Pharmaceutical Water and Water Purification PDF

Transcript Pharmaceutical Water and Water Purification Slide 1: Introduction............................................................................................................ 2 Slide 2: Section 1: Grades of Water....................................................................

Transcript Pharmaceutical Water and Water Purification Slide 1: Introduction............................................................................................................ 2 Slide 2: Section 1: Grades of Water................................................................................... 3 Slide 3: Potable Water......................................................................................................... 3 Slide 4: Types of Impurities Present in Potable Water...................................................... 4 Slide 5: Purified Water......................................................................................................... 5 Tab 1: Purified Water in Bulk Ph Eur................................................................................ 6 Tab 2: Purified Water in Containers Ph Eur..................................................................... 7 Tab 3: The United States Pharmacopeia Purified Waters.............................................. 8 Slide 6: Water for Injections................................................................................................ 9 Tab 1: Water for Injections in Bulk Ph Eur..................................................................... 10 Tab 2: Sterilised Water for Injections Ph Eur................................................................. 11 Tab 3: Water for Injection USP....................................................................................... 12 Slide 7: Differences Between Purified Water and Water for Injections......................... 13 Slide 8: Types of Water: Their Preparation and Uses...................................................... 14 Slide 9: Section 2: The Production of Pharmaceutical Water......................................... 14 Slide 10: Water Quality for Particular Pharmaceutical Purposes..................................... 15 Slide 11: Water Purification Unit Processes...................................................................... 16 Tab 1: Deionisation......................................................................................................... 17 Tab 2: Electrodeionisation.............................................................................................. 19 Tab 3: Distillation............................................................................................................. 20 Tab 4: Reverse Osmosis................................................................................................. 24 Slide 12: Other Water Purification Unit Processes............................................................ 26 Tab 1: Filtration............................................................................................................... 27 Tab 2: Water Softening................................................................................................... 27 Tab 3: Sanitisation.......................................................................................................... 28 Slide 13: Example 1: Industrial Water Purification Systems............................................. 29 Slide 14: Example 2: Industrial Water Purification Systems............................................. 30 Slide 15: Controls and Tests in Industrial Plants............................................................... 31 Slide 16: Summary............................................................................................................... 31 1  Transcript Slide 1: Introduction Hello and welcome to this presentation on pharmaceutical water and water purification. My name is Anne Marie Healy and I will lead this presentation. Water is the most common liquid used in pharmaceutical processing, manufacture and in finished pharmaceutical products. Pure water, H2O, is a 'concept' and does not exist in practice. Even if it were possible to produce, storage would quickly result in contamination. Water is a unique solvent and has the ability to dissolve, to a greater or lesser extent, just about everything. Impurities can be leached from the storage vessel and taken in from the atmosphere. Natural water is, therefore, a complex 'aqueous solution and suspension' and may be treated by a variety of techniques in order to improve its level of purity. This presentation concentrates on the grades of water specified in the pharmacopoeias and on the methods and unit processes used to achieve these grades. 2  Transcript Slide 2: Section 1: Grades of Water Slide 3: Potable Water Potable water is drinking water suitable for human consumption and is derived mainly from surface sources such as lakes, rivers and streams and from underground sources such as wells and springs. In emergencies, it may be obtained from the sea by distillation or by demineralisation with ion-exchange materials. It must be both palatable and safe to drink; it must be clear, colourless, odourless and tasteless and it must be free from toxic substances, pathogenic organisms and excessive amounts of certain other materials. There are restrictions on the content of such substances as arsenic, barium, cadmium, chromium, copper, cyanide, lead, selenium, fluoride and nitrates. In Europe, EU directive 98/83/EEC stipulates maximum permissible levels for minerals and microbes. 