GMP Updated Training Modules* | PQ Workshop, Abu Dhabi | October 2010
Objective
Design and engineering aspects of water systems
Inspection of water systems
Water for Pharmaceutical Use
World Health Organization
Contaminants of water:
Because of the wide variation in source and because of water’s unique chemical properties, which makes it the “universal solvent”, there is no pure water in nature. A wide variety of compounds may be present. There are more than 90 possible unacceptable contaminants of potable water listed by health authorities. The trainer can expand on other contaminants that are important, or on any local requirements that are relevant. For example, in some areas hormone-like compounds may be a problem.
Contaminants can be put into the following groups:
Inorganic contaminants, such as chloramines, magnesium carbonate, calcium carbonate and sodium chloride;
Organic contaminants, such as detergent residues, solvents and plasticizers;
Solids, such as clays, sols, cols and soils;
Gases, such as nitrogen, carbon dioxide and oxygen; and
Micro-organisms. These can be particularly troublesome because of the numbers that can grow in nutrient-depleted conditions. Bacteria may even multiply in pure water.
* | PQ Workshop, Abu Dhabi | October 2010
Background to water requirements and use
Water is the most widely used substance / raw material
Used in production, processing, formulation, cleaning, quality control
Different grades of water quality available
Water for Pharmaceutical Use
1.2 Background to water requirements and uses
Water is the most widely used substance, raw material or starting material in the production, processing and formulation of pharmaceutical products. It has unique chemical properties due to its polarity and hydrogen bonds. This means it is able to dissolve, absorb, adsorb or suspend many different compounds. These include contaminants that may represent hazards in themselves or that may be able to react with intended product substances, resulting in hazards to health.
Different grades of water quality are required depending on the route of administration of the pharmaceutical products. One source of guidance about different grades of water is the European Medicines Evaluation Agency (EMEA) Note for guidance on quality of water for pharmaceutical use (CPMP/QWP/158/01). Control of the quality of water throughout the production, storage and distribution processes, including microbiological and chemical quality, is a major concern. Unlike other product and process ingredients, water is usually drawn from a system on demand, and is not subject to testing and batch or lot release before use. Assurance of
quality to meet the on-demand expectation is, therefore, essential.
Additionally, certain microbiological tests may require periods of incubation and, therefore, the results are likely to lag behind the water use. Control of the microbiological quality of WPU is a high priority. Some types of microorganism may proliferate in water treatment components and in the storage and distribution systems. It is very important to minimize microbial contamination by routine sanitization and taking appropriate measures to prevent microbial proliferation.
* | PQ Workshop, Abu Dhabi | October 2010
Background to water requirements and use
Control quality of water
Contaminants, microbial and chemical quality
Microbial contamination risk and concern
Water is used on demand
not subjected to testing and batch or lot release before use, therefore has to meet specification "on demand" when used
Micro test results require incubation periods
Water for Pharmaceutical Use
Water system requirements
Operate within design capacity
Prevent unacceptable microbial, chemical and physical contamination during production, storage and distribution
Quality Assurance involved in approval of use after installation and maintenance work
Water for Pharmaceutical Use
2. General requirements for pharmaceutical water systems
Pharmaceutical water production, storage and distribution systems should be designed, installed, commissioned, validated and maintained to ensure the reliable production of water of an appropriate quality. They should not be operated beyond their designed capacity. Water should be produced, stored and distributed in a manner that prevents unacceptable microbial, chemical or physical contamination (e.g. with dust and dirt).
The use of the systems following installation, commissioning, validation and any unplanned maintenance or modi.cation work should be approved by the quality assurance (QA) department. If approval is obtained for planned preventive maintenance tasks, they need not be approved after implementation.
Water sources and treated water should be monitored regularly for quality and for chemical, microbiological and, as appropriate, endotoxin contamination. The performance of water puri.cation, storage and distribution systems should also be monitored. Records of the monitoring results and any actions taken should be maintained for an appropriate length of time.
Where chemical sanitization of the water systems is part of the biocontamination control programme, a validated procedure should be followed to ensure that the sanitizing agent has been effectively removed.
