World Health Organization

World Health Organization
12 April, 2017 Supplementary Training Modules on Good Manufacturing Practice Water for Pharmaceutical Use Part 1: Introduction and treatment In this section of the programme we are going to address all the issues relating to the quality management of pharmaceutical manufacturing. Note for the Trainer: these times are very approximate. As part of the preparation phase, the trainer will need to get an understanding of the audience and any special issues involved such as language ability. The times for the different sections may then have to be altered accordingly. The programme is approximately as follows: Presentation minutes Group session I minutes with 20 minutes for feedback Group session II minutes with 30 minutes feed back Test paper minutes The timing for the test paper allows 25 minutes for the test itself and the remaining time for a review of the answers. The timing is flexible since this is a very important area. We want to ensure that the participants really understand this subject. WHO Technical Report Series No 929, Annex 3

12 April, 2017 Water for Pharmaceutical Use Objective Water system requirements Water quality specifications Application of specific water to processes and dosage forms Water purification methods Storage and distribution systems Commissioning, qualification, operation and maintenance 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.

12 April, 2017 Water for Pharmaceutical Use Introduction Information on Water for Pharmaceutical Use (WPU) Quality of water for APIs, finished products, etc. GMP for design, installation, operation of systems Supplementary to general GMP guidelines See also other guidelines, pharmacopoeia, etc. 1. Introduction 1.1 Scope of the document The guidance contained in this document is intended to provide information about the available specifications for water for pharmaceutical use (WPU), guidance about which quality of water to use for specific applications, such as the manufacture of active pharmaceutical ingredients (APIs) and dosage forms, and to provide guidance on the good manufacturing practice (GMP) regarding the design, installation and operation of pharmaceutical water systems. Although the focus of this document is on water for pharmaceutical applications, the guidelines may also be relevant to other industrial or speci.c uses where the speci.cations and practices can be applied. The GMP guidance for WPU contained in this document is intended to be supplementary to the general GMP guidelines for pharmaceutical products published by WHO (WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-seventh report. Geneva, World Health Organization, 2003 (WHO Technical Report Series, No. 908), Annex 4). This document refers to available speci.cations, such as the pharmacopoeias and industry guidance for the use, production, storage and distribution of water in bulk form. In order to avoid confusion it does not attempt to duplicate such material. Note: This document does not cover waters for administration to patients in their formulated state or the use of small quantities of water in pharmacies to compound individually prescribed medicines. The guidance provided in this document can be used in whole or in part as appropriate to the application under consideration. Where subtle points of difference exist between pharmacopoeial speci.cations, the manufacturer will be expected to decide which option to choose in accordance with the related marketing authorization submitted to the national drug regulatory authority. 1.1

12 April, 2017 Water for Pharmaceutical Use Additional guidelines WHO Guideline for Drinking water quality (WHO) Water and steam systems (ISPE) Bioprocessing Equipment Standard (ASME – BPE 2000) European Pharmacopoeia, United States Pharmacopeia, International Pharmacopoeia Inspection of Utilities (PIC/S) 1.3 Applicable guides In addition to the speci.c guidance provided in this document, the Bibliography lists some relevant publications that can serve as additional background material when planning, installing and using systems intended to provide WPU. 1.3

12 April, 2017 Water for Pharmaceutical Use Principles Like any starting material, production of water should conform to Good Manufacturing Practice (GMP) norms Potential for microbial growth Systems must be properly validated / qualified Water for parenteral use should not be contaminated with pyrogens or endotoxins Specifications and periodic testing are required

12 April, 2017 Water for Pharmaceutical Use Why purify raw water? Although reasonably pure, it is always variable due to seasonal variations, regional variation in water quality Must remove impurities and control microbes to avoid contaminating products Treatment depends on water’s chemistry and contaminants, influenced by, e.g. rainfall, erosion, pollution, dissolution, sedimentation, decomposition (The trainer should emphasize that raw water, even from municipal supplies, needs to be purified before use for manufacture of pharmaceuticals, because the quality varies over time, according to seasonal variations and potable standards are not always met.) Although reasonably pure, raw water from the sources described previously can be of variable quality with potable water from some regions of very poor quality, by pharmaceutical standards. Seasonal variations may occur and contamination may vary. In some areas there are droughts and floods, in other areas winter, spring, autumn and summer weather can have an affect on raw water quality. In many countries even tap water is not safe to drink. Water from municipal reticulation systems needs to be purified because of variation in quality, microbial loads and natural seasonal variations. Manufacturers must remove impurities to prevent product contamination. It is also important to control microbes to avoid contaminating products.

