High Purity water system service provider in bangladesh

Date 15 February 2023

This book focuses, mostly from a microbiological perspective, reviewing and evaluating high quality water systems utilized in the production of drug-related products and substances. It also offers a brief overview of the structure of various kinds of systems and some of the issues which have arisen with these systems. Similar to other guides, this one is not comprehensive, but it provides an overview and direction for the evaluation and review of high-purity water systems. The guide To Inspections of Microbiological Pharmaceutical Quality Control Laboratories (May 1993) gives additional information.


I. Design of the System

One of the most important factors to be considered when designing the system is the type of product to be produced. In the case of parenteral products in which there is a risk of the presence of pyrogens, it is likely that Water for Injection be employed. This is the case for the formulation of products as well as the final washing of the components and equipment employed in their manufacturing. Distillation and reverse osmosis (RO) Filtration are the only methods that can be considered acceptable mentioned in the USP for the production of Water for Injection. In the vast pharmaceutical and Biotechnology industries, as well as some foreign firms Ultra Filtration (UF) is utilized to reduce the amount of endotoxins found in pharmaceutical substances which are administered via parenteral route.

Certain ophthalmic items like the ophthalmic irrigating solution and some inhalation solutions, like the Sterile Water For Inhalation when there are pyrogen requirements It is normal to use Water to be Injected is included in the formulation. In the majority of products for inhalation or ophthalmic use that use purified water, it is utilized in the formulation. The same is true for cosmetics, topicals and oral medications.

Another important aspect of design concerns the heat of the device. It is widely accepted that hot (65 between 80 and 65oC) systems will self-sanitize. Although other systems could be lower for an organization but the cost of maintaining, testing and the possibility of problems could be more expensive than the amount of energy savings. If a system is circulated or one-way is an important consideration in the design. It is evident that water that is constantly moving is less likely to contain the highest levels of contaminants. One-way water systems are fundamentally the definition of a "dead-leg".

Perhaps the most important factor is the risk assessment , or quality level which is sought. It is important to recognize that different products require different water sources. For example, parenterals require water that is very pure without any endotoxins. Oral and topical treatments need less purified water, and do not require for endotoxins. However, with both products, there are elements that determine the quality of water. For instance, preservatives found in antacids may be ineffective which is why more rigorous limits on microbial activity must be established. Quality control departments must examine each product made with the water in their system and establish Microbial Action Limits in accordance with the most sensitive product. Instead of strict water action limits within the process, the manufacturer may incorporate a microbial removal step during the process of manufacturing the drug that is sensitive product(s).

II. System Validation

A reference that is essential to verify High Purity water system is Parenteral Drug Association Technical Report No. 4. The report is titled "Design Concepts for the Validation of the System of Water for Injection System."

The introduction gives instructions and states that "Validation typically requires the application of a suitable test. In this scenario it is not advisable to introduce microorganisms to an on-line system. Therefore, the emphasis is placed on the regular examination of the microbiological quality as well as on the establishment monitors at certain locations to make sure that the entire system is functioning efficiently and consistently fulfilling its purpose."

When reviewing an evaluation report or when evaluating an ultra-pure drinking water treatment system, it is important to consider a variety of factors to be taken into consideration. Documentation should contain the description of the system, as well as an image. The drawings should include all the equipment within the system, starting from the water feed up to the points that are in use. It must also display the locations of all sampling points as well as their names. If the system does not have a print, it's usually considered to be a problem. The reasoning is that if there isn't a print what can the system be verified? What is the best way to let a quality assurance manager or microbiologist determine which area to take samples? If the facility was not observed with up-to-date prints, serious issues were discovered within these facilities. The print must be compared with the actual system every year to ensure its accuracy, as well as to find non-reported modifications and verify confirmed changes to the system.

Once all equipment and pipes have been checked for correct installation and operating as intended The initial phase of water system's validation can begin. In this phase, the operational parameters and cleaningand sanitization processes as well as frequency of operation will be formulated. The sampling should be conducted daily following each stage of the purification process, and at every point of use for a period of two or four weeks. The procedure used for sampling at point of use should be based on how the water will be drawn e.g. when a hose is connected to the hose, the sample is collected at the bottom of the line. If the SOP requires it to flush the line prior to taking use of the water at this point and the sample is taken following the flush. After the two-to-four week period, the company has to have created its SOPs to operate this water line.