* | PQ Workshop, Abu Dhabi | October 2010
Water system requirements (2)
Chemical and microbiological
Records of results, and action taken
Validated sanitization procedure followed on a routine basis
Water for Pharmaceutical Use
Purified Water (PW)
Meet pharmacopoeia specification for chemical and microbial purity
Protected from recontamination
Puri.ed water (PW) should be prepared from a potable water source as a minimum-quality feed-water, should meet the pharmacopoeial speci.cations for chemical and microbiological purity, and should be protected from recontamination and microbial proliferation.
* | PQ Workshop, Abu Dhabi | October 2010
Highly Purified Water (HPW)
Specification only in the European Pharmacopoeia
Same quality standard as WFI including limit for endotoxins, but treatment method considered less reliable than distillation
Prepared by combination of methods including reverse osmosis (RO), ultrafiltration (UF) and deionization (DI)
Water for Pharmaceutical Use
3.4 Highly purified water
Highly puri.ed water (HPW) should be prepared from potable water as a minimum-quality feed-water. HPW is a unique speci.cation for water found only in the European Pharmacopoeia. This grade of water must meet the same quality standard as water for injections (WFI) including the limit for endotoxins, but the water-treatment methods are not considered to be as reliable as distillation. HPW may be prepared by combinations of methods such as reverse osmosis, ultra.ltration and deionization.
* | PQ Workshop, Abu Dhabi | October 2010
Water for Injections (WFI)
WFI is not sterile
WFI is an intermediate bulk product
According to The International and European Pharmacopoeias – final purification step should be distillation
Water for Pharmaceutical Use
3.5 Water for injections
Water for injections (WFI) should be prepared from potable water as a minimum-quality feed-water. WFI is not sterile water and is not a .nal dosage form. It is an intermediate bulk product. WFI is the highest quality of pharmacopoeial WPU. Certain pharmacopoeias place constraints upon the permitted purification techniques as part of the speci.cation of the WFI. The Internationa Pharmacopoeia and The European Pharmacopoeia, for example, allow only distillation as the .nal puri.cation step.
* | PQ Workshop, Abu Dhabi | October 2010
General
Water can be used directly, or stored in a storage vessel for subsequent distribution to points of use
Design appropriately to prevent recontamination after treatment
Combination of on-line and off-line monitoring to ensure compliance with water specification
Water for Pharmaceutical Use
6.1 General
The storage and distribution system should be considered as a key part of the whole system, and should be designed to be fully integrated with the water puri.cation components of the system. Once water has been puri.ed using an appropriate method, it can either be used directly or, more frequently, it will be fed into a storage vessel for subsequent distribution to points of use. The following text describes the requirements for storage and distribution systems. The storage and distribution system should be con.gured to prevent recontamination of the water after treatment and be subjected to a combination of online and of.ine monitoring to ensure that the
appropriate water speci.cation is maintained.
* | PQ Workshop, Abu Dhabi | October 2010
WPU system contact materials (6)
Suitable materials include:
Polypropylene (PP)
Polyvinylidenedifluoride (PVDF)
Perfluoroalkoxy (PFA)
Water for Pharmaceutical Use
Microorganisms – Biofilm formation
Contaminants of water: (Contd.)
One of the major obstacles to successful treatment of water is the presence of micro-organisms. These are usually found in biofilms that develop on wet surfaces in almost any condition. The next slide explains how biofilm forms.
The major groups of contaminating micro-organisms are:
Algae: These arrive from raw water but can also grow where water is uncovered and there is a light source. Sometimes algae grow when UV lights lose their lethal effect and are emitting only visible light.
Protozoa: These include Cryptosporidium and Giardia. They can usually be easily filtered out since they are relatively large organisms.
Bacteria. Of these, the normal aquatic microflora cause the most problems. Most of these belong to the Pseudomonas family or are Gram negative, non-fermenting bacteria. Some of them easily pass through 0.2 micrometer filters and are known to cause disease. Other Gram negative bacteria that are objectionable are Escherichia coli and coli forms. These are indicator organisms pointing to faecal contamination.
* | PQ Workshop, Abu Dhabi | October 2010
Biofilm formation
Complex communities evolve which shed
microcolonies and bacteria
This illustration is shown in handout 2-1-12.
