel vessels and pipes although plastic alternatives have been successfully used. To maintain the quality of stored purified water, the system should have a good hygienic design, have a re-circulating distribution system and be sanitized routinely. For example it is possible to add ozone to the storage tank and to remove the ozone with UV light during distribution. Periodically turning off the UV light and letting the ozonated water circulate will sanitize the distribution system. Other methods with stainless steel systems are to periodically heat the purified water to about 80°C and circulate the heated water through the distribution system or to steam sanitize the system. If the water is not recirculated, it should be used within 24 hours.
Use of purified water in manufacturing systems
Purified water is intended as the ingredient water used in manufacturing non-sterile dosage forms. It is used in the final isolation and purification step for the manufacture of APIs and as the final rinse of containers, closures and manufacturing and product contact packaging equipment for non-sterile dosage forms. Purified water may also be used as the initial rinse for containers, closures and equipment for sterile product manufacturing.
Purified water is the defined water used in laboratories to produce chemical reagents,
Water for Injection (WFI)
Water for Injection (WFI) is considered the highest quality water in use in pharmaceutical systems. It must meet the most stringent requirements of all water used in pharmaceutical manufacturing. It should be free from microbial contaminants, and meet a strict level of endotoxin and chemical criteria.
Sampling and Testing
The tests, methodology and specifications for Water for Injection can be found in respective pharmacopeias.
Requirements for total microbial count are not more than 10 cfu/100ml. WFI systems are typically operated hot (70 – 80 C). The isolation of vegative microorganisms should be a rare event. Repeated isolation of any microorganisms would require an investigation to determine the cause with corrective action being taken.
Analytical testing of a WFI system would typically be performed weekly. However, as with Purified Water systems it is now common to install in-line meters to perform TOC and Conductivity measurements.
The WFI system, through one point in the WFI loop should be tested each week. All points of use should be tested weekly. Alternating sampling points in a way that microbiological testing is performed each day is a typical way to sample. Other less frequent sampling programs may be applied but should be based on usage of water, historical data and risk assessment.
The source water should also be tested on a weekly basis. WFI that is used to clean but not used in final rinses should be tested on a monthly basis.
Storage conditions
Water for Injection is held and distributed in stainless steel tanks and distribution systems. It is typically maintained at an elevated temperature (70 -80 C) and cooled at the point of use just prior to use. It should be monitored for Total Organic Carbon and conductivity. These may be monitored through an in-line system connected to an alarm system.
The tanks should also have vent filters on them that should be monitored on a routine basis.
Use of Water for Injection in Manufacturing
WFI is intended as the ingredient water used in sterile product manufacturing. It is used as the final rinse for containers, closures and equipment used in sterile product manufacture. It may also be used as a product diluent.
Steam
Pure, pyrogen-free steam (called Clean Steam) must be used where steam can come into contact with product, or “product contact surfaces”, e.g. sterilization-in-place (SIP) equipment. It must:
Ø Have the same chemical quality as water for injections
Ø Have no pyrogens or endotoxins
Ø Have no volatile additives such as amines or hydrazines
Ø Be produced by stills without condensation
Ø Have a limit on non-condensable gases
Clean steam should be tested periodically.
Maintenance
Water systems should be scheduled for routine maintenance. Parts of the system that should be included are:
Ø Replacement of resins for deionizer/softener
Ø Inspection and replacement of heat exchanger parts, stills, vent filters, fittings, membranes, valves
Compressed Gases
Compressed gases such as nitrogen (N2 ), argon (Ar), and compressed air (CA) may be used in the production of drug product and contact the product. Depending on the use of the gas, qualification may be required. Gases may be
1) Manufactured and distributed by the site, 2) purchased from an outside vendor and distributed
2) Through a site distribution system, or
3) Purchased from an outside vendor and used at point of source (gas cylinders). In all cases the gas must meet specifications.
These specifications are determined based on the use of the gas and the environment in which it is used. If the gas is supplied by an outside vendor a Certificate of Analysis should be required to prove that the gas meets identity and other specifications.
If the gas is to be circulated throughout a plant distribution system, the system should be qualified both at the source and points of use. Qualification should include testing of points of use farthest from the source, identification of the gas, testing for hydrocarbons, and particulate and microbial monitoring. A qualification program should demonstrate that the distribution system for the gas does not adulterate the quality of the gas from the controlled source to the point of contact in manufacture. If the gas will be used within a controlled environment, it should meet both the particulate and microbial requirements of that environment. Qualification samples should be taken when the system is in use by multiple users, at various points of use, “worse case” points of use where the system does not have long stretches of straight piping. The system should be checked for leaks.
If the site is manufacturing its own compressed air (CA) and/or nitrogen for use in a controlled environment, it should use an oil-free compressor.
A monitoring program should be based on the criticality of the gas to the product. The monitoring program should provide information on the quality of the gas being monitored, and serve to demonstrate that the distribution system has not deteriorated or degraded the quality of gas being distributed. Monitoring frequency should be based on the variability of the gas supply to demonstrate that the supply at point of use is consistent across a period of time.
Test samples taken for the monitoring program should be taken under identical conditions as used in the process. If production flushes the point of use for 3 minutes, the sample should be taken after a flush of 3 minutes. If a filter is installed at point of use, the sample should be taken from a point of use filter. If maintenance work is performed on the system, test samples should be taken to verify that the system has not been compromised through the work. All routine monitoring should be documented as appropriate.
The system should be placed on a routine maintenance schedule.
Computer control systems for utilities
Computer systems may be used to control and monitor utility systems. They should be validated.
Summary
The plant utility system must be reliable and properly installed, maintained and qualified or validated to ensure the quality of the product. Computers that may control a utility system should be validated. The plant utility system should be part of the site change control system.