12 April, 2017 Water for Pharmaceutical Use Contaminants of water (1) There is no pure water in nature, as it can contain up to 90 possible unacceptable contaminants Contaminant groups: Inorganic compounds Organic compounds Solids Gases Microorganisms 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.

12 April, 2017 Water for Pharmaceutical Use Contaminants of water (2) Problem minerals Calcium, magnesium, copper, aluminium, heavy metals, arsenic, lead, cadmium, nitrates Iron, manganese, silicates, carbon dioxide Hydrogen sulfide Phosphates Contaminants of water: (Contd.): Calcium and magnesium are probably the two most common mineral contaminants. They cause water hardness discussed in another slide. Heating or boiling water can precipitate these minerals leaving behind a scale deposit. Iron and manganese discolour water and can react with drug products, or act as catalysts in decomposition processes. Silicates may interfere with distillation equipment. Carbon dioxide picked up in the atmosphere can change the pH and hence the conductivity of water. Carbonates can cause precipitation of calcium, and carbonic acid can cause corrosion of water treatment systems. In areas of thermal activity, the water may be contaminated with sulphides, which even at low levels cause a rotten egg odour. Phosphates can also cause precipitation of metal ions and scaling, e.g. in boilers. (The trainer can also point out any local mineral-related contaminants that may be relevant in the region. For example, in some areas radioactive minerals may be a problem. )

12 April, 2017 Water for Pharmaceutical Use Contaminants of water (3) Microorganisms – Biofilm formation Protozoa Cryptosporidium Giardia Bacteria Pseudomonas Gram negative, non-fermenting bacteria Escherichia coli and coliforms 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.

12 April, 2017 Water for Pharmaceutical Use Biofilm formation Free-swimming aquatic bacteria use polymucosaccharides to colonize surfaces Complex communities evolve which shed microcolonies and bacteria Biofilm formation: This illustration is shown in handout 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.

12 April, 2017 Water for Pharmaceutical Use Background to water requirements and use Water is the most widely used substance / raw material Used in production, processing, formulation, cleaning, quality control Unique chemical properties Able to dissolve, absorb, adsorb, suspend compounds and contaminants Different grades of water quality available See also EMEA "Note for guidance on the quality of 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. 1.2

12 April, 2017 Water for Pharmaceutical Use Background to water requirements and use (2) Control quality of water Production Storage and distribution 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 1.2

12 April, 2017 Water for Pharmaceutical Use Water system requirements Design, installation, commissioning, qualification / validation, operation, performance and maintenance to ensure reliable, consistent production of water of required quality 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 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. 2.

12 April, 2017 Water for Pharmaceutical Use Water system requirements (2) Monitoring of water sources regularly Chemical and microbiological Endotoxin level where relevant Monitoring of system performance, storage and distribution systems Records of results, and action taken Validated sanitization procedure followed on a routine basis 2.

12 April, 2017 Water for Pharmaceutical Use Water quality specifications Here address water in bulk (not for patient administration) Specifications in pharmacopoeia – relevant to national or international recommendations. Types of water include: Drinking water / potable water Purified water (PW) Highly Purified Water (HPW) Water for Injection (WFI) 3. Water quality specifications 3.1 General The following requirements concern water processed, stored and distributed in bulk form. They do not cover the speci.cation of waters formulated for patient administration. Pharmacopoeias include specifications for both bulk and dosage-form waters. Pharmacopoeial requirements for WPU are described in national and international pharmacopoeias and limits for various contaminants are given. Companies wishing to supply multiple markets should set speci.cations that meet the strictest requirements from each of the relevant pharmacopoeias. 3.

