Supaporn Phumiamorn 17-18 Jan, 2006 Water System GMP course Supaporn Phumiamorn 17-18 Jan, 2006 เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Topic Water system - Objectives and Principles - Storage, Treatment - Contaminants, Sampling Water system inspection Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Objectives - Introduction to water for pharmaceutical use - Sources and types of water for pharmaceutical use - Storage of bulk, untreated raw water - Pre-treatment of water Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Principles Like any starting material, water must conform to GMP norms. It must be “potable and comply with WHO guidelines for drinking-water quality. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Principles Potential for microbial growth Systems must be properly validated Water for parenteral use could not be contaminated with pyrogens or endotoxins Specifications and periodic testing is required Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Water hardness Water hardness mg/L or ppm Classification as CaCO3 Soft 0-60 Moderate 61-120 Hard 121-180 Very hard >180 Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Raw water storage May be required prior to pre-treatment according to local circumstances Check material of construction - Concrete, steel are acceptable but check corrosion - Plastics or plastic linings may leach Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Raw water storage Check cover - to keep out insects, birds and animals Check contamination Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

pharmaceutical processes Types of water used in pharmaceutical processes Water for Injections – PFW & WFI Softened Water Water for Final Rinse Pure, or Clean Steam Purified Water Water for Cooling Autoclaves Water used as an ingredient in the formulation of pharmaceutical products must be either of the purified water type or must be water for injections. The most common type of water in use in a pharmaceutical factory is purified water. This is used as an ingredient for manufacture of non-sterile pharmaceuticals. It is described in pharmacopeias. The highest quality is Water For Injections. Water for Injections is used in parenteral products. It is also described in pharmacopeias. In bulk, this type of water is also called Pyrogen Free Water, or PFW, and if sterilized, it is called Sterilized Water for Injections. For other purposes, other types of water may also be used. Besides potable water, there is softened water, which has had its Calcium and Magnesium removed. Such a water can be used e.g. for first washing steps. Certain processes require special well-defined qualities of water. “Water for Final Rinse” is used for rinsing equipment after washing. It must be of the same quality as the water used for manufacturing the product. In some countries this can be prepared using different equipment to the ingredient water. For example, ultra-filtered water may be used for rinsing equipment for parenteral use, but WFI must be used as the parenteral ingredient. Pure, pyrogen-free steam (called Clean Steam) is needed for sterilization, if the steam comes into contact with parenteral product or equipment that is going to be used for preparing parenteral products. Steam, and Water for Cooling Autoclaves, are also used and must be properly prepared if they have the potential to come into contact with sterile or non-sterile product. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Pre-treatment steps Primary filtration and multi-media filter Coagulation of flocculation Desalination Softening Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Water pre-treatment complex External raw water storage These photographs illustrate initial raw water storage and softening. The top photograph shows a large scale storage tank, with automatic chlorine dosing. The bottom photograph shows a water pre-treatment room with a water softener in place. In the foreground is the zeolite exchange column and in the background are the brine tanks used to recharge the zeolite column. The equipment is well laid-out, and the water treatment room looks well-organized and clean. There do not appear to be any leaks from pumps or pipes. Please note it is important that equipment is tagged, lines are marked and labeled with direction of flow and instruments are calibrated. These rooms do not need to be environmentally controlled or the surfaces prescribed, but in this example the surfaces are smooth and impervious, which assists cleaning. The lighting levels should be good, allowing easy checking of instruments, recording of data and maintenance of equipment. Pretreatment room เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 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 anti-microbial. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Why purify raw water? Although reasonably pure, it is always variable Seasonal variations may occur in water Some regions have very poor quality water Must remove impurities to prevent product contamination. Control microbes to avoid contaminating products (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. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

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 Micro-organisms 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. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

Contaminants of water (2) Treatment depends on water’s chemistry and contaminants, influenced by: 1. Rainfall 5. Evaporation 2. Erosion 6. Sedimentation 3. Pollution 7. Decomposition 4. Dissolution Contaminants of water: (Contd.) The type of treatment is influenced by the impurities in water. These vary because of effects such as: Rainfall, which can dissolve acid from the atmosphere and pick up other contaminants, such as fouling from roofs upon which it collects; Erosion, which introduces minerals, clays and soils; Pollution, from the atmosphere and from groundwater contamination; Dissolution, whereby minerals and solids slowly dissolve in the stored water; Evaporation, which can concentrate and precipitate minerals; Sedimentation, whereby dissolved minerals re-precipitate and block pipes and filters; Decomposition, for example when contaminants arise from degraded pollutants. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