3  Transcript Unless processed further potable water is considered unsuitable for many pharmaceutical purposes. Slide 4: Types of Impurities Present in Potable Water There are four main groups of impurities present in potable water: 1. Particulate matter: this includes suspended solids of various types. 2. Fully dissolved impurities: these may be organic e.g. carbohydrates, and inorganic e.g. salts. 3. Colloidal matter: this consists of particles from 0.005 to 0.2µ which tend not to sediment for a variety of reasons including surface charge. 4. Microfungi, bacteria, viruses and algae. The abundance of these impurities varies widely from one geographical region to another, and it also depends on the source. Underground supplies usually contain high levels of inorganics e.g., calcium, magnesium and clay. Surface supplies have low levels of inorganics but relatively high levels of dissolved organic impurities as a result of the water coming into contact with vegetation. It should be noted that the nature and abundance of impurities, especially in surface water, is prone to seasonal variations. In addition to its solvent powers, water provides an excellent medium for the growth of microbes. 4  Transcript Slide 5: Purified Water Purified Water Ph Eur (i.e. of European Pharmacopeia grade or quality) is defined as ‘water for the preparation of medicinal products other than those that are required to be both sterile and apyrogenic, unless otherwise justified and authorised.’ Note that: apyrogenic means the water is free from pyrogens; pyrogens being substances that cause a febrile reaction - a rise in core body temperature - if they get into the blood stream. Pyrogens can potentially also cause low blood pressure, increased heart rate and low urine output if they get into the bloodstream. As we’ll see later, water that is used in injectable preparations must be pyrogen-free. The most important pyrogens in a pharmaceutical manufacturing context are bacterial endotoxins. Bacterial endotoxins are lipopolysaccharide (LPS) that are part of the outer membrane of the cell wall of Gram- negative bacteria and are released upon cell lysis. The European Pharmacopeia and the United States Pharmacopeia (the USP) provide information on different categories of purified water. Click the tabs to learn about each category, outlined in the different pharmacopeial monographs. When you are ready, click “Next” to continue. Reference(s): 1. European Medicines Agency. (2020). Guideline on the quality of water for pharmaceutical use. https://www.ema.europa.eu/en/documents/scientific- guideline/guideline-quality-water-pharmaceutical-use_en.pdf 5  Transcript Tab 1: Purified Water in Bulk Ph Eur Purified Water in Bulk Ph Eur may be produced by distillation, by ion exchange or by any other suitable method from water that complies with the regulations on water intended for human consumption laid down by the competent authority. During production and subsequent storage, appropriate measures should be taken to prevent the growth of microorganisms and to ensure that the total viable aerobic count is adequately controlled and monitored. An appropriate action limit is recommended to be 100 microorganisms per millilitre (i.e. 100 CFU (colony forming units)/ml). Tab 1.1: Purified Water in Bulk Ph Eur 6  Transcript There are various tests in the European Pharmacopeia for purified water that must be satisfied before it can be called Purified Water Ph Eur. Reference should be made to the pharmacopeia for a full account. Tests on Purified Water in Bulk include a test for total organic carbon, with a limit of 0.5 mg/L, or alternatively a test for oxidisable substances; a limit tests for nitrates and aluminium and a test for conductivity. A limit on bacterial endotoxin content is only imposed if the purified water is intended for use in the manufacture of dialysis solutions ‘without a further appropriate procedure for the removal of bacterial endotoxins’. The limit is set at not more than 0.25 I.U. of endotoxin per millilitre in this case. Reference(s): 1. European Directorate for the Quality of Medicines and HealthCare. (2021). European Pharmacopoeia (Ph. Eur.) (10th ed.). European Directorate for the Quality of Medicines and HealthCare. Tab 2: Purified Water in Containers Ph Eur Purified Water in Containers Ph Eur is a clear and colourless liquid. It is Purified Water in Bulk that has been filled and stored in conditions designed to assure the required microbiological quality and is free from any added substances. It must comply with the tests outlined above for Purified Water in Bulk and with additional tests for: acidity or alkalinity, residue on evaporation (not more than 0.001%) and microbial contamination (total viable aerobic count of not more than 100 microorganisms per millilitre). There are also limit tests for chlorides, sulfates, ammonium, calcium and magnesium. 