12 April, 2017 Water for Pharmaceutical Use Drinking water / potable water Must comply with specification (WHO, ISO and national or regional agencies) – regular testing needed Supplied under continuous positive pressure Defect free plumbing system to prevent contamination Could be from public water supply system or natural sources Source water quality influences the treatment required 3.2 Drinking-water Drinking-water should be supplied under continuous positive pressure in a plumbing system free of any defects that could lead to contamination of any product. Drinking-water is unmodi.ed except for limited treatment of the water derived from a natural or stored source. Examples of natural sources include springs, wells, rivers, lakes and the sea. The condition of the source water will dictate the treatment required to render it safe for human consumption (drinking). Typical treatment includes softening, removal of speci.c ions, particle reduction and antimicrobial treatment. It is common for drinking-water to be derived from a public water supply that may be a combination of more than one of the natural sources listed above. It is also common for public water supply organizations to conduct tests and guarantee that the drinkingwater delivered is of potable quality. Drinking-water quality is covered by the WHO drinking-water guidelines, standards from the International Organization for Standardization (ISO) and other regional and national agencies. Drinking-water should comply with the relevant regulations laid down by the competent authority. If drinking-water is used directly in certain stages of pharmaceutical manufacture or is the feed-water for the production of higher qualities of WPU, then testing should be carried out periodically by the water user’s site to con.rm that the quality meets the standards required for potable water. 3.2.

Water for Pharmaceutical Use
World Health Organization 12 April, 2017 Water for Pharmaceutical Use Drinking water: Natural sources could include springs, wells, rivers and lakes Treatment includes softening, ion removal, particle reduction, antimicrobial treatment 3.2 Drinking-water Drinking-water should be supplied under continuous positive pressure in a plumbing system free of any defects that could lead to contamination of any product. Drinking-water is unmodi.ed except for limited treatment of the water derived from a natural or stored source. Examples of natural sources include springs, wells, rivers, lakes and the sea. The condition of the source water will dictate the treatment required to render it safe for human consumption (drinking). Typical treatment includes softening, removal of speci.c ions, particle reduction and antimicrobial treatment. It is common for drinking-water to be derived from a public water supply that may be a combination of more than one of the natural sources listed above. It is also common for public water supply organizations to conduct tests and guarantee that the drinkingwater delivered is of potable quality. Drinking-water quality is covered by the WHO drinking-water guidelines, standards from the International Organization for Standardization (ISO) and other regional and national agencies. Drinking-water should comply with the relevant regulations laid down by the competent authority. If drinking-water is used directly in certain stages of pharmaceutical manufacture or is the feed-water for the production of higher qualities of WPU, then testing should be carried out periodically by the water user’s site to con.rm that the quality meets the standards required for potable water. 3.2

12 April, 2017 Water for Pharmaceutical Use Purified Water (PW) Prepared from potable water source Meet pharmacopoeia specification for chemical and microbial purity Protected from recontamination Protected from microbial proliferation 3.3 Purified water 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. 3.3.

12 April, 2017 Water for Pharmaceutical Use Highly Purified Water (HPW) Prepared from potable water source 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) 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. 3.4.

12 April, 2017 Water for Pharmaceutical Use Water for Injections (WFI) Prepared from potable water source WFI is not sterile WFI is not a final dosage form WFI is an intermediate bulk product According to The International and European Pharmacopoeias – final purification step should be distillation 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. 3.5

12 April, 2017 Water for Pharmaceutical Use Application of specific water to processes and dosage forms Water used for different stages of: Washing, preparation, synthesis, production, formulation, control Which grade of water is suitable for a particular stage? Consider nature and intended use of intermediate or finished product, and stage at which water is used Let's look at types of water and indicate their use 4. Application of specific waters to processes and dosage forms Product licensing authorities de.ne the requirement to use the speci .c grades of WPU for different dosage forms or for different stages in washing, preparation, synthesis, manufacturing or formulation. The grade of water used should take into account the nature and intended use of the intermediate or .nished product and the stage in the manufacturing process at which the water is used. HPW can be used in the preparation of products when water of high quality (i.e. very low in microorganisms and endotoxins) is needed, but the process stage or product requirement does not include the constraint on the production method de.ned in some of the pharmacopoeial monographs for WFI. WFI should be used in injectable product preparations, for dissolving or diluting substances or preparations for parenteral administration before use, and for sterile water for preparation of injections. WFI should also be used for the .nal rinse after cleaning of equipment and components that come into contact with injectable products as well as for the .nal rinse in a washing process in which no subsequent thermal or chemical depyrogenization process is applied. When steam comes into contact with an injectable product in its .nal container, or equipment for preparing injectable products, it should conform with the speci.cation for WFI when condensed. 4.

