The document discusses water purification for pharmaceutical use. It describes various types of water (e.g. purified water, highly purified water, water for injection) and their specifications. The purification process involves multiple validation phases to demonstrate the system can consistently produce water meeting specifications. Quality must be controlled during production, storage and distribution to prevent microbial or chemical contamination.

1. Water for Pharmaceutical use Dr. A. Amsavel

2. Introduction Water is important material like any other reagent, it Quality should conform to Pharmacopeias Systems must be properly validated / qualified to meet GMP Potential for microbial growth Water for parenteral use should not be contaminated with pyrogens or endotoxins Specifications and periodic testing are required

3. Why purify the water? Quality always variable due to seasonal variations, regional variation 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

4. Contaminants of water There is no pure water in nature, as it can contain contaminants Contaminant groups: Inorganic compounds Organic compounds Solids Gases Microorganisms

5. Contaminants of water (2) Possible minerals Calcium, magnesium, c opper, aluminium, heavy metals, arsenic, lead, cadmium, nitrates Iron, manganese, silicates, carbon dioxide Hydrogen sulfide , Phosphates Microorganisms – Biofilm formation Protozoa Cryptosporidium Giardia Bacteria Pseudomonas Gram negative, non-fermenting bacteria Escherichia coli and coliforms

6. Water requirement and use Water is the most widely used substance / raw material Different grades of water used for different stages: 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

7. Water requirement and use Requirements: EMEA &quot;Note for guidance on the quality of water for pharmaceutical use“ USP <1231> Water For Pharmaceutical Purposes Guide To Inspections Of High Purity Water Systems (FDA) WHO guidelines Water for Pharmaceutical use- IP 2007- p576

8. Water requirements and use Control the 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 &quot;on demand&quot; when used Micro test results require incubation periods

9. Water quality specifications Types of water: Drinking water / potable water Purified water (PW) Highly Purified Water (HPW) Water for Injection (WFI) Other……

10. Drinking water / potable water Comply with specification (WHO, ISO and national or regional agencies) – regular testing needed Supply 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

11. Purified water Spec as per IP Conform to the test Chloride NMT 0.1 ppm Heavy Metals (2.4.8) Conform to the test 0.5ml of 0.01M EDTA Ca and Mg NMT 0.2 ppm Ammonium NMT 5.1 µS/cm (EP) Conductivity ( at 25° C ) NMT 0.2 ppm Nitrates Conform to the test Acidity or Alkalinity Clear, Colourless, Odourless and tasteless Nature Limit Parameter

12. Purified water Spec as per IP Conform to the test Oxid. Substances < 0.25 EU/ml Endotoxins (2.6.14) NMT 80 cfu/ml (alert limit) NMT 100 cfu/ml Bioburden (2.6.12) NMT 10ppb Aluminium NMT 0.001% Res. on Evaporation Conform to the test Sulphates Limit Parameter

13. Purified Water (PW) Prepared from potable water source Meet pharmacopoeia specification for chemical and microbial purity Protected from recontamination Protected from microbial proliferation

14. Quality of water Purified Water (USP) Conductivity ≤ 1.3 µS/cm @ 25º C 2.1 µS/cm Total Organic Carbon (TOC) ≤ 500 ppb Microbial ≤ 100 cfu/ml No endotoxin requirement Water for Injection (WFI) Conductivity ≤ 1.3 µS/cm @ 25º C Total Organic Carbon (TOC) ≤ 500 ppb Microbial ≤ 10 cfu / 100 ml Endotoxin requirement < 0.25 EU/ml

15. Purified water Spec USP/EP Conform to the test Oxid. Substances Conform to the test Acidity or Alkalinity NMT 0.1 ppm Heavy Metals (2.4.8) Conform to the test NO2 NMT 0.2 ppm NO3 < 0.5 ppm TOC NMT 2.1 µS/cm (USP) NMT 5.1 µS/cm (EP) Conductivity ( at 25° C ) 5 - 7 pH Clear, Colourless, Odourless Nature Limit Parameter