The second step of system validation is to prove that the system is able to consistently provide the desired quality of water when operating in accordance to the SOPs. The sampling procedure is conducted similar to the initial phase but during the same time. After this phase , the results should be able to prove that the system consistently provide the quality of water.

The third stage of validation is intended to prove that if the system for water is run according to the SOPs for a lengthy period of time, it produces water with the required quality. Any changes with regards to the quality and quantity of water that can affect the process and eventually the water's quality will be identified during this phase of verification. Testing is carried out in accordance with routine procedures and frequency. In the case of Water for Injection systems the samples must be taken every day at a minimum of one location of use, and all the points of use being tested every week. The testing of the water system is complete when the company is able to provide a complete year of information.

Although the above validation method isn't the only method an system could be validated but it does include the basic components for validating an water system. First, there needs to be evidence to back the SOPs. Then, there needs to be evidence to show that the SOPs are in fact valid in the sense that it is capable of continuously producing water that is in line with the requirements. In addition, there needs to be proof that seasonal fluctuations in the water feed do not negatively impact the functioning of the system, or the quality of the water.

The final phase of validation involves the collection of the information, and any conclusions incorporated into an overall report. Final validation reports has to have the signature of persons responsible for running and quality assurance in the water supply system.

The most frequent issue is the inability of operating procedures that prevent pollution of the process by non-sterile air that remains in the pipe after draining. In the system shown in Figure 1 (below) the most common issue is when a washer or fitting is flushed then drained at the conclusion of the procedure. After the draining process is completed the valve (the second valve off part of the system) is shut. If the next day or when the operation is set to begin, the valve that is used to shut off the system that circulates is opened, the non-sterile air within the pipe after draining could be a source of contamination for the system. It is recommended to provide the operational procedures an opening of the secondary valve prior to the primary valve in order to clean the pipe prior to usage.

Another important aspect when it comes to the verification for high-purity water systems are acceptance conditions. Continuously consistent results across the system over a certain period of time are the main component.


Water For Injection Systems

Concerning the results of microbiological tests in the case of Water For Injection, it is anticipated that the results will be mostly sterilized. Because sampling is often conducted in non-sterile environments and isn't truly aseptic, occasionally low numbers due to sampling errors can occur. The policy of the agency states that no less than 10 CFU/100ml is considered to be an acceptable level of action. There are no limits on water are pass/fail limit. The limits are all action limits. When the limits of action are exceeded the company must determine the root cause then take the necessary steps to rectify the issue and evaluate the effect of the microbes on the products made using the water, and record the results of their investigations.

Regarding the size of the sample, 100 to 300 mL is recommended when taking samples of water for injection systems. Samples smaller than 100mL are considered to be unacceptable.

The main concern with WFI is the presence of endotoxins. Since WFI is able to successfully pass tests for endotoxins such as the LAL endotoxin test, but be unable to meet the above microbial activity limitation, it's essential to check WFI systems for microorganisms and endotoxins.

Purified Water Systems

In purified water systems, microbiological specifications aren't always as precise. The USP XXII specifications, which ensure that is in compliance with the federal Environmental Protection Agency regulations for drinking water, are acknowledged as minimum specifications. There have been efforts made by some to create useful microbiological specifications that would allow purified water. The CFTA suggested a standard that does not exceed 500 microorganisms per ml. In the USP XXII has an action recommendation of not exceeding 100 organisms per milliliter. While microbiological requirements have been discussed but no standards (other other than EPA standards) has been set. The agency policy is that any limit that exceeds 100 CFU/mL in the purification of water systems is not acceptable.

The goal of establishing an measure limit is to ensure your water supply is in control. The action limit set is contingent on the overall purified water system, as well as the subsequent processing of the product as well as its usage. For instance, the purified water used for the manufacture of pharmaceutical products using cold processing must have no objectionable microorganisms. We've described "objectionable species" as any organism which could cause infection when the drug product is utilized according to the directions or any other organism that is capable of growing within any drug substance. As stated in the Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories, the specific contaminant rather than the number , is typically more important.