7  Transcript Tab 3: The United States Pharmacopeia Purified Waters The United States Pharmacopeia (the USP) has separate monographs for Purified Water and Water for Hemodialysis, which are both described as “Bulk Monographed Waters”. Within these monographs there are “Additional” requirements specified for bulk packaging for commercial use elsewhere (i.e. for packaged water, which is equivalent to Purified Water in Containers Ph Eur). Water for Hemodialysis USP contains no added antimicrobial agents but has an endotoxin limit of 1 USP Endotoxin Unit/ml (with a maximum recommended Action Level for bacterial endotoxins of no greater than 0.25 USP Endotoxin Unit/ml). In addition, the absence of Pseudomonas aeruginosa should be routinely determined because this is an opportunistic pathogen hazardous to acutely ill haemodialysis patients. The USP also has a monograph for Sterile Purified Water which has no equivalent in the European Pharmacopeia. Sterile Purified Water is purified water, packaged and rendered sterile. It can be used in the preparation of non-parenteral compendial dosage forms or in certain circumstances in analytical applications requiring purified water. Note that term sterile means the absence of viable microorganisms. 8  Transcript Slide 6: Water for Injections Purified water, of pharmacopoeial specifications, is not suitable for preparing injections. Water for Injections is defined in the European Pharmacopeia as "water for the preparation of medicines for parenteral administration when water is used as vehicle (Water for Injections in Bulk) and for dissolving or diluting substances or preparations for parenteral administration before use (Sterilised Water for Injections)”. Click the tabs to learn more about the different classifications of Water for injections. When you are ready, click “Next” to continue. Reference(s): 1. European Medicines Agency. (2020). Guideline on the quality of water for pharmaceutical use. https://www.ema.europa.eu/en/documents/scientific- guideline/guideline-quality-water-pharmaceutical-use_en.pdf 9  Transcript Tab 1: Water for Injections in Bulk Ph Eur As per the description in the pharmacopeia, Water for Injections in Bulk Ph Eur is obtained from potable water or purified water by: Distillation in an apparatus of which the parts in contact with the water are of neutral glass, quartz or a suitable metal and which is fitted with an effective device to prevent the entrainment of droplets; or A purification process that is equivalent to distillation. Reverse osmosis, which may be single-pass or double-pass, coupled with other appropriate techniques such as electro- deionisation, ultrafiltration or nanofiltration, is suitable. Notice is given to the supervisory authority of the manufacturer before implementation. For all methods of production, correct operation monitoring and maintenance of the system are essential. In order to ensure the appropriate quality of the water, validated procedures, in-process monitoring of the electrical conductivity, and regular monitoring of total organic carbon and microbial contamination are applied. The first portion of water obtained when the system begins to function is discarded. Water for Injections in Bulk is stored and distributed in conditions designed to prevent growth of microorganisms and to avoid any other contamination and is a clear and colourless liquid. 10  Transcript Tab 1.1: Tests and Limits Water for Injections in Bulk complies with the tests for Purified Water in Bulk Ph Eur. For some tests, higher standards or specifications are set. During production and storage, the total viable aerobic count is controlled and monitored. An action limit of 10 microorganisms per 100 ml is normally appropriate (10 CFU/100 ml). The specification for total organic carbon is a maximum of 0.5 mg/L. In addition, the maximum conductivity allowable is lower than for Purified Water (i.e. 1.1 mS.cm-1 at 20 oC compared to 4.3 mS.cm-1 at 20 oC for Purified Water) and there is also a limit on bacterial endotoxin content of 0.25 I.U./ml. Tab 2: Sterilised Water for Injections Ph Eur 11  Transcript Sterilised Water for Injections Ph Eur is Water for Injections in Bulk Ph Eur that has been distributed into suitable containers, closed and sterilised by heat in conditions which ensure that the product still complies with the test for bacterial endotoxins. Sterilised Water for Injections is free from any added substances. Sterilised water for injections complies with the tests outlined in the pharmacopeia for acidity or alkalinity, conductivity, oxidisable substances, residue on evaporation and a number of different inorganic contaminants – chlorides, nitrates, sulfates, aluminium, ammonium, calcium and magnesium. It also complies with tests for particulate contamination and bacterial endotoxins (0.25 I.U./ml). A sterility test is one of the tests to which this grade of water must comply. Tab 3: Water for Injection USP The USP has equivalent monographs to the European Pharmacopeia for “Water for Injection” and “Sterile Water for Injection”. The