12 April, 2017 Water for Pharmaceutical Use Complete the table Which type of water? Use ? Preparation of injectable products Final rinse of equipment after cleaning Final rinse of equipment and components that come into contact with injectable products HPW Potable water

12 April, 2017 Water for Pharmaceutical Use Water purification methods Manufacturer to select appropriate method of purification Appropriate sequence of purification steps Influenced by, e.g. Water quality specification Yield (efficiency) of the system Feed water quality Reliability and robustness of treatment system Supplier support, maintenance and operation costs 5. Water purification methods 5.1 General considerations The speci.cations for WPU found in compendia (e.g. pharmacopoeias) are generally not prescriptive as to permissible water puri.cation methods other than those for WFI (refer to section 3.5). The chosen water puri.cation method, or sequence of puri.cation steps, must be appropriate to the application in question. The following should be considered when selecting the water treatment method: — the water quality speci.cation; — the yield or ef.ciency of the puri.cation system; — feed-water quality and the variation over time (seasonal changes); — the reliability and robustness of the water-treatment equipment in operation; — the availability of water-treatment equipment on the market; — the ability to adequately support and maintain the water puri.cation equipment; and — the operation costs. The speci.cations for water puri.cation equipment, storage and distribution systems should take into account the following: — the risk of contamination from leachates from contact materials; — the adverse impact of adsorptive contact materials; — hygienic or sanitary design, where required; — corrosion resistance; — freedom from leakage; — con.guration to avoid proliferation of microbiological organisms; — tolerance to cleaning and sanitizing agents (thermal and chemical); — the system capacity and output requirements; and — the provision of all necessary instruments, test and sampling points to allow all the relevant critical quality parameters of the complete system to be monitored. The design, con.guration and layout of the water puri.cation equipment, storage and distribution systems should also take into account the following physical considerations: — the space available for the installation; — structural loadings on buildings; — the provision of adequate access for maintenance; and — the ability to safely handle regeneration and sanitization chemicals. 5.1

12 April, 2017 Water for Pharmaceutical Use Water purification system considerations Leaching from contact materials Adsorption Hygienic and sanitary design Corrosion resistance Leakage Proliferation of microbiological organisms 5.1

12 April, 2017 Water for Pharmaceutical Use Water purification system considerations (2) Tolerance to cleaning and sanitizing agents Capacity and output capability Instruments, sensors, controls, sampling points Space needed for installation and structural loading of premises Access needed for maintenance Regeneration and sanitization 5.1

12 April, 2017 Water for Pharmaceutical Use Pre-treatment steps Primary filtration and multimedia filter Coagulation or flocculation Desalination Softening A typical water pre-treatment system involves several steps, from physical removal of impurities to chemical treatment. Water is passed through coarse filters or screens to remove sticks, leaves and other large objects. Sand and grit settle out of the water during this stage. Next is filtration with a multi-media filter. The different media types are effective at removing suspended solids at sizes as small as 5 to 10 micrometers. Some manufacturers may simply use a sand filter. All these filter types need to be periodically back-washed. Flocculation, coagulation, and sedimentation are the subsequent treatments. During coagulation, aluminium or iron sulphate is added to the raw water, forming sticky elements that attach to small particles made up of bacteria, silt and other impurities. This “floc” sinks. This is called flocculation, sedimentation and clarification. Manufacturers who source their own water should have as a minimum screens and sand filters before further purification. Desalination is sometimes used by manufacturers to remove sodium chloride if only brackish water is available. Softening, to remove “hardness” due to calcium and magnesium, is covered in greater detail in some of the following slides.