Organisms live in a water system , either free floating on the surface of water, or attached on the wall of tanks and pipes. When they are connected to the walls, they're called biofilms, and they constantly sloughs off the organisms. Therefore, the contamination isn't evenly distributed throughout the system, and the samples could not accurately reflect the degree and type of contamination. A CFU count of 10 CFU/mL in a sample, and even 100 or 1000 CFU/mL for a second sample isn't too far off.

So, to determine the degree of contamination that is allowed in a water of high purity system that is used for the production of non-sterile goods, it is necessary to have an awareness of purpose for the item, its formula (preservative method) and the manufacturing procedure. For instance, antacids, that do not come with an effective preservative system require an action limit that is lower than 100 CFU/mL.

The USP provides some guidelines with regard to microbiological attributes of non-sterile products. It states that "The importance of microorganisms found that are present in non-sterile pharmaceuticals must be evaluated in light of the purpose for the item, its characteristics of the product and the possibility of damage to the consumer." Therefore, not only the organisms that are listed as indicators in a few of the monographs, but all of them pose issues. It is the responsibility of each manufacturer to examine their product and the method by which it is made and to determine an acceptable amount of contamination that is that is not over the maximum in the system of water determined by the highest risk product produced using the water.



When evaluating and reviewing the performance of Water For Injection systems, there are a variety of issues to be considered.

The pretreatment of feedwater is suggested by many distillation equipment manufacturers. equipment and is absolutely required to operate RO equipment. The quality of the feedwater that is pumped into the system can fluctuate throughout the lifetime of the system, based on seasonal fluctuations as well as other external variables that are outside that of the facility's control. For instance in springtime (at minimum within the N.E. ) there is an increase in the number of Gram negative organisms are identified. Additionally, construction or fires may cause loss of water storage in old mains that could result in an increase in heavily polluted water from a different species of flora.

A water system must be constructed to operate in these extremes. The only way to identify how extremes are, is to check the feedwater. If the water is coming from the municipal water system, the results of the municipal testing may be used instead of testing in-house.


In another system that was experiencing endotoxin-related issues it was found that there were approximately 50 Liters of WFI in the condenser when it was first started. As this water can remain inside the unit for many days (i.e. over weekends) it was concluded to be the main reason for the high levels of endotoxins.

The most frequent issue is the failure to treat feedwater to lower the levels of endotoxins. Most still manufacturers can only guarantee the promise of a 2.5 or 3 log decrease in endotoxin levels. So, it's not unexpected that in systems in which the feedwater can occasionally rise to 250 EU/ml, inacceptable levels of endotoxins can sometimes be present within WFI (WFI). As an example, in recent times, the three latest stills comprising two multi-effects, were found to periodically produce WFI that was higher that .25 EU/ml. The pretreatment systems of the stills only included deionization equipment, without RO, UF, or distillation. If a business does not have a reliable pretreatment system it is very difficult for them to prove that the system has been validated.

The above examples of issues with distillation units that create WFI can be traced to issues in the maintenance of the equipment or ineffective functioning of the system, indicating that the system hasn't been properly validated, or the validation that was initially issued has been invalidated. If you encounter these types of issues, it is important to examine the design of the system and any modifications that were introduced to the system as well as the validation report, and the test results from routine tests to verify if the system is operating under control.

Usually, conductivity meters are employed in water systems to check chemical quality , but they do not have any importance in determining the quality of microbiological conditions.

Figures 3 and 4 are also a good illustration of petcocks or tiny sampling ports that connect each piece of equipment, for example between the still and the tank holding. They are part of the system to separate the major components of equipment. This is essential to validate the equipment as well as the analysis of any issues that might arise.


One of the main components that makes up the majority of the distillation process are the heaters. Because of the in ionic qualities of both distillate and deionized water meters are not able to assess the microbiological quality. Positive pressure, such as double tubesheet or vapor compression design is recommended to stop feedwater from distillate contamination from an unreliable heat exchanger.

A FDA Inspectors technical guide on the topic of "Heat Exchangers to Prevent Contamination" describes the design and the potential issues that could arise from heat exchangers. The guide suggests the existence of two ways to prevent leakage-related contamination. One option is to install gauges to continuously check pressure differentials and make sure that the pressure remains on the clear fluid side. Another option is to use the double-tubesheet form for heat exchangers.