USP also contains an additional monograph for Bacteriostatic Water for Injection, which is Water for Injection, packaged and rendered sterile, to which has been added one or more suitable antimicrobial agents. It is intended to be used as a diluent in the preparation of parenteral products, most typically for multi-dose products that require repeated content withdrawals. It may be packaged in single-dose or multiple-dose containers not larger than 30 ml. 12  Transcript Slide 7: Differences Between Purified Water and Water for Injections The quality attributes of Purified Water and Water for Injection(s) differ with respect to their bioburden expectation (and allowed microorganism contamination limits), the presence of a bacterial endotoxin requirement for Water for Injection, and in their methods of preparation. The critical differences in terms of water purification systems for producing Purified Water compared to Water for Injections relate to the required degree of control of the system and the final purification steps needed to ensure removal of bacteria and bacterial endotoxins, and to minimise opportunities for biofilm re-development in the purification processes and equipment that could become in situ sources of bacteria and endotoxin in the finished water. Chapter 〈1231〉 of the USP, Water for Pharmaceutical Purposes is a useful informative chapter on pharmaceutical water topics and includes some of the chemical and microbiological concerns unique to water and its preparation and uses. The chapter provides information about water quality attributes and processing techniques that can be used to improve water quality. It also discusses water system validation and gives a description of minimum water quality standards that should be considered when selecting a water source including sampling and system controls. The USP may be accessed via the TCD library website. You should create an account with USP.org via the library website to gain access to this full chapter. Reference(s): 1. Pharmacopeia. (n.d.). General Chapters: Water For Pharmaceutical Purposes. Pharmacopeia Online. Retrieved September 27, 2021, from http://www.uspbpep.com/usp29/v29240/usp29nf24s0_c1231.html 13  Transcript Slide 8: Types of Water: Their Preparation and Uses This figure is reproduced from Chapter 〈1231〉 of the USP and is helpful in depicting some of the various types of waters, their preparation, and uses. Take some time to view this figure. When you are ready, click “Next” to continue. Image(s): 1. Pharmacopeia. (n.d.). General Chapters: Water For Pharmaceutical Purposes. Pharmacopeia Online. Retrieved September 27, 2021, from http://www.uspbpep.com/usp29/v29240/usp29nf24s0_c1231.html Slide 9: Section 2: The Production of Pharmaceutical Water 14  Transcript Slide 10: Water Quality for Particular Pharmaceutical Purposes Production of pharmaceutical water involves sequential unit operations (or processing steps) that address specific water quality attributes and protect the operation of subsequent treatment steps. Click the images to see decision trees for selecting an appropriate water quality for a particular pharmaceutical purpose. These diagrams may be used to assist in defining requirements for specific water uses and in the selection of unit operations in a pharmaceutical water purification system. When you are ready, click “Next” to continue. Image(s): 1. Pharmacopeia. (n.d.). General Chapters: Water For Pharmaceutical Purposes. 15  Transcript Pharmacopeia Online. Retrieved September 27, 2021, from http://www.uspbpep.com/usp29/v29240/usp29nf24s0_c1231.html 2. Pharmacopeia. (n.d.). General Chapters: Water For Pharmaceutical Purposes. Pharmacopeia Online. Retrieved September 27, 2021, from http://www.uspbpep.com/usp29/v29240/usp29nf24s0_c1231.html Slide 11: Water Purification Unit Processes Industrial pharmaceutical plant water purification systems will consist of a number of water purification steps or unit processes combined in series. I will speak briefly about some of these unit operations in this presentation, while more detail of other unit operations and water purification processes and control measures can be found in the extend section of the session home page. Click the tabs to learn more about these unit operations. When you are ready, click “Next” to continue. 16  Transcript Tab 1: Deionisation The first unit process for water purification that I'm going to look at is deionisation. With deionisation, the potable water is passed through columns of anionic and cationic exchange resins to remove ionisable compounds from the water, mainly inorganic salts. So if, for example, we have a cationic exchange resin here and we have anionic exchange resin here, when you pass the water containing inorganic salt contaminants through those resins, the positively charged ions will be exchanged in the cation exchange resin for hydrogen ions while the negatively charged ions will be exchanged in the anion exchange resin for hydroxyl ions. These resins are beads of polymers that have the capacity to exchange ions - to exchange hydrogen ions for positively charged ions that are in the water and hydroxyl ions for negatively charged ions that are in