12 April, 2017 Water for Pharmaceutical Use raw water in « S” trap to sewer Water is kept circulating To water softener & DI plant Pretreatment – schematic drawing cartridge filter 5 micrometers activated carbon spray ball break tank air break to drain centrifugal pump air filter float operated valve sand filter excess water recycled from deioniser This schematic drawing is shown in handout and illustrates a typical storage and preliminary treatment system for water. Raw water arrives into a buffer or break tank via a level controlled valve. If there are further stages of treatment (such as DI or RO), the tank does not, generally, have to have sophisticated spray balls or air filters. The water is pumped through a sand filter to remove large particles. This filter must be fitted with a back-flush facility, not shown here. The water then enters an activated carbon (AC) filter which removes organic impurities and chlorine. The AC filter can become heavily contaminated with bacteria. There should be some means of sanitizing it, such as a steam supply. Chemicals are generally not used to disinfect activated carbon filters. The water is then “polished” through a 5 micron filter before it enters the next treatment step. If there is no demand for the water it must be re-circulated to the buffer tank. Water that is kept constantly circulating is less likely to grow bacteria, because they cannot settle and form a “biofilm”. All equipment such as pumps, pipes and tanks should be stainless steel wherever possible. Plastic should be avoided. Plasticizers may leach and this can result in out-of-specification Total Organic Carbon (TOC) levels. Adhesives used for welding plastic pipes may also leach into the water and cause problems.

Water for Pharmaceutical Use
Water pre-treatment complex in a pre-treatment room

12 April, 2017 Water for Pharmaceutical Use Water Softener – schematic drawing by pass valve "soft" water to deioniser brine and salt tank brine zeolite water softener exchanges Ca and Mg for Na This schematic drawing give in handout If the pharmaceutical manufacturer’s water supply is “hard” it needs to be “softened” by removal of calcium and magnesium salts. Water is softened in a zeolite exchange column where the calcium and magnesium ions are exchanged for sodium. The sodium then has to be removed by de-ionization or reverse osmosis. When the zeolite reaches its exchange limit, it needs to be stripped of calcium and magnesium. This can be done using a brine solution, which exchanges sodium for calcium and magnesium, and the cycle starts again. The inspectors should ensure that there is a proper procedure for the regeneration of the unit, and that the system is properly monitored and sanitized. The frequency of regeneration is something that the inspectors should ask the manufacturer to justify. "hard" water in drain

12 April, 2017 Water for Pharmaceutical Use Chlorine removal (Activated-carbon (AC) filtration or bisulphite) AC removes chlorine but bacteria can then grow AC filtration can remove organic impurities Bisulphite leaves sulphate residues but is antimicrobial Dechlorination of municipal water (or where chlorine is added to storage tanks) needs to be done; with either activated carbon (AC) filtration or bisulphite injection. While AC filters reduce chlorine levels, the carbon provides an environment which is conducive to the growth of micro-organisms because of the huge surface area and the ready availability of nutrients. The carbon bed should be sanitised daily if possible. At a minimum, the bed should be sanitised weekly. Steam is useful for disinfecting the AC filters. AC filters are also useful in removing organic contaminants. The advantage of using bisulphite is that it does not facilitate microbial growth as does an AC filter. It is also less costly than AC. When bisulphite is injected into the process stream, it is oxidised to sulphate, and it also reduces free chlorine to the chloride ion. The by-products, sulphate and chloride, are removed or reduced by a de-ionizer or an RO system. Note that bisulphite does not remove organic contaminants, whereas AC does remove organic contaminants.