In certain systems there are heat exchangers that are used to cool water at the use points. Most of the time cooling water isn't circulated through them if they aren't being used. In some instances there were pinholes that formed inside the tubing when they were empty (on the side that cools water) but not used. It was discovered that a small amount water that remained within the tubes, when combined with air led to a degrading to the stainless steel tubing on the water cooling side. It is therefore recommended that, when not in use heat exchangers should not be taken out of cool water.


When using hot system, the temperature is generally maintained by applying heat to a jacketed storage tank or by installing an exchanger within the line prior to an insulated tank.

The element of the tank that is the subject of most discussion includes the vent filter. It is anticipated that there will some sort of program for integrity testing this filter to confirm that it's in good condition. In general, filters are lined to stop condensate or liquid from blocking hydrophobic vent filters. If this happens (the vent filter gets blocked) it is possible that the filter will break or the tank could collapse. There are ways to conduct tests of the integrity of vent filters.

It is therefore expected that the vent filter is placed in a location near the tank that it is easily accessible.

Simply because the WFI system is not new and that distillation is used however, it's not a problem-free system. In an inspection conducted by the parenteral manufacturer, the 1984 model of the system was found to be in good working order. While the system might appear to be complex in initial inspection but it was later found to be fairly easy to use.The findings at the end of the inspection conducted by the manufacturer were "Operational methods for the Water for Injection system did not allow the required flushing and draining. The system also was open to the outside air and surrounding. Compounding equipment consisted of sealed open tanks that had lids. Its Water for Injection holding tank was sealed but was not tested for endotoxins." In light of these and other complaints the company recalled a number of products and stopped operations.


Pumps wear out and components wear. Additionally, if the pump is stationary and not constantly in operating, their reservoir may be a static space in which water can collect. For instance, during an examination, it was found that a business was required to construct a drain from the bottom of the pump's housing. Pseudomonas sp. contamination was found periodically in their water system . This was partly attributed to a pump that operates only occasionally.


Piping used in WFI systems is typically made of high polished stainless steel. In some instances manufacturers are beginning to make use of PVDF (polyvinylidene fluoride) pipe. It is believed that this pipes can handle heat, with the leaching of extractables. One of the major issues for PVDF tube is the fact that it needs a lot of support. If the tubing gets heated up, it is likely to stretch and can strain it's welding (fusion) connection, resulting in leakage. Also, in the beginning there is a high level of fluoride. Pipelines are beneficial in delivery systems for products where low-level metal contamination can speed up the degradation of the drug for example, within biotech. Biotech industry.

A frequent issue with pipes is "dead-legs". In the draft LVP Regulations defined dead-legs as having an unutilized section larger than the diameter of six inches of pipe not in use, that is measured from the axis the pipe that is in use. It is worth noting that this regulation was created for hot 75-80o circulating systems. In colder systems (65 75oC - 65oC) every drop or unutilized portion of pipe could lead to the development of biofilms. They should be removed if it is it is possible, or use special cleaning procedures. There shouldn't be threaded fittings within the water supply system for pharmaceuticals. All pipe joints must use fittings that are sanitary or be joined. Sanitary fittings are usually utilized where the piping connects tanks, valves and other equipment that needs to be removed to replace or maintain. So, the company's procedure for sanitization, as the actual pipe, must be evaluated and reviewed when examining the piping.


Another option for producing water for injection uses Reverse Osmosis (RO). But, since the systems used are not cold and since RO filters aren't 100 microbiological contamination isn't uncommon. Figure 8 illustrates a system operating for several years. There five RO units within this system, which are connected in parallel. Since RO filters aren't absolute, the manufacturers of filters suggest that at the very least two of them be in series. The drawing also shows the Ultraviolet (UV) illumination source in the system that is downstream of those RO units. This light was necessary to reduce the microbiological contamination.

In this system, there was ball valves. They aren't considered as sanitary because the middle of the valve may be filled with water after the valve has been closed. It is a stagnant pool of water which can be home to microorganisms as well as provide a starting place for the formation of biofilm.

In addition to the above comments on RO systems, in the awareness of microbiological issues certain manufacturers have put in heat exchangers right following RO filters in order to raise the temperature of the water to between 75 and 80oC to reduce microbiological contamination.