the water. In cation exchange resins, the cations in the water are replaced by hydrogen ions from the resin, while in anion exchange resins, the anions are replaced by hydroxyl ions from the resin. The hydrogen and the hydroxyl lines unite to form water, and the ionic impurities stay firmly attached to the resin, and so are removed from the water. This method of purification can only remove ionisable compounds and is therefore mainly used to remove inorganic salt contaminants from the water. Because free endotoxin is negatively charged, some removal of endotoxin is also achieved by the anion exchange resin. This diagram shows a situation where we have ionic contaminants in the water, salts in the water, passing through a cation exchange resin and subsequently passing through anion exchange resin. Image(s): 1. Purushothaman, R. (2018, September 23). Demineralisation Process / Ion Exchange Process [Illustration]. Demineralisation Process (Deionization/Ion-Exchange Process) - Water Technology. https://www.youtube.com/watch?v=ctlHNf1s6RM 17  Transcript Tab 1.1: The Resin This picture shows you what these resins look like. So, you have beads of polymer material which contain the ions that can be exchanged for ionic contaminants in the water. And these resins can be packed into beds like this through which the water is flushed. You can have separate beds of cation exchange resin and anion exchange resin - two separate modules or two separate columns containing the different resin systems - or alternatively, you can have a single column with a mixed bed of resin, containing a mixture of cation exchange resin and anion exchange resin. Of course, eventually the resin will become depleted of exchangeable ions. So as the contaminants from the water get held on to by the resin, then the resin loses its capacity to exchange hydrogen or hydroxyl ions for the ions that are in the water. So, the resin beds must be regenerated, to replenish the exchangeable ions. The anion exchange resin bed is regenerated using sodium or potassium hydroxide by flushing periodically to replenish the hydroxyl ions in the resin and flush away the contaminants from the resin bed. Likewise, the cation exchange resin bed is regenerated usually using hydrochloric acid, so it will be flushed periodically with hydrochloric acid to replenish the resin. An issue to look out for with deionisation is that microorganisms can multiply in the resin bed, particularly if there's any stagnant water allowed to reside or accumulate in the resin bed. Microbial contamination of the resin can be minimised by using the deioniser continuously and regenerating at regular intervals. Image(s): 1. EZ Filter Store. (n.d.). Refillable Inline Mixed Bed De ionization Filter [Photograph]. AliExpress. https://www.aliexpress.com/item/32900202834.html 18  Transcript 2. AquaFX. (n.d.). Non Color Indicating Mixed Bed DI Resin [Photograph]. AquaFX. https://www.aquariumwaterfilters.com/DI-Deionization-Resin-bulk-mb-di-NCI.htm Tab 2: Electrodeionisation A variation on the standard deionisation process, which has become popular, is electrodeionisation (EDI). With an EDI system, you have a combination of mixed resin bed, selectively permeable membranes and an electric charge. A schematic of one of these systems is shown here. In this case, the feed water is coming in at the top and is being flushed through different compartments of the deioniser unit. In the centre, we have a mixed resin bed. And holding the resin in place, we have selectively permeable membranes. In this case, this membrane here is shown to be an anion permeable membrane, and anions can pass through the membrane, but cations cannot. In this case, we have a cation permeable membrane so cations can pass through the membrane, but anions cannot. And here we have another anion permeable membrane. And on the far side, we have a cation permeable membrane. In addition to the mixed resin bed and the selectively permeable membranes, we have an anode and a cathode and an electric charge can be made to pass across the resin bed. When the feed water comes in, it comes in to these three channels, a diluting compartment and two concentrating compartments. The diluting compartment is where the water is cleaned up. So we have ions in the water being exchanged for ions from the resins. Water enters both the resin section and the waste or the concentrate 19  Transcript sections, but it's in the mixed bed region that ion exchange takes place and the ion exchange resins capture any dissolved ions. However, rather than remaining sitting on the resin, the ions are pulled away from the resin towards either the anode or the cathode, depending on their charge. Positively charged ions will be pulled towards the cathode and negatively charged ions will be pulled towards the anode. In that way, ions are pulled into the waste channels away from the resin bed itself. The purpose of the selectively permeable membranes is to funnel the ions into these waste channels or these concentrating compartments. The waste water is flushed away and the product water, the cleaned water, the purified water is collected from the diluting compartment that has passed through the