Free swimming aquatic bacteria use polymucosaccharides, as a glue, to colonise surfaces. Biofilm is composed of cellular debris, organic material and very few apparent vegetative cells.
Complex communities then evolve which, when mature, shed micro-colonies and bacteria into the downstream water. This gives rise to sporadic high counts.
Even when disinfected, the biofilm can remain, to be recolonised quickly when the disinfecting agent is removed. Biofilms can form readily if water is stagnant, such as in dead legs or where there are rough surfaces, such as poorly finished welds.
* | PQ Workshop, Abu Dhabi | October 2010
System sanitization and bioburden control
Systems in place to control proliferation of microbes
Techniques for sanitizing or sterilization
Consideration already during design stage – then validated
Special precautions if water not kept in the range of 70 to 80 degrees Celsius
Water for Pharmaceutical Use
6.3 System sanitization and bioburden control
Water treatment equipment, storage and distribution systems used for PW, HPW and WFI should be provided with features to control the proliferation of microbiological organisms during normal use, as well as techniques for sanitizing or sterilizing the system after intervention for maintenance or modi.cation. The techniques employed should be considered during the design of the system and their performance proven during the commissioning and quali.cation activities. Systems that operate and are maintained at elevated temperatures, in the range of 70–80 °C, are generally less susceptible to microbiological contamination than systems that are maintained at lower temperatures. When lower temperatures are required due to the water treatment processes employed or the temperature requirements for the water in use, then special precautions should be taken to prevent the ingress and proliferation of microbiological contaminants (see section
6.5.3 for guidance).
Biocontamination control techniques
Avoid dead legs
Pipe work of ambient temperature systems, isolated from hot pipes
Water for Pharmaceutical Use
6.5.3 Biocontamination control techniques
The following control techniques may be used alone or more commonly in combination.
• Maintenance of continuous turbulent .ow circulation within water distribution systems reduces the propensity for the formation of bio.lms. The maintenance of the design velocity for a speci.c system should be proven during the system quali.cation and the maintenance of satisfactory performance should be monitored. During the operation of a distribution system, short-term .uctuations in the .ow velocity are unlikely to cause contamination problems provided that cessation of .ow, .ow reversal or pressure loss does not occur.
• The system design should ensure the shortest possible length of pipework.
• For ambient temperature systems, pipework should be isolated from adjacent hot pipes.
• Deadlegs in the pipework installation greater than 1.5 times the branch diameter should be avoided.
• Pressure gauges should be separated from the system by membranes.
• Hygienic pattern diaphragm valves should be used.
• Pipework should be laid to falls to allow drainage.
• The growth of microorganisms can be inhibited by:
— ultraviolet radiation sources in pipework;
— maintaining the system heated (guidance temperature 70– 80 °C);
— sanitizing the system periodically using hot water (guidance temperature >70 °C);
— sterilizing or sanitizing the system periodically using superheated hot water or clean steam; and
— routine chemical sanitization using ozone or other suitable chemical agents. When chemical sanitization is used, it is essential to prove that the agent has been removed prior to using the water. Ozone can be effectively removed by using ultraviolet radiation.
* | PQ Workshop, Abu Dhabi | October 2010
Biocontamination control techniques (2)
Water for Pharmaceutical Use
Water scours dead leg
greater than 50mm, we have
a dead leg that is too long
Dead leg section
There should be no dead legs!
Stagnant areas allow microbial contamination as a result of colonization of surfaces with the formation of biofilm, as discussed in Part 1. Dead legs are stagnant areas where there is no water flow.
There do not appear to be any regulations which give a specification for dead legs. Deciding when a dead leg is unacceptable is therefore not easy, as it involves the respective diameters of the pipes and the velocity, but there is a consensus in the industry that a dead leg should not be greater than twice the diameter of the pipe.
If there are long runs of pipe to outlets without circulation, the pharmaceutical manufacturer must have a procedure in place which allows the pipework to be completely drained, left dry and sanitized or sterilized before use. This should be done on a daily basis. Special attention needs to be given to samples and test frequency for microbial counts from this type of outlet.
Check that the piping has direction arrows on it. If the flow is in the wrong direction through a fitting it will not “scour” the fitting, resulting in the formation of biofilm.
