As you may know, there are several types of water purity available depending on what you’re tackling at the bench. This includes a range from Type III for general use such as rinsing out your beakers, all the way up to Type I+ for sensitive applications like the intriguingly sounding ‘graphite furnace atomic absorption spectrometry’ (GF-AAS).
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Making the decision on which type of pure water you need for your application can be challenging. Knowing this informs the purification technology you use and systems you require to produce the right water grade.
As we’ve said, there are several different types of water, however at ELGA we specialise in the production of three types in particular: Type I, Type II and Type III.
Type I grade water, also known as Ultrapure Water, is the purest form of water to be produced. It’s used for the most critical applications and advanced analytical procedures.
This includes:
• Cell and Tissue Cultures
• Liquid Chromatography, including High Performance Liquid Chromatography (HPLC)
• Gas Chromatography
• Inductively Coupled Plasma Mass Spectrometry (ICP-MS)
• Molecular Biology
Type I can also be used in applications that require Type II water. This is quite a common practice that can help to avoid the generation of by-products during applications.
Type II water grade doesn’t have the same pureness of Type I, but still maintains high levels of purity. It is a good feed water for clinical analyzers as the calcium build-up is reduced with this water type.
It can also be used in applications such as:
• General Lab Practices
• Microbiological Analysis and preparation
• Electrochemistry
• FAAS
• General Spectrophotometry
It can also be used as feed water for Type I water production.
Type III grade water, also known as RO water, is water produced through the purification technology reverse osmosis. Of all the pure water types it has the lowest level of purity, but is typically the starting point for basic lab applications, such as cleaning glassware, heating baths or media preparation. It can also be used as a feed water for Type I water production.
To implement a coherent classification system for water purity, we make use of several key factors describing the various properties of water.
Conductivity is reported as microSiemens per centimeter (µS/cm) at 25oC and is the reciprocal of resistivity and provides a measure of a fluid's ability to conduct electrical current. Conductivity is typically used when assessing water ranging from 'raw water' through to 'drinking water' and provides a valuable, non-specific indication of the level of ions in the water.
Reported as Mega-Ohms per centimeter (MO-cm) at 25oC, resistivity is related to conductivity: a high resistivity equals a low conductivity. As such, it also provides a measure of the water's ionic content. Unlike conductivity, resistivity is primarily used in the assessment of ultrapure water.
Organic compounds can exist in water in numerous forms and so measuring every single one individually is impractical. Instead, the most useful indicator is considered to be the total organic carbon (TOC) content of the solution. This is measured via a process that oxidizes the organic compounds present and then quantifies the oxidation products generated. TOC is as close as we can currently get to a 'universal indicator' for the presence of organic impurities.
Alternatively, chromatographic techniques may be employed to determine the specifics of organic content, but this is frequently considered both too expensive and time-consuming to be used in general monitoring workflows.
The presence of biological contaminants such as bacteria and other microorganisms is a common issue in untreated water. Bacterial levels reported as colony forming units per milliliter (CFU/ml) are kept low via filtration, UV treatment and sterilant solutions.
Following an incubation period in suitable growth media, individual bacterial species and total viable cell counts can be determined. Bacteria counts may also be monitored through the use of epifluorescence testing to rapidly detect and distinguish between dead and living microorganisms.
In addition to the bacteria themselves, endotoxins produced from the cell wall of gram-negative microorganisms (reported as endotoxin units per milliliter, EU/ml; 1 EU/ml approximately equal to 0.1 ng/ml) can be assessed using standard tests based on Limulus Amebocyte Lysate activity.
Suspended particles can cause water turbidity (measured in Nephelometric Turbidity Units, NTU) and are therefore filtered out of laboratory water as much as possible. This colloidal material is defined as being less than 0.5 µm in size and may contain iron, silica, aluminium or organic materials. The Fouling Index (FI) is frequently used to estimate the potential of water to block filters under 0.45 µm filter conditions.
There are several international boards around the world that have been working to establish some degree of consistency in the standards of water purity – the more people we have agreeing to these standards, the easier it is to generate reproducible data. Some labs will also adopt standards as outlined by the regulatory body overseeing the region they work in, for example, as found in the European, US or Japanese Pharmacopoeias. However, very few of these standards are specific to a particular application.
As of , the CLSI has moved away from the typical Type I, II and III designations, instead preferring to suggest that water be simply ‘fit for purpose’, and only describes one grade in significant detail: Clinical Reagent Laboratory Water. The CLSI has also briefly outlined other grades in less detail, such Special Reagent Water (SRW) and instrument feed water.
The ISO based its specification on ISO :, and specifies three grades of water: Grade 1, Grade 2 and Grade 3, where Grade 1 is the most pure (see below):
Water quality parameters for ISO grades
The ASTM uses D-06 and has four grades of water (see table below).
Water quality parameters for ASTM types
*Requires use of 0.2 μm membrane filter; **Prepared by distillation; ***Requires the use of 0.45 μm membrane filter.
Water for Injection (WFI) is a critical utility with increasing demand for vaccines and therapeutics. Traditionally, WFI production uses distillation, but producers that use such systems want options with lower ownership costs and more sustainability. Reverse osmosis (RO) membrane-based systems with ultrafiltration can meet some of these challenges.
If you are a manufacturer of pharmaceutical or biologic medicines, you’ll want to evaluate all the pros and cons surrounding your design choice for a new WFI generation system.