16. Purified water Spec USP/EP < 0.5 ppm TOC < 0.25 EU/ml Endotoxins (2.6.14) NMT 80 cfu/ml (alert limit) NMT 100 cfu/ml Bioburden (2.6.12) NMT 0.001% Res. on Evaporation Conform to the test Ca / Mg NMT 0.2 ppm Ammonium Conform to the test Sulphate Conform to the test Chloride Limit Parameter

17. Water purification methods Manufacturer to select appropriate method of purification and sequence of purification steps Basis; Water quality specification Yield (efficiency) of the system Feed water quality Reliability and robustness of treatment system Location and design of sampling points Appropriate instrumentation for measurements maintenance and operation

18. 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

19. Water system requirements 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

20. Typical water storage and distribution schematic Water must be kept circulating Spray ball Cartridge filter 1 µm Air break to drain Outlets Hygienic pump Optional in-line filter 0,2 µm UV light Feed Water from DI or RO Heat Exchanger Ozone Generator Hydrophobic air filter & burst disc

21. Sampling of purified water There must be a sampling procedure, plan Sample integrity must be assured Sampler training Sample point Sample size Sample container Sample label Sample storage and transport Arrival at the laboratory Start of test

22. USP tests <643> Total Organic carbon <645> Water Conductivity <791> pH

23. <645> Water Conductivity The instrument must have a minimum resolution of 0.1 µS/cm Stage 1 Determine the temperature of the water and the conductivity The measured conductivity should not be greater than the table value, If the conductivity is higher than the table value, proceed with Stage 2. 1.9 50 1.3 25 1.5 35 1.1 20 1.4 30 1.0 15 Conductivity Requirement (µS/cm) Temp (°C) Conductivity Requirement (µS/cm) Temp (°C)

24. <645> Water Conductivity Satge-2 Transfer a sufficient amount of water (100 mL or more) and stir. Adjust the temperature, to 25 ± 1°C, agitate and periodically observe the conductivity. (change in conductivity (due to uptake of CO 2 ) is less than 0.1 µS/cm per 5 minutes, note the conductivity. Conductivity must not greater than 2.1 µS/cm, If it is greater, proceed with Stage 3.

25. <645> Water Conductivity Stage-3 Add a saturated potassium chloride solution to the same water sample (0.3 mL per 100 mL ), and determine the pH to the nearest 0.1 pH unit Stage 3—pH and Conductivity Requirements determine the conductivity limit at the measured pH value. Should meet requirements. If either the measured conductivity is greater than this value or the pH is outside the range of 5.0 to 7.0, the water does not meet the requirements of the test for conductivity.

26. <645> Water Conductivity 2.8 5.5 2.4 6.0 2.2 6.5 2.1 6.6 3.1 6.8 4.6 7.0 4.7 5.0 Conductivity Requirement (µS/cm) pH

27. Water system Validation Phase-1 (2 - 4 Weeks) Phase-2 (2 - 4 Weeks) Phase-3 (52 Weeks)

28. Phase- I; Validation To demonstrate production and delivery of produced water of the required quality and quantity. Develop and finalize operating, cleaning, sanitizing and maintenance procedures. Chemical and microbiological testing as per plan. feed-water daily to verify its quality. each step in the purification process daily. each point of use and at other points

29. Phase- I; Validation Outcome of Phase –I Use and or refine the SOPs for operation, maintenance, sanitization procedure and acceptance criteria to be finalized. Verify alert and action levels. Develop and refine test-failure procedure.

30. Phase- II; Validation The approach should: To demonstrate consistent operation within established ranges; and To demonstrate consistent production and delivery of water of the required quantity and quality, when operated according to SOPs. To demonstrate the water is meets the established acceptance criteria. Use same sampling scheme as in phase 1. Water can be used for manufacturing purposes during this phase.

31. Phase- III; Validation To demonstrate extended reliable performance to ensure that seasonal variations are evaluated to meet the established acceptance criteria are met for a period of one year. The sample locations, sampling frequencies and tests should be reduced as per routine monitoring & testing

32. Control and monitoring 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) chemical and microbiological attributes & trend analysis. Appropriately controlled, monitored & maintain records Regeneration and sanitization