central resin bed channel. By removing the ions from the resin bed, we get a continuous cleaning up of the resin bed and pulling away of the ions. At the same time the electric charge causes a splitting of some of the water molecules into hydrogen and hydroxyl ions which has the effect of replenishing the resin bed. So these EDI units can be operated on a continuous basis without having to worry about stopping the system for regeneration using caustic or corrosive chemicals like sodium hydroxide or hydrochloric acid. These EDI systems have become quite popular in large scale pharmaceutical manufacturing. Image(s): 1. Arar, O. et al. (2014, March 4). Electodeionisation process [Illustration]. Various Applications of Electrodeionization (EDI) Method for Water Treatment—A Short Review. https://www.sciencedirect.com/science/article/abs/pii/S0011916414000745 Tab 3: Distillation 20  Transcript Distillation is another process that can be used for water purification. This process can remove non-volatile impurities from the water. The simplest type of still that you can have is what's called a single stage or single effect still. In this case, the water is heated to boiling. So, it's converted from a liquid phase to a vapour phase, and the vapour is subsequently condensed by means of cooling coil and is collected. Anything that is less volatile than water will not be carried over in the vapour phase, or should not be carried over in the vapour phase and should therefore be eliminated or removed from the collected water. In some cases, a baffle is used in the still. The baffle comprises of some type of glass or stainless steel projections or rods that are at the top of the still and that meet with the vapour phase. The idea is that if there's any little droplets of water that are entrained in the vapour phase as it's boiling and as it's moving across towards the condenser, they will hit off these baffles and fall back down into the still, into the water that's being boiled up. So the purpose of the baffle is to stop water droplets being carried over because those water droplets, the liquid phase, may carry impurities that are non-volatile impurities. In saying that, dissolved, volatile components can travel over. So things like carbon dioxide, ammonia, chlorine and low molecular weight amines, anything that volatilises at a temperature that's lower than the boiling point of water will travel across in the vapour phase and can end up in the collected distilled water. 21  Transcript This schematic shows a simple distillation apparatus. Click on the image and take some time to study this diagram and read through the detailed steps in the distillation process. When you are ready, click Next to continue. Image(s): 1. Thermo Fisher Scientific Inc. (2010). Step-by-step Technologies Used in Distillation Systems [Illustration]. Barnstead Water Purification Stills. http://apps.thermoscientific.com/media/LPG/PDF/waterbook_stills.pdf Tab 3.1: Thermocompression: Greater Enerfy Efficiency Water purification by distillation is an expensive and energy inefficient process because you are removing a large volume of water from a generally small volume of contaminants. And by doing that, you have to put in enough energy to cause the water to change from a liquid into a vapour phase, which demands a lot of energy and makes the process very expensive. We can adjust the process, still using distillation, but make it a more energy efficient process. One way of doing that is to use what's called a vapour compression or thermocompression still, which is shown here. With a vapour compression still, when vapour condenses, it emits energy and that energy can be harnessed and used to heat the water that's coming into the still. This is one way of improving the energy efficiency of the process. Also, the vapour that's evolved is mechanically compressed and by doing so, we cause a rise in its temperature and generate steam. That steam can be used to heat the incoming water, again, improving the energy efficiency of the process. 22  Transcript In the vapour compression still shown, feed water is heated by a heating element but also by means of hot steam which is evolving from the centrifugal compressor. The hot steam is also what ends up being our distillate as it is condensed. Image(s): 1. Shono, C., Nong, M., Arboleda, N., Simons, C., Chuang, R., & Martin, I. (2016, January 9). Theoretical Design of an MVC Desalination System [Illustration]. Vapor Compression Desalination Proposal. https://docplayer.net/30068875-Vapor- compression-desalination-proposal.html Tab 3.2: Multiple Effect Still Another type of distillation process, that’s used particularly in the generation of Water for Injection, employs what's called a multiple effect still. Here, rather than having a single stage or a single effect where we heat the water, convert it into a vapour, condense that vapour and collect it, instead we have a number of different stages or a number of different effects where we have a sequence of vaporisations and partial condensations. Typically, you would have between three and seven stages or effects. In this diagram each of these stainless-steel columns is a single stage