12 April, 2017 Water for Pharmaceutical Use Production of drinking water Derived from raw water (e.g. well, river, reservoir) Processes may include: Filtration, softening Disinfection or sanitization Iron (ferrous) removal Precipitation Inorganic / organic reduction 5.2 Production of drinking-water Drinking-water is derived from a raw water source such as a well, river or reservoir. There are no prescribed methods for the treatment of raw water to produce potable drinking-water from a speci.c raw water source. Typical processes employed at a user plant or by a water supply authority include: — .ltration; — softening; — disinfection or sanitization (e.g. by sodium hypochlorite (chlorine) injection); — iron (ferrous) removal; — precipitation; and — reduction of speci.c inorganic/organic materials. The drinking-water quality should be monitored routinely. Additional testing should be considered if there is any change in the raw-water source, treatment techniques or system con.guration. If the drinking-water quality changes signi.cantly, the direct use of this water as a WPU, or as the feed-water to downstream treatment stages, should be reviewed and the result of the review documented. Where drinking-water is derived from an “in-house” system for the treatment of raw water, the water-treatment steps used and the system con.guration should be documented. Changes to the system or its operation should not be made until a review has been completed and the change approved by the QA department. Where drinking-water is stored and distributed by the user, the storage systems must not allow degradation of the water quality before use. After any such storage, testing should be carried out routinely in accordance with a de.ned method. Where water is stored, its use should ensure a turnover of the stored water suf.cient to prevent stagnation. The drinking-water system is usually considered to be an “indirect impact system” and does not need to be quali.ed. Drinking-water purchased in bulk and transported to the user by tanker presents special problems and risks not associated with potable water delivered by pipeline. Vendor assessment and authorized certi.cation activities, including con.rmation of the acceptability of the delivery vehicle, should be undertaken in a similar way to that used for any other starting material. Equipment and systems used to produce drinking-water should be able to be drained and sanitized. Storage tanks should be closed with appropriately protected vents, allow for visual inspection and for being drained and sanitized. Distribution pipework should be able to be drained, or .ushed, and sanitized. Special care should be taken to control microbiological contamination of sand .lters, carbon beds and water softeners. Once microorganisms have infected a system, the contamination can rapidly form bio.lms and spread throughout the system. Techniques for controlling contamination such as back-.ushing, chemical or thermal sanitization and frequent regeneration should be considered. Additionally, all water-treatment components should be maintained with continuous water .ow to inhibit microbial growth. 5.2

12 April, 2017 Water for Pharmaceutical Use Production of drinking water (2) When done "in-house" – steps used and system configuration documented, and water quality routinely monitored Change control in case of changes to system Storage of water: no degradation, ensure turnover, routine testing "indirect impact system" – qualification not needed 5.2

12 April, 2017 Water for Pharmaceutical Use Production of drinking water (3) System permits draining and sanitization Storage tanks: Closed, with protected vents Allows visual inspection, draining and sanitization Care to prevent and control microbiological contamination of sand filters, carbon beds, water softeners Back-flushing, chemical or thermal sanitization and frequent regeneration, continuous waterflow 5.2

12 April, 2017 Water for Pharmaceutical Use Production of drinking water (4) Drinking water supplied by tanker – associated problems and risks Required vendor assessment Authorized certification activities Acceptability of delivery vehicle As receiving any other starting material 5.2

12 April, 2017 Water for Pharmaceutical Use Water treatment purification stages downstream of the pre-treatment system may include: Filtration Disinfection Reverse osmosis (RO) or deionization (DI) Distillation or ultrafiltration Water treatment purification stages: Water needs to be further purified after the pretreatment phase discussed in Part 1. Filtration is needed to remove particulates (that may have been shed by softeners and downstream equipment) and micro-organisms, which always tend to exploit any environmental niche. Disinfection is necessary because water systems are required to be sanitary, but not sterile. The commonly used disinfection agents are heat, UV, ozone, chlorine, and peroxygen products. More information on these agents is provided at the end of Part 2. Reverse osmosis (RO) or de-ionisation (DI) are the most common methods for preparing Purified Water that meets pharmacopoeia requirements for pharmaceutical manufacturing. Due to increased pharmacopeia requirements for resistivity, it is frequently necessary to have two consecutive RO treatments (two-stage RO), whereby the second RO passage can be replaced by a “continuous de-ionization” or “electro- de-ionisation” (CDI or EDI). RO and/or DI treated water is also used as the feed for further purification by distillation or ultra-filtration (UF) for the preparation of water for injections, which is needed for high risk products.