* | PQ Workshop, Abu Dhabi | October 2010
3. The water is contaminated as it passes through the valve
2. Bacteria can grow when
the valve is closed
Biocontamination control techniques (3)
Stagnant water
inside valve
Water system design: (Contd.)
Although ball valves can be used in the early stages of water treatment, they (and the related cone valve) should not be used in the water treatment system downstream of RO and DI outlets. This is because the “ball in socket” construction can be easily contaminated. Ball valves are not easy to clean unless dismantled. The space between the ball and the housing can be easily colonised by bacteria. Consequently, the water will become contaminated as it passes through the valve.
Valves that can be used include diaphragm valves (as long as the diaphragm is made of a suitable material, ideally teflon coated neoprene), and butterfly valves.
Zero dead leg valves are now available for high purity water systems.
* | PQ Workshop, Abu Dhabi | October 2010
Biocontamination control techniques (4)
Pipe work laid to fall (slope) – allows drainage
Maintain system at high temperature (above 70 degrees Celsius)
Use UV radiation
Suitable construction material
Biocontamination control techniques (5)
Periodic sanitization with super-heated hot water or clean steam
Reliable
Removal of agent before use of water important
Water for Pharmaceutical Use
Storage and distribution - Storage vessels
Design and size important
Avoid inefficiencies and equipment stress during frequent on-off cycles
Short-term reserve in case of failure
Contamination control consideration
Nozzles (no dead zone design)
Vent filters (type, testing, use of heat)
Pressure relief valves and burst discs (sanitary design)
Water for Pharmaceutical Use
6.4 Storage vessel requirements
The water storage vessel used in a system serves a number of important purposes. The design and size of the vessel should take into consideration the following.
6.4.1 Capacity
The capacity of the storage vessel should be determined on the basis of the following requirements.
• It is necessary to provide a buffer capacity between the steady-state generation rate of the water-treatment equipment and the potentially variable simultaneous demand from user points.
• The water treatment equipment should be able to operate continuously for signi.cant periods to avoid the inef.ciencies and equipment stress that occur when the equipment cycles on and off too frequently.
• The capacity should be suf.cient to provide short-term reserve capacity in the event of failure of the water-treatment equipment or inability to produce water due to a sanitization or regeneration cycle. When determining the size of such reserve capacity, consideration should be given to providing suf.cient water to complete a process batch, work session or other logical period of
demand.
6.4.2 Contamination control considerations
The following should be taken into account for the ef.cient control of contamination.
• The headspace in the storage vessel is an area of risk where water droplets and air can come into contact at temperatures that encourage the proliferation of microbiological organisms. The water distribution loop should be con.gured to ensure that the headspace of the storage vessel is effectively wetted by a .ow of water. The use of spray ball or distributor devices to wet the surfaces should be considered.
• Nozzles within the storage vessels should be con.gured to avoid dead zones where microbiological contamination might be harboured.
• Vent .lters are .tted to storage vessels to allow the internal level of liquid to .uctuate. The .lters should be bacteria-retentive, hydrophobic and ideally be con.gured to allow in situ testing of integrity. Of.ine testing is also acceptable. The use of heated vent .lters should be considered to prevent condensation within the .lter matrix that might lead to .lter blockage and to microbial growthrough that could contaminate the storage vessels.
• Where pressure-relief valves and bursting discs are provided on storage vessels to protect them from over-pressurization, these devices should be of a sanitary design. Bursting discs should be
provided with external rupture indicators to prevent accidental loss of system integrity.
* | PQ Workshop, Abu Dhabi | October 2010
Storage and distribution – Pipes and heat exchangers
Continuous circulating loop needed
Filtration not recommended in loop and take-off point
Heat exchangers:
Designed to ensure no stasis of water
Where water is cooled before use, done in minimum time, and validated process
Water for Pharmaceutical Use
6.5 Requirements for water distribution pipework
The distribution of PW, HPW and WFI should be accomplished using a continuously circulating pipework loop. Proliferation of contaminants within the storage tank and distribution loop should be controlled. Filtration should not usually be used in distribution loops or at takeoff user points to control biocontamination. Such .lters are likely to conceal system contamination.