As biotechnology is developing products, numerous small companies are using RO or UF equipment to create high-purity water. For instance, Figure 9 shows a wall-mounted system which is supplied by a single-pass RO unit.

As can be seen, the majority of these systems use PVC or some other type of plastic tubing. Because these systems are usually cold, the joints can be contaminated. Another issue that could be a problem that could arise with PVC tubing is that it can be contaminated by extractables. Examining the WFI from an inspection system to ensure that it is in compliance with USP specifications without a guarantee that there aren't any extractables is not acceptable.

They also include 0.2 micron point of use filters that could conceal the amount of microbiological contamination that is present in the system. Although it is acknowledged that endotoxins are the main problem in this system the filter can lower microbiological contaminants however, it is not necessary to reduce endotoxin contamination. When using filters in a water treatment system, there must be a clearly stated reason to the use of the filter i.e. particle removal, or microbial reduction and an SOP that outlines the frequency that the filter should be replaced dependent on the data collected during the testing for the filter.

As was previously explained in relation to the volume of water examined (.1ml for endotoxins in comparison to. 100ml in WFI) The microbiological test provides a reliable indicator of the amount of contamination in a given system. Thus that unless the water has been taken for sampling prior to the 0.2 micron filter, the microbiological test is not a reliable indicator.

In a re-inspection of the building, they discovered that they had corrected the inefficient water system using the use of a stainless steel piping system, which was connected to four RO units that were connected. Since the manufacturer didn't have a need for a large quantity of water (the total capacity of the system was around 30 gallons) the company decided to allow the system to sit for a day. The figure 9 illustrates that at the point of no time (at 9 am on the 3/10) the system was free of discernible levels of microorganisms or of endotoxins. After a few days the static system could be found infected. The four one-hour samples also demonstrate the variance between samples from an entire system. When the final sample at 12pm was collected the system was cleaned with a 0.5 peroxide solution at 1 flushed, recirculated, and then resampled. There was no evidence of microbiological contamination were detected on daily samples once the system was re-in operation. This is the reason why the agency has suggested that water systems with no recirculating capability be flushed daily and the water should not be permitted to sit within the system for too long.


Many of the suggestions regarding equipment used in WFI systems can be used for Purified water systems. One type of system that is used to combat microbiological contamination uses Ozone. 10. shows an example of an example of a typical system. While the system is claimed to be reasonably priced however, there are some issues that are associated with it. For maximum efficiency it is essential that the residual dissolved in ozone remain within the system. This can cause safety concerns as well as use issues when drugs are made.

The data published from Vicks Greensboro, NC facility revealed that their system had been affected by the contaminant within two to 3 days following the time when their ozone generator had been shut off. In an inspection of a different producer, the company found that the company was suffering from an issue with contamination caused by Pseudomonas. Due to the possibility of issues regarding safety of employees the ozone was eliminated out of the water prior to putting it in the recirculating system. It was reported that Ozone dissolved at a rate of 0.45 mg/liter can remain in the system for 5 to 6 hours.

Another manufacturer in their regular sanitization routine, cleans every drop of water from the ozonated system. They disinfects them using filters that are sterilized by 70 70% isopropyl alcohol. The manufacturer has reported impressive results in microbiology. However, the sampling is conducted immediately after sanitization but not after the completion of the process. So, the outcomes don't have any significance.

Figure11 and Figure 12 show another system for purifying water that was not without its problems. Contrary to other systems that are discussed it is a single-way system and not a recirculating one. A heat exchanger is employed to warm the water on a regular basis and clean the system. In reality, the whole system is an "dead-leg."

Figure 11 also illustrates an 0.2 micron line filter that is used to clean the water purified every day. Alongside the filter housing that provides a suitable environment for microbiological contamination the most common issue is water hammer which could result in "ballooning" within the filter. If a valve that is downstream of to the filter shuts too quickly the pressure in the water reverses and could result in "ballooning". Pipe vibration is a common indication of high back pressure , while the passage of contaminants upstream onto the face of the filter is an actual issue. The system also includes a number of vertical drops located at points of use. When sanitizing, it's essential that you "crack" these terminal valves to ensure that all bends and elbows in the piping are filled with water, thereby allowing all exposure to the sanitizing agents.