12 April, 2017 Water for Pharmaceutical Use Cationic column Anionic column Hygienic pump Outlets or storage. Ozone generator UV light HCl NaOH Eluates to neutralization plant Air break to sewer Drain line from water softener Water must be kept circulating Typical deionizer schematic 1 2 3 4 5 6 Return to deionizer Cartridge filter 5 µm filter 1 µm This schematic drawing of a typical de-ionizer is given in handout Use it to explain the pathway of water through a twin bed de-ionizer. Softened water enters at the top right into the twin bed de-ionizer. Cation and anion exchange agents are resins with large surface areas. Cations are exchanged for H+, anions for OH-, the combination is H-OH, or water! After Cation and anion exchange, the water is filtered (to remove resin particles and sometimes bacteria) before being re-circulated through the distribution system and returned to the de-ionizer, usually via a buffer tank. The Cation and anion resins are regenerated using hydrochloric acid and sodium hydroxide respectively. There should be specifications available for these two materials for the inspector to check. Mixed bed de-ionizers are also common. They may be more prone to bacterial contamination and so the inspector should check them carefully. They should be disinfected at regular intervals. Heat is not a option, because of the resin material. Furthermore, many of the de-ionizers are made of plastic materials. However, the regenerating chemicals are very effective biocides and so the system should be regenerated frequently, at least once a week, regardless of the conductivity readings. Inspectors should ask for the sanitation records so that these can be checked. Disinfection of the circulating water is necessary; this can be achieved by inline UV irradiation and or ozonization.

12 April, 2017 Water for Pharmaceutical Use Reverse osmosis (RO) theory raw water High pressure Feed water under pressure Reject Semi-permeable membrane Permeate drain or recycle Low pressure Purified water High salt solutions will draw water from low salt solutions if they are separated by a semi-permeable membrane, until an equilibrium is achieved. The height of the column of water that results is the osmotic pressure. Conversely, if pressure is applied above the osmotic pressure, pure water will be driven the other way through the membrane. This is called reverse osmosis (RO). Ions and particles are left behind in the reject water. Water is continuously passed over the membrane with the reject water being recycled or sent to drain. Although the “permeate“ is purified, it may need to undergo a second RO stage to meet pharmacopeia specifications, as far as resistivity is concerned.

12 April, 2017 Water for Pharmaceutical Use Branch 2nd stage buffer tank Cartridge filter 1 µm Second stage RO cartridge First stage filtrate feeds second stage RO with excess back to 1st stage buffer tank . 1st stage reject concentrate Air break to sewer Second stage reject water goes back to first stage buffer tank Second stage RO water meets Pharmacopoeia standards Outlets or storage 1st stage buffer tank Water from softener or de-ioniser Water returns to 1st stage buffer tank Typical 2-stage RO schematic Hygienic pump First stage RO cartridge High pressure pump This schematic drawing of a typical Reverse Osmosis (RO) system is included in handout Use it to explain the pathway of water through a two-stage RO. Softened water enters the 1st stage buffer tank and is passed under pressure (achieved by a series of hygienic pumps) across the membrane in the first stage cartridge. The first stage filtrate feeds into the 2nd stage buffer tank. The 1st stage reject water is discarded, or can be collected and used, for example, for washing floors and walls. Water from the 2nd stage buffer tank is forced under pressure across a 2nd series of membranes in the second stage RO cartridge. The 2nd stage filtrate (also called the permeate) can be used for pharmaceutical manufacturing. It should be re-circulated through the distribution system and back to 1st stage buffer tank. The 2nd stage reject water is also returned to the 1st stage buffer tank. In-line filters in both stages remove particulates. However, the membrane may still foul, and so has to be back-washed periodically, usually on an automatic cycle. Bacteria can grow in the system, as well as on and through the membrane, so the RO system needs to be periodically sanitized. Because of the plastics used (eg. in the membrane), heat is usually not an option. Some RO membranes can, however, be heat sanitized. Peroxygen products (such as hydrogen peroxide or peracetic acid) are preferred, but some membranes are able to tolerate chlorine. Inspectors should ask for back-wash and sanitation records.