Membrane-based production for WFI continues to be at the forefront of discussions as it presents a design alternative to the traditional distillation-based system. Membrane-based production of WFI has the potential to lower total cost of ownership and possibly provide a more sustainable solution long-term.
Producers implementing membrane-based WFI systems must first consider regulatory and quality requirements, including those from the United States Pharmacopeia (USP), European Pharmacopeia (EP), and Japanese Pharmacopeia (JP).
Each set of regulatory standards differs slightly in the allowed WFI production processes. The standards require purification processes equivalent or superior to distillation, with some unique requirements, like no added substances. These equivalent systems can include membrane-based purification.
USP Monograph outlines WFI must be purified by distillation or a purification process that is equivalent or superior to distillation and that it contains no added substances.
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The European Pharmacopeia (Ph. Eur. Monograph 169) outlines a purification process that is equivalent to distillation. Reverse osmosis, which may be single-pass or double-pass, depending on water coming into your facility and other risk-based questions, coupled with other appropriate techniques such as electrodeionization, ultrafiltration or nanofiltration, is suitable. Notice should be given to the supervisory authority before implementation.
Japanese Pharmacopeia requires WFI by distillation or reverse osmosis and/or ultrafiltration. It’s important to know that the JP requires the molecular weight cut-off of your final membrane barrier to be at 6,000 Dalton.
The regulatory standards also set slightly different benchmarks for conductivity, total organic carbon, bacterial, and microbial levels.
Learn more about navigating global pharmacopeia standards for water quality here.
Membrane-based WFI systems meet regulatory standards through comprehensive system design, including the following components:
Before you implement a membrane-based system, there are four main areas to evaluate before designing your system. For example purposes, we’ll be using Water for Injection (WFI) to explain the importance of each.
There are a number of contaminant groups that need to be considered when designing your membrane-based system. The purpose of pretreatment is to condition the water before it is fed to the generation system. The typical three groups of contaminants are particulates (suspended solids), scalants/foulants (calcium/magnesium) and disinfectants (C12).
Our Membrane WFI System cannot tolerate high levels of particulates. Particulates can be removed through a variety of options in our pretreatment subsystem, such as bag filter cartridge or multimedia filter.
Scalants and foulants have to be removed or reduced during pretreatment as they produce chemical compounds that interfere with the membrane’s performance. This jeopardizes the output quality and quantity of the system.
Lastly, disinfectants must be removed. Disinfectants are added to public water to protect the public health but those disinfectants are damaging to the membrane by causing oxidative damages to membranes and EDI stacks.
In our pretreatment subsystem for membrane-based water purification systems we remove particulates through a multimedia filter composed of anthracite, sand, fine garnet, course garnet, medium or course gravel. The typical removal rate is about 10 microns, which is industry standard for media filters.
For companies who want to cut down their water footprint, we can use pleated dev filter or bag filter for the pretreatment subsystem. The downside to these filters are they have higher maintenance as someone will consistently need to change the filters.
The filtrate will exit that vessel and move on to the next step of water softening. We use a resin bed in order to remove the calcium and magnesium from the feed water. The hardness must be removed so it does not scale the membranes. This will release sodium, since we are using salt to regenerate that bed.
Chlorine is then removed from the feedwater using activated carbon. Our membranes have about PPM hours of chlorine tolerance so you can run at 1PPM of chlorine for hours before you see damage to the membrane. The EDI stacks generally cannot handle chlorine, which is why this stage of chlorine removal from feedwater is so important.
Carbon filters are tried and true when it comes to removing chlorine. Chemical injections can be tricky to manage, for example you don’t have a good injection rate, your pump isn’t putting out what it needs or a bad batch got mixed up. Chemical injections are just not as reliable in removing chlorine as carbon filters. For UV chlorine removal, it is hard to get 100% kill of the chlorine guaranteed.
Dechlorinated water will then exit the carbon filter and proceed to final treatment.
First step is the RO, which will reduce the bulk of all contaminant groups (single or double pass depending on water quality). Next step is EDI stack, which uses a mix of electricity, membranes and resin in order to polish what comes out of the RO. This further reduces inorganics and some organics. The final barrier is the UF, which is where the Dalton membrane will be used in order to reduce biological contaminants.
After this step the system sends the water to a storage tank.
Learn more about the cost differences between the four main system designs for Water for Injection here.
There are three types of sanitation methods for storage and distribution:
Water for Injection (WFI) is one of the most critical pharmaceutical manufacturing ingredients and therefore extra precaution must be taken in identifying and preventing risks. Controlling risks involves:
Membranes can grow bacteria at any point in the system and the best way to deal with that is hot water sanitization. This is the most popular way to reduce risk of contamination of your membrane-based water purification system.
Since membrane systems operate at ambient temperatures, they require robust predictive maintenance, and their complexity can also influence reliability. In distillation water purification systems, you’re operating at self-sanitizing temperatures (65-80C).
It’s important to have a preventative maintenance (PM) protocol set up for any membrane-based WFI system as well.
Read more about WFI risk, reliability, and sustainability from our whitepaper here.
The compact MASTERpak™ULTRA provides a complete solution for producing ambient WFI using membranes. The unit incorporates MECO’s pretreatment, RO, electrodeionization and ultrafiltration capabilities. Get in touch today to see how MECO can help with a membrane-based WFI system.
Water our full webinar on Membrane WFI Systems below.
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