Contaminants of water (3) Problem minerals Calcium and magnesium Iron and 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. ) Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Contaminants of water (4) Further problem minerals Copper Aluminium Heavy metals Arsenic, lead, cadmium Nitrates Contaminants of water: (Contd.): Copper contamination can arise from corrosion of copper piping. Aluminium can pose a problem in the manufacture of dialysis products. It can be introduced from the flocculation treatment used to reduce sols and clays. Heavy metals, particularly arsenic, may be problematic in wells in certain areas. Lead contamination can arise from tanks which have had lead solder repairs. Lead pipes are not recommended. Cadmium can also be an issue depending on the where the aquifer percolates. Nitrates are an increasing problem for drinking water, but are easily removed by de-ionizers. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Contaminants of water (5) Micro-organisms – Biofilm Algae 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. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

Water is kept circulating Pretreatment – schematic drawing float operated valve To water softener & DI plant excess water recycled from deioniser activated carbon filter sand filter air filter spray ball Water is kept circulating raw water in break tank This schematic drawing is shown in handout 2-1-21 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. cartridge filter 5 micrometers centrifugal pump air break to drain « S” trap to sewer เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

Plumbing Source water chlorination 1.Filtration . Pre-treatment Distillation S S S S S Holding Take  80oc chlorination S 1.Filtration -Sand filter -Charcoal filter -Cartridge filter . S S Pump * S: Sampling 2. Primary water treatment Water solftener Deionizer Reverse Osmosis

Water Softener – schematic drawing brine and salt tank brine "hard" water in zeolite water softener exchanges Ca and Mg for Na drain "soft" water to deioniser by pass valve This schematic drawing give in handout 2-1-22. 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. เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

Water purification RO / Deionizer Cartridge filtration

Water purification Reverse Osmosis Remove particles, bacteria, pyrogen, organic, inorganic ions and silica

Water purification Deionization Remove organic, inorganic ions, silica and carbon dioxide

Water purification Distillation Remove particles, bacteria, pyrogen, organic, non-volatile, inorganic ions and silica for WFI

Water purification Ultrafiltration Kill bacteria and breakdown TOC

Auto DI RO/Auto DI 2 stages RO Purified water

-Conductivity meter - pH meter -Temperature meter(80oC) -Alarm meter

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Sampling There must be a sampling procedure. Sample integrity must be assured. Sampler training Sample point Sample size Sample container Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Sampling Sample label Sample storage and transport Arrival at the laboratory Start of test Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Water for Injections International pharmacopoeia requirements for WFI are those for purified water plus it must be free from pyrogens. Usually prepared by distillation. Storage time should be less than 24 hours. Microbial limits must be specified. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Pyrogens and endotoxins Any compound injected into mammals which gives rise to fever is a “Pyrogen”. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 WFI testing Microbial test, < 1 CFU/10 ml WFI Endotoxin test, < 0.25 Eu/ml Total organic count, < 500 g/l Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Water system inspection Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Inspection plan Water quality manual - water system drawing - validation - sampling procedures, location and plan - records of testing - sanitation and maintenance - schedules of maintenance Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Review water quality manual A water quality manual is advisable. A brief description of water systems is required. Include drawings of the purification, storage distribution system. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

The manual should contain Chemical and microbiological specifications Sampling instructions Test procedures Responsible persons Training requirements Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Review validation Validation for water systems consists of 3 phases: Phase 1: 2-3 weeks Phase 2: 4 weeks Phase 3: 1 year Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Phase 1 Investigational phase (2-4 weeks) - DQ, IQ and OQ - Develop - operational parameters - cleaning and sanitization procedures and frequencies - Sample daily at each point of use -End of phase 1, develop SOPs for the water system Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Phase 2 Verifying control (4- 5 weeks) - Demonstrate the system is in control -Sampling as in phase 1 Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Phase 3 Verifying long- term control ( 1 year) - Demonstrate the system in control over a long period of time -Weekly sampling Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Conducting the inspection Take the drawing and walk around the entire system Check: - dead legs - pumps -filter - UV light -pipe and fittings - sample points -DI - RO -storage tank - non return valves -by –pass lines - heat exchangers

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Check: - stainless steel – PVC and most plastics not recommended - water quality - hygienic couplings - passivation - air breaks or “Tundish” Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Check: - condition and equipment corrosion on plates of heat exchangers indicates possible contamination - maintenance records Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 Check: - air filter - integrity testing, sterilization - replacement frequency - burst discs Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006 References WHO,1997. Joint training on GMP for biological products in Thailand, 2-11 September, 1997 Chung Keel Lee, 2003. GMP and related topics, 13-15 October, 2003. Chung Keel Lee, 2004. Current GMP for biological products and its practical implementation, 22-23 March, 2004. FDA and WHO, 2004. GMP inspection workshop, 21-29 June, 2004. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006