or a single effect. A multiple effect still contains a number of boiling columns (or effects, stills) with the first column, which is heated by external steam or electrical energy, producing pure steam, which is condensed and re-distilled in the following columns, decreasing the operational costs. The pure steam generated in each effect and the non-evaporated water are fed to the subsequent one. So in this case, the emerging vapour from one effect is used to heat the water in the next stage or the next effect, and each stage operates at a lower pressure than the one before it. Because it's operating at a lower pressure than the 23  Transcript one before it requires less heat input to get the water to boil and to be converted into a vapour. At each stage we will have a purer form of water then the preceding stage and so the purest grade of water is collected at the final stage where we allow our distilled water out. Image(s): 1. Meco Incorporated. (2021). Multiple Effects Still [Photograph]. Meco.com. https://www.meco.com/product/biopharmaceuticals-multiple-effect-stills Tab 4: Reverse Osmosis Another very commonly used technique to purify water is reverse osmosis. In reverse osmosis, or RO, the raw water, which could be potable water or it could be potable water that has already been subjected to some type of purification process, is fed into what's called a module or permeator that contains a semi-permeable membrane. In reverse osmosis, you apply a high pressure to the raw water. This exceeds the normal osmotic pressure and reverses the direction of normal osmotic flow, with the result that the water molecules are forced through the membrane, but impurities are left behind. What’s shown here is a semi-permeable reverse osmosis membrane. On one side of this reverse osmosis membrane is impure water, so we have water that contains a number of different types of impurities, as are listed here. And on the other side of the membrane, we have pure water that is cleaned of these contaminants. Now, the natural direction of movement would be for water to move from right to left to try and dilute this more concentrated water that contains the contaminants. If we want to get the movement to go from left to right and separate out the pure water from the contaminants, we have to apply a high enough pressure to this raw water that we 24  Transcript exceed the normal osmotic pressure, and cause the water to move in the other direction. So, we apply a very high pressure on this (left hand) side, forcing water through the small pores in the membrane. But the impurities can't pass through unless they're really very small in size. And so they are removed and drained away. Image(s): 1. Water Treatment. (n.d.). Reverse Osmosis Water Treatment Plant Process [Illustration]. The Water Treatments. https://www.thewatertreatments.com/water- treatment-filtration/reverse-osmosis-plant-ro-desalination/ Tab 4.1: The Use of Spiral Membranes Often you will have these reverse osmosis membranes presented in these modules as spirals, and the spiral effect increases the area that's available for the filtration process. The filtrate is referred to as the permeate and is the purified water. The contaminated stream is referred to as the concentrate. Reverse osmosis can remove a wide range of different types of contaminants including suspended solids, bacteria, fungi, viruses, and endotoxins. The efficiency of removal relates to the size of the contaminants. For carbohydrates, for example, there is a hundred percent rejection if the molecular weight is greater than 250 atomic units and for ions between 93 and 99 percent rejection, depending on the size. So larger ions will be more effectively removed from the water in a reverse osmosis separation process than will smaller ions. Image(s): 25  Transcript 1. Hansen, J. (2018, March 20). Spiral Wound Element Design [Illustration]. The Advantageous Upside to Pure Water. https://www.dultmeier.com/blog/high-pressure- cleaning/reverse-osmosis-advantages/ Slide 12: Other Water Purification Unit Processes Rarely do we use one water purification process on its own. Usually, we use a number of processes in combination or in sequence. So, for example, if we are using reverse osmosis as our main water purification process, we need to clean up the water quite a bit before it gets as far as the RO unit such that the RO membrane doesn't get overburdened or clogged too quickly with contaminants from the water. Click the tabs to learn about additional water purification unit processes. When you are ready, click “Next” to continue. 