6.5.1 Temperature control and heat exchangers
Where heat exchangers are employed to heat or cool WPU within a system, precautions should be taken to prevent the heating or cooling utility from contaminating the water. The more secure types of heat exchangers of the double tube plate or double plate and frame con-guration should be considered. Where these types are not used, an alternative approach whereby the utility is maintained and monitored at a lower pressure than the WPU may be considered.
Where heat exchangers are used they should be arranged in continually circulating loops or subloops of the system to avoid unacceptable static water in systems. When the temperature is reduced for processing purposes, the reduction should occur for the minimum necessary time. The cooling cycles and their duration should be proven satisfactory during the quali.cation
of the system.
Water for Pharmaceutical Use
Water must be kept circulating
Spray ball
World Health Organization
The storage of highly purified water types is critical because of the risk of re-contamination by micro-organisms and other contaminants. This schematic drawing is included in handout 2-2-14. Use it to explain the design features of a good storage system.
Good design elements, not mentioned previously, include:
Closed system with continuous re-circulation at 1-2 (or more) linear metres per second;
Hydrophobic vent filters, which can be sterilized and integrity-tested;
Burst disc if tank is heated, to prevent the tank collapsing as it cools; Re- circulation via spray ball, to ensure the tank lid is wet with moving water;
In-line disinfection, by periodic heating, ozonization or UV;
Air breaks to drains;
In-line 0.2 micrometer filter to “polish” the water in purified water systems
WFI storage, which must be 70oC or above, and preferably above 80oC. (No ozone and filtration in WfI storage and distribution systems).
* | PQ Workshop, Abu Dhabi | October 2010
On site inspection:
Walk through the system, verifying the parts of the system as indicated in the drawing
Review procedures and "on site" records, logs, results
Verify components, sensors, instruments
Water for Pharmaceutical Use
Water for Pharmaceutical Use
Checks may include:
Water for Pharmaceutical Use
Checks may include:
Water for Pharmaceutical Use
Check pipes and pumps.
The photograph shows a good example of a neatly laid-out water treatment room with good equipment and pipes. There are hygienic couplings (Ladish® or Tri-Clover ® clamps), welded pipes and hygienic pumps. Note also hygienic sampling points.
* | PQ Workshop, Abu Dhabi | October 2010
Water for Pharmaceutical Use
Corrosion on plates of heat exchangers indicates possible contamination
Other checks
Inspection: (Contd.)
Assess physical condition of equipment. Look for stains and leaks that could indicate problems.
Check to make sure heat exchangers are double tube or double shell. If not, there should be continuous pressure monitoring to ensure the heating or cooling liquid does not contaminate the pure water through any pinholes. For single plate heat exchangers, the pressure of the heating or cooling liquid must be LOWER than the purified water at all times. An exception may be where the liquid is of a higher purity than the water being produced.
Note from the heat exchanger example above that even high grade stainless steel, such as 318SS, can be subject to pit corrosion!
* | PQ Workshop, Abu Dhabi | October 2010
Water for Pharmaceutical Use
World Health Organization
Inspection: (Contd.)
Check maintenance of the entire system by examining the maintenance procedure and records. For example, check the “O” rings of connections and the maintenance of the pump seals. The pump on the left shows good connections and a good standard of engineering.
The one on the right shows a threaded coupling, called a milk coupling or sanitary coupling. Threaded couplings and couplings in general should be avoided whenever possible.
Where welding is impossible, hygienic couplings should be used or milk (sanitary) coupling, which are acceptable since the threaded fitting is not part of the fluid pathway, and so should not contaminate the water.
The inspector must be satisfied that hidden seals and “O” rings have actually been removed, examined and/or replaced during maintenance.
* | PQ Workshop, Abu Dhabi | October 2010
Water for Pharmaceutical Use
Check burst discs
Inspection: (Contd.)
Check air filters which should be hydrophobic (otherwise, they can be blocked by a film of water condensate) and should be able to be sanitized. Those on WFI plants should be be able to be sterilized and integrity-tested.
Check replacement frequency, which the pharmaceutical manufacturer should determine with assistance from the filter supplier.
Check burst discs because if they have ruptured without being noted the storage system can become contaminated.