Key Parameters in Auditing a Utilities System
Prior to the Audit
a. Determine the relevant utilities to be covered
b. Determine if there are any risks of cross contamination needing specific attention
c. Request drawings for the site’s water systems, steam systems (if applicable), HVAC systems, and compressed gas distribution systems (if applicable).
During the audit
For any utility system, ensure that:
Ø All piping or duct work is correctly labeled with the utility name (clean steam, distilled water, compressed air, etc.).
Ø Directional arrows are in place to indicate flow.
Ø Valves, pressure gauges, sampling points, etc. are identified with unique IDs.
Ø Minimum and maximum operating rates are shown.
HVAC
For a walk through specifically focused on the HVAC system, ensure that:
Ø The room air returns are not blocked.
Ø The room air supplies are not blocked.
Ø The pressure differential gauges and/or manometers are operating properly
Ø Cross contamination is minimized by not recirculating air if required, correct pressure differences as designed
Ensure that each heating, air conditioning and ventilation system has been qualified and operates according to the necessary requirements and specifications.
Ø Verify that preventive maintenance is scheduled on a regular basis and that:
o Pressure differential manometers on AHUs are monitored.
o Fans and motors are checked on a scheduled basis to determine if they are operating properly.
o Ducts are checked for leaks from the external environment
o ULPA filters are monitored through pressure differential measurements and that the system is alarmed if an over limit is obtained.
Ensure that critical filters within the HVAC are monitored for drops in pressure.
Ensure that the following documentation is in place.
Ø A complete description of installation (drawings, installed elements, description of the elements, etc.).
Ø An SOP that establishes action and alert levels and what actions to take when these are reached.
Ø An SOP defining how to operate the system and what performance factors need to be monitored.
Ø A maintenance SOP for the system.
Ø Maintenance records and the preventive maintenance schedule showing that the system has been properly maintained.
Ensure that adequate and appropriate training for all personnel working with the HVAC is in place.
Ø Verify that personnel have been qualified in their jobs.
Ø Verify that appropriate training has been received
Water
Determine what material the water system to the plant is composed of.
Ø Verify that an acceptable material, 316L stainless steel or polypropylene PTFE, is used.
Ø Verify that internal welds in the stainless steel have been electropolished either by inspecting the welds or inspection of records.
Ø Verify that if Polypropylene PTFE (e.g., Teflon â ) is used for purified water and systems, that it has been specifically designed for this use.
Ensure that any fittings for the purified or WFI systems are sanitary fittings with no threaded portions.
Ensure that there is no direct connection to drains or sewers.
Ensure that the system has non-return valves that prevent water from backing up into the system.
Ensure that the piping system and holding tanks appear intact.
Ø Verify that there are no stains and leaks that could indicate problems.
Ø Verify that the tank is kept at an acceptable temperature and that the water is circulating.
Ensure that the valve positions indicated on the drawing of the water system correlate with the actual positions, i.e., if valve is marked “normally open” it should be physically open.
Ensure that valves are stainless steel ball valves with no gaskets. Check where detachable hoses are used these are removed immediately after use to drain freely
Ensure that the appropriate monitoring is performed on each plant water system.
Ø Verify that potable water meets at least the WHO drinking water standards.
Ø Verify that the following tests are performed on purified water.
o Total microbial count
o Chemical tests
Ø Verify that the following tests are performed on WFI:
o Total microbial count and typing if required
o Chemical tests
o Pyrogen and endotoxin testing
Ensure that water sampling is performed by trained employees who practice good aseptic technique when sampling.
Ø Verify that sample containers are clean and, for WFI, sterile.
Ø Verify that there is a water testing SOP that includes sampling points, frequency of sampling, testing requirements, specifications, and tests to be performed for each type of water, sampling technique to be used, additional tests based on special products being manufactured.
Ø Verify that the testing laboratory is equipped to conduct microbial limits testing, total microbial counts, objectionable organism testing, USP chemical water tests.
Ø Verify that water samples are held under refrigeration if not tested immediately.
Ensure that all personnel working with a water system are trained in both their GMPs and job duties.
Ø Verify that they are trained to take “clean” or aseptic samples.
Ø Verify that they are trained on responding to system alarms.
Ensure that there is documentation for qualification, maintenance, and monitoring.
Ø Verify that there is an SOP for maintenance of the water system and that it includes frequency of:
o Maintenance.
o Filter replacement.
o Sanitization.
o Maintenance of stills and heat exchangers.
Ø Verify that the maintenance documentation includes records for:
o Passivation of the system.
o Regeneration of the deionizer.
o Sanitization.
o Replacement of UV light if UV sterilization method is used.
Ø Verify that validation records are complete and that qualification takes place over a year to determine what seasonal and environmental conditions affect the water.
Ensure that the steam system operates correctly.
Ensure critical operating parameters (temperature, pressure, etc.) are monitored.
Compressed Gases
Ensure that the diagrams of the compressed gas system, if used at site, are the same as observed.
Verify that a Certificate of Analysis accompanies all compressed gases. If purchased from a vendor ensure that a Certificate of Analysis accompanies the cylinder.
Ensure that the site compressed gas distribution system has been qualified.
Ø Verify that during qualification that following were completed:
o Points of use farthest from the source were tested.
o Use of the system by multiple users at various points of use was tested.
o “Worse case” points of use where the system does not have long stretches of straight piping were tested.
o Particulate and microbial tests were conducted to ensure that the gas meets the same environmental conditions as the room or location.
Ø Monitoring is in place to determine if the gas is not changing the particulate level in the environment.
Ensure that the gas is tested for particulates, identity, total hydrocarbon content, moisture content, and microbial content.
Ensure that all test results are documented.