26  Transcript Tab 1: Filtration We can use cruder filtration steps in the water purification system and use filtration as a pre-treatment to remove suspended solids. We can also use what's called ultrafiltration, which will remove colloidal material. Tab 2: Water Softening We can use water softeners. With water softeners, we replace calcium and magnesium ions with sodium. So it's like an ion exchange process, but we're exchanging calcium and magnesium for sodium, adding two sodium ions for each calcium or magnesium ion. The purpose of this, what's referred to as sodium displacement, is to protect 27  Transcript downstream equipment from hard water. So, for example, if you're using a still and you're heating up the water, you don't want to get precipitation of insoluble calcium or magnesium carbonates from the hard water in the still, which will adversely affect the efficiency of the still. Sodium ions will be eventually removed sufficiently by other steps in the water purification process, which can be demonstrated by passing the water sample through a conductivity metre to test for water conductivity. Tab 3: Sanitisation In sanitisation, UV, chlorine and ozone can be used to remove microorganisms from the water. And so, for example, ozone can be added to a storage tank for microbial control. You can also use chlorine, which can be added to kill bacteria in a pre-treatment system. This is particularly important if the water is being held or is stagnant in any region of the purification system. If water is left to stand, it's more likely that it will become subject to microbial contamination. If you've added chlorine in an earlier step in the purification process to kill bacteria, subsequently, carbon adsorption filters can be used to remove that chlorine because it can damage some reverse osmosis membranes, those that are made of cellulose polymers. Thermal approaches to system sanitisation include periodically or continuously circulating hot water and the use of steam. Temperatures of 65°–80° are most commonly used for thermal sanitisation. Frequent use of thermal sanitisation at appropriate temperatures can eliminate the need for other sanitisation methods. 28  Transcript Slide 13: Example 1: Industrial Water Purification Systems This is an example of a water purification system that could be used to produce Purified Water of pharmacopoeial standard on an industrial scale. Drinking water or potable water comes in and passes through water softener tanks, and then through a pre filter. So, this would be a crude filtration process to remove suspended solids. The water then goes through a UV system, so it is exposed to UV light, and then it is pumped into a double reverse osmosis unit. So that means it goes through one reverse osmosis module and a second reverse osmosis module. Or it could go through a reverse osmosis module, followed by an electrodeionisation module, and then into a storage tank. The purified water then passes through another UV unit before being allowed exit to different outlets in the manufacturing facility. You’ll also see that there's also an ozone generation system here which can be used to feed into the storage tank or can be used to feed back to pre-treatment systems earlier in the overall water purification system to keep the system clean of microbial contamination. Image(s): 1. Stucki, S., Schulze, D., Schuster, D., & Stark, C. (2005). Flow diagram of a water treatment system [Illustration]. Semantic Scholar. https://www.semanticscholar.org/paper/Ozonization-of-Purified-Water-Systems-by-Dr-.- Stucki-Schulze/7ea3100211c4645b2fcbaade9db988a3f1335ea0/figure/2 29  Transcript Slide 14: Example 2: Industrial Water Purification Systems This is another example of a water purification system which can be used to produce purified water and also to produce water for injection, with the purified water, when it's produced, being sent to a still whereby it can be it can be made into water for injection. A water softener, reverse osmosis tank feeding into reverse osmosis units and then into a deionisation unit are used to prepare purified water, which is kept in a storage tank and then pumped around what's referred to as a distribution loop, where you have different outlet points feeding different parts of the manufacturing facility. The purified water could be used for washing equipment. It could be used for making up preparations or formulations and so on. Image(s): 1. Kremesti, R. E. (2017, September 23). Industrial Water Purification System [Illustration]. GMP Quality Ultra Pure Water for Pharmaceutical Industry. https://www.kremesti.com/water/water_for_pharma.htm 30  Transcript Slide 15: Controls and Tests in Industrial Plants In industrial plants the control and use of water supplies is of paramount importance, as is regular monitoring of water quality. Microbial contamination is a particular hazard requiring rigorous scrutiny of the design and operation of the plant. A variety of microbial and chemical tests are routinely carried out to monitor the performance of water purification systems and, in many instances, the 'in-house' standards far exceed the regulatory stipulations. Other resources which may be found in the extend section of the session home page should be consulted for further information relating, in particular, to water sampling, and to the operation, maintenance and control of water purification systems. Slide 16: Summary 31  Transcript Having completed this presentation, you should be able to: Differentiate between potable and Purified Water. List and explain the different classifications of Purified Water List and explain the different classifications of Water for Injection(s) Describe the different unit processes that can be used to generate Purified Water and Water for Injection(s) 32