12 April, 2017 Water for Pharmaceutical Use Use of reverse osmosis Advantages Disadvantages Many uses purified water feeding of distillation units or ultrafiltration units Water for Final Rinse Water for Injections (if permissible) Use of Reverse Osmosis: Advantages of RO: Less chemical handling than ion exchange More effective microbial control than ion exchange Integrity test possible Removes most of organic and non-organic contaminants Less energy consumption than distillation Disadvantages of RO: Water consumption higher than IE unless waste-water is re-used Danger of microbial growth on membrane Sterilization/sanitization with steam not possible No removal of dissolved gases Working at high temperature (>65 °C) only possible with certain types of membrane Uses of RO: Purified water that meets Pharmacopoeia specifications Feeding of distillation units– prevents scaling and ensures quality WFI Water for Final Rinse Water for Injection – only if permitted by local regulations

12 April, 2017 Water for Pharmaceutical Use Production of Purified Water (PW) Use appropriate, qualified methods for production Factors to consider: Feed water quality and required water quality specification Sequence of purification stages needed Energy consumption, extent of pre-treatment needed Yield and efficiency of unit treatment steps Location and design of sampling points Appropriate instrumentation for measurements 5.3 Production of purified water There are no prescribed methods for the production of PW in the pharmacopoeias. Any appropriate quali.ed puri.cation technique or sequence of techniques may be used to prepare PW. Typically ion exchange, ultra.ltration and/or reverse osmosis processes are used. Distillation can also be used. The following should be considered when con.guring a water purification system: — the feed-water quality and its variation over seasons; — the required water-quality speci.cation; — the sequence of puri.cation stages required; — the energy consumption; — the extent of pretreatment required to protect the .nal puri.cationsteps; — performance optimization, including yield and ef.ciency of unit treatment-process steps; — appropriately located sampling points designed in such a way as to avoid potential contamination; and unit process steps should be provided with appropriate instrumentation to measure parameters such as .ow, pressure, temperature, conductivity, pH and total organic carbon. Ambient-temperature PW systems are especially susceptible to microbiological contamination, particularly when equipment is static during periods of no or low demand for water. It is essential to consider the mechanisms for microbiological control and sanitization. The following techniques should be considered: — maintenance of .ow through water-puri.cation equipment at all times; — control of temperature in the system by pipeline heat exchange or plant-room cooling to reduce the risk of microbial growth (guidance value <25 °C); — provision of ultraviolet disinfection; — selection of water-treatment components that can be thermally sanitized; and/or — application of chemical sanitization (including agents such as ozone). 5.3

12 April, 2017 Water for Pharmaceutical Use Production of Purified Water (2) Measurements: Flow Pressures Temperature Conductivity pH Total organic carbon (TOC), etc. Appropriately controlled, monitored, records maintained 5.3

12 April, 2017 Water for Pharmaceutical Use Production of Purified Water (3) Ambient temperature PW systems are susceptible to microbiological contamination – especially when static and periods of low or no demand Controls may include: Maintain flow at all times Control temperature in the system ( <25 degrees Celsius) UV disinfection Water treatment components that can be thermally sanitized Chemical sanitization (e.g. with ozone) 5.3

12 April, 2017 Water for Pharmaceutical Use Production of Highly Purified Water (HPW) Use appropriate, qualified methods for production Appropriate sequence of techniques As for PW Processes may include: Ion exchange Ultrafiltration Reverse Osmosis 5.4 Production of highly purified water There are no prescribed methods for the production of HPW in any major pharmacopoeia, including the European Pharmacopoeia. Any appropriate quali.ed puri.cation technique or sequence of techniques may be used to prepare HPW. Typically ion exchange, ultra.ltration and/or reverse osmosis processes are used. The guidance provided in section 5.3 for PW is equally applicable to HPW. 5.4

12 April, 2017 Water for Pharmaceutical Use Production of Water for Injections (WFI) Pharmacopoeia requires distillation as preferred technique for final purification step Factors to consider: Feed water quality Required water quality specification Optimum generator sizing (prevent frequent start/stop) Blow-down and dump functions Cool-down venting (avoid contamination ingress) 5.5 Production of water for injections The pharmacopoeias prescribe or limit the permitted .nal water puri.cation stage in the production of WFI. Distillation is the preferred technique; it is considered a more robust technique based on phase change, and in some cases, high temperature operation of the process equipment. The following should be considered when designing a water puri.cation system: — the feed-water quality; — the required water quality speci.cation; — the optimum generator size to avoid over-frequent start/stop cycling; — blow-down and dump functions; and — cool-down venting to avoid contamination ingress. 5.5

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