* | PQ Workshop, Abu Dhabi | October 2010
Water for Pharmaceutical Use
Validating ozone dosage
Specifications for acids, alkalis for DI and sodium chloride for water softener
World Health Organization
Further points to check:
UV light – monitoring performance and lamp life. The lethal radiant energy from UV lights drops off quickly, so many have to be replaced approximately every 6 months. Does the manufacturer have an hour meter and is the lamp replaced according to the supplier’s recommendations? Can the intensity of the light be measured?
Validating ozone dosage is difficult. It may be possible for the manufacturer to get the supplier’s validation studies showing worst case lethal effects.
Water softener sodium chloride specifications. Like any ancillary material, the salt, acids and alkalis used as consumables in water treatment plant should have purchase specifications. Note: testing is not required unless for trouble shooting purposes.
Check the drawings to see if valves are marked as “Normally Open” or “Normally Closed”, then physically check the valve position. It is surprising sometimes that valves are not returned to the correct operating position; for example, after de-ionizer regeneration.
* | PQ Workshop, Abu Dhabi | October 2010
Additional documentation to review:
Qualification protocols and reports
Requalification (where applicable)
Sampling
Sample integrity must be assured
Sampler training
Sample point
Sample size
There must be a sampling procedure.
The sample integrity must be assured. The sample received in the laboratory must reflect the bulk water’s physical, chemical, and biological quality. Because of water’s solvent properties and the nature of micro-organisms, this can change very quickly. For example, the microbe population in ideal circumstances can double or triple every hour. Microbes can grow at very low temperatures and in extremely low nutrient levels. Even distilled water may have enough nutrients to support organisms such as some of the pseudomonas species.
The persons who take the sample should also have training on aseptic handling practices, to ensure that they do not contaminate the sample while it is being taken.
The sample point should be hygienic and the practice of flushing it, or not, should follow manufacturing practice. Sample points for subsystems, such as de-ionizers and RO’s, should be as close to the downstream side as possible in order to reflect the quality of the water being fed to the next subsystem. All water outlets in the factory should also be checked periodically. This should be done unannounced, if possible, so that water can be sampled through any attachments to the outlet, such as hoses or pumps.
Sample sizes of at least 100 – 500mL are required; samples of 1 or 2 mL are unacceptable.
* | PQ Workshop, Abu Dhabi | October 2010
Testing
Testing:
Method Verification - The methods must be validated or verified in the laboratory, even if they are pharmacopoeial methods.
Chemical testing - Chemical testing follows normal laboratory practices. However, TOC requires sophisticated, expensive equipment and trained technicians, which may put it beyond the reach of some manufacturers.
Microbiological testing - It is important that microbiological testing be conducted in a well-equipped laboratory with adequate resources.
Method: The common methods for microbial total count are Most Probable Number Test (not reliable for low numbers), Spread or Pour Plate (can only test only 1 or 10mL respectively; not reliable for low counts) or membrane filtration, which is preferred.
Media: There are various types of test media that can be used.
Incubation time and temperature: Preferably 32oC or lower (higher temperatures than this inhibit aquatic microflora) and up to 5 days (sub-lethally damaged organisms may not revive quickly).
Objectionable and indicator organisms: Any organism which can grow in the final product, or can cause physical and chemical changes to the product, or is pathogenic, is unacceptable in purified water. Indicator organisms, such as Escherichia coli or coliforms, point to faecal contamination. They “indicate” possible contamination by other pathogenic organisms.
The manufacturer must set specifications for total count and absence of objectionable and indicator organisms. The USP recommends a limit of 100 total aerobic microbial colony-forming units (CFU) per mL for purified water.
* | PQ Workshop, Abu Dhabi | October 2010
Suggested bacterial limits (CFU /mL)
Water for Pharmaceutical Use
Sampling locations and limits for microbiological testing:
The limits are not from any official literature and are thus intended merely as a guide. The table is a suggested list of sampling locations and limits (for total aerobic microbial plate count). Note that in some countries, the “Action” required if out of specification results are detected may well include recall of therapeutic goods even if they meet finished goods specification. This is because the water treatment system is seen to be out of control.
Prudent manufacturers should react promptly to “alert” limits so that the system remains in control.
CFU = colony forming units
Thank you for listening!