It is important to note that, despite being an unidirectional system, it's not insufficient. If it is based on Standard Operational Procedures that are based upon validation information, and regular hot flushing that are part of the system may be considered acceptable. A lengthy installation (over 200 feet) that had more than 50 outlets was deemed acceptable. The system was based on every day flushing of all outlets using 80oC water.

The last system that will be considered is one which was found to be unacceptable. Pseudomonas sp. was identified as a contaminant in the system (after FDA testing) was also detected on a topically applied steroid (after FDA testing). Recall of the product and the issuance of an Warning Letter resulted. This method ( Figure 13) is another method which uses an ultraviolet light to limit microbiological contamination. The light is on at times when the water required. This means that there are times that water can remain within the system. It also comes with a flexible hose , which is extremely difficult to disinfect. UV light bulbs must be properly maintained to ensure their effectiveness. The glass sleeves that surround the bulb(s) should be kept clean otherwise their effectiveness will be diminished. In multibulb units, there should be a way to ensure whether each bulb is working. It is important to remember that, at the very best, the UV light can kill 90% of organisms in the unit.


Presently in the present, the USP, page. 4, of the General Notices Section permits the manufacture of drugs using Potable Water. It states that any dosage form has to be produced using Purified Water, Water For Injection or any other form in Sterile Water. There's a niggle in these two assertions, as Purified Water is utilized for the granulation of tablets, however Potable Water can be used to finalize the purification of the drug ingredient.

The FDA Guide to Inspection of Bulk Pharmaceutical Chemicals discusses the need regarding the quality of water used to make of drugs, specifically the drugs that are used in the parenteral manufacturing process. The presence of excessive levels of microbiological and/or endotoxin contamination were found in various drugs which have the origin of the contamination being the water used for the purification process. At this time, Water For Injection does not have to be used in the finishing steps of synthesis/purification of drug substances for parenteral use. However, water systems utilized during the final stages of processing drug substances to be used in parenteral applications must be validated in order to guarantee the least amount of microbiological and endotoxin contamination.

For the large drug industry, especially for parenteral grade substances it is not uncommon to find ultrafiltration (UF) as well as reverse Osmosis (RO) devices employed within water system. While ultrafiltration might not be as effective at decreasing pyrogens as RO, they can lower the weight of high molecular endotoxins which are a source of contamination within water system. Similar to RO, UF is not 100%, but it does lower the amount of. As previously mentioned in relation to other cold systems it is a lot of maintenance for the maintenance of the system.

When it comes to the manufacturing of substances for use in the treatment of diseases which are not intended for parental use, there's the possibility of microbiological contamination, though not as much that it is for parenteral-grade drug substances. In certain regions around the globe, potable (chlorinated) water might not pose a microbiological risk. But, there are additional issues. For instance chlorinated water can increase the levels of chloride. In certain areas the process water can be sourced directly from sources that are neutral.

In one of the inspections one time, a company was getting the process waters from a river that was located in a region of agriculture. At some point they encountered a problem with excessive levels of pesticides, which was the result of run-off from the farms that were located in the area. The process for manufacturing and method of analysis was not intended to eliminate and detect pesticide trace contaminants. Thus, it is likely that the process water utilized in the purification process of drugs would be incompatible.


Manufacturers generally regularly print out or table of the purified systems they use for water. The printouts or data summaries must be looked over. In addition, reports of investigations in the event that values are higher than limits, must be examined.

The results of microbiological tests of a water system typically are not available until after the drug is produced, results that exceed thresholds should be evaluated with respect to the drug formulation from this water. Be aware that the subsequent process or release of product will depend on the specific contaminant being used as well as the method used and the application that the substance. These situations are typically evaluated on an individual basis. It is recommended in such instances to provide an investigation report that outlines the reasoning behind release or rejection that is discussed in the report of the company. Microbiological testing at the end of the product is a good source of information, but is not to be used as the sole reason in the decision to allow the distribution of the. The limitations of microbiological samples and testing must be acknowledged.

Manufacturers must also keep maintenance logs or records for equipment, like the still. The logs must also be reviewed in order that issues related to the system or equipment are identified and rectified.

Alongside looking over test results, summaries of report of the investigation, data and other information The print of the system needs to be scrutinized when performing the physical inspection. It is important to have the correct description and printing of the system are required to show that the system is valid.