Transcript of 1 4c Pharmaceutical Water Systems
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!