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Water | Slide 1 of 44 January 2006 Water for Pharmaceutical Use Part 1: Introduction and treatment Supplementary Training Modules on Good Manufacturing.

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Presentation on theme: "Water | Slide 1 of 44 January 2006 Water for Pharmaceutical Use Part 1: Introduction and treatment Supplementary Training Modules on Good Manufacturing."— Presentation transcript:

1 Water | Slide 1 of 44 January 2006 Water for Pharmaceutical Use Part 1: Introduction and treatment Supplementary Training Modules on Good Manufacturing Practice WHO Technical Report Series No 929, Annex 3

2 Water | Slide 2 of 44 January 2006 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 Water for Pharmaceutical Use

3 Water | Slide 3 of 44 January 2006 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. Water for Pharmaceutical Use 1.1

4 Water | Slide 4 of 44 January 2006 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) Water for Pharmaceutical Use 1.3

5 Water | Slide 5 of 44 January 2006 Principles Like any starting material, production of water should conform to Good Manufacturing Practice (GMP) norms lPotential for microbial growth lSystems must be properly validated / qualified lWater for parenteral use should not be contaminated with pyrogens or endotoxins lSpecifications and periodic testing are required Water for Pharmaceutical Use

6 Water | Slide 6 of 44 January 2006 Why purify raw water? lAlthough reasonably pure, it is always variable due to seasonal variations, regional variation in water quality lMust remove impurities and control microbes to avoid contaminating products l Treatment depends on water’s chemistry and contaminants, influenced by, e.g. rainfall, erosion, pollution, dissolution, sedimentation, decomposition Water for Pharmaceutical Use

7 Water | Slide 7 of 44 January 2006 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 Water for Pharmaceutical Use

8 Water | Slide 8 of 44 January 2006 Contaminants of water (2) Problem minerals lCalcium, magnesium, copper, aluminium, heavy metals, arsenic, lead, cadmium, nitrates l Iron, manganese, silicates, carbon dioxide l Hydrogen sulfide l Phosphates Water for Pharmaceutical Use

9 Water | Slide 9 of 44 January 2006 Contaminants of water (3) Microorganisms – Biofilm formation l Protozoa –Cryptosporidium –Giardia l Bacteria –Pseudomonas –Gram negative, non-fermenting bacteria –Escherichia coli and coliforms Water for Pharmaceutical Use

10 Water | Slide 10 of 44 January 2006 Biofilm formation 1.Free-swimming aquatic bacteria use polymucosaccharides to colonize surfaces 2.Complex communities evolve which shed microcolonies and bacteria Water for Pharmaceutical Use

11 Water | Slide 11 of 44 January 2006 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" Water for Pharmaceutical Use 1.2

12 Water | Slide 12 of 44 January 2006 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 Water for Pharmaceutical Use 1.2

13 Water | Slide 13 of 44 January 2006 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 Water for Pharmaceutical Use 2.

14 Water | Slide 14 of 44 January 2006 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 Water for Pharmaceutical Use 2.

15 Water | Slide 15 of 44 January 2006 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) Water for Pharmaceutical Use 3.

16 Water | Slide 16 of 44 January 2006 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 Water for Pharmaceutical Use 3.2.

17 Water | Slide 17 of 44 January 2006 Drinking water: Natural sources could include springs, wells, rivers and lakes Treatment includes softening, ion removal, particle reduction, antimicrobial treatment 3.2 Water for Pharmaceutical Use

18 Water | Slide 18 of 44 January 2006 Purified Water (PW) Prepared from potable water source Meet pharmacopoeia specification for chemical and microbial purity Protected from recontamination Protected from microbial proliferation Water for Pharmaceutical Use 3.3.

19 Water | Slide 19 of 44 January 2006 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) Water for Pharmaceutical Use 3.4.

20 Water | Slide 20 of 44 January 2006 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 Water for Pharmaceutical Use 3.5

21 Water | Slide 21 of 44 January 2006 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 Water for Pharmaceutical Use 4.

22 Water | Slide 22 of 44 January 2006 Complete the table Water for Pharmaceutical Use 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?

23 Water | Slide 23 of 44 January 2006 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 Water for Pharmaceutical Use 5.1

24 Water | Slide 24 of 44 January 2006 Water purification system considerations Leaching from contact materials Adsorption Hygienic and sanitary design Corrosion resistance Leakage Proliferation of microbiological organisms Water for Pharmaceutical Use 5.1

25 Water | Slide 25 of 44 January 2006 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 Water for Pharmaceutical Use 5.1

26 Water | Slide 26 of 44 January 2006 Pre-treatment steps lPrimary filtration and multimedia filter l Coagulation or flocculation l Desalination l Softening Water for Pharmaceutical Use

27 Water | Slide 27 of 44 January 2006 Water for Pharmaceutical Use

28 Water | Slide 28 of 44 January 2006 Water pre-treatment complex in a pre- treatment room Water for Pharmaceutical Use

29 Water | Slide 29 of 44 January 2006 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 Water Softener – schematic drawing Water for Pharmaceutical Use

30 Water | Slide 30 of 44 January 2006 Chlorine removal (Activated-carbon (AC) filtration or bisulphite) lAC removes chlorine but bacteria can then grow lAC filtration can remove organic impurities lBisulphite leaves sulphate residues but is antimicrobial Water for Pharmaceutical Use

31 Water | Slide 31 of 44 January 2006 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 Water for Pharmaceutical Use 5.2

32 Water | Slide 32 of 44 January 2006 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 Water for Pharmaceutical Use 5.2

33 Water | Slide 33 of 44 January 2006 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 Water for Pharmaceutical Use 5.2

34 Water | Slide 34 of 44 January 2006 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 Water for Pharmaceutical Use 5.2

35 Water | Slide 35 of 44 January 2006 Water treatment purification stages downstream of the pre-treatment system may include: l Filtration l Disinfection l Reverse osmosis (RO) or deionization (DI) l Distillation or ultrafiltration Water for Pharmaceutical Use

36 Water | Slide 36 of 44 January 2006 Cationic column Anionic column Hygienic pump Outlets or storage. Ozone generator UV light HClNaOH Eluates to neutralization plant Air break to sewer Drain line from water softener Water must be kept circulating Typical deionizer schematic Return to deionizer Cartridge filter 5 µm Cartridge filter 1 µm Water for Pharmaceutical Use

37 Water | Slide 37 of 44 January 2006 raw water High pressure Feed water under pressure Reject water Semi-permeable membrane Permeate water drain or recycle Low pressure Purified water Reverse osmosis (RO) theory Water for Pharmaceutical Use

38 Water | Slide 38 of 44 January 2006 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 Water for Pharmaceutical Use

39 Water | Slide 39 of 44 January 2006 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) Water for Pharmaceutical Use

40 Water | Slide 40 of 44 January 2006 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 Water for Pharmaceutical Use 5.3

41 Water | Slide 41 of 44 January 2006 Production of Purified Water (2) Measurements: –Flow –Pressures –Temperature –Conductivity –pH –Total organic carbon (TOC), etc. Appropriately controlled, monitored, records maintained Water for Pharmaceutical Use 5.3

42 Water | Slide 42 of 44 January 2006 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) Water for Pharmaceutical Use 5.3

43 Water | Slide 43 of 44 January 2006 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 Water for Pharmaceutical Use 5.4

44 Water | Slide 44 of 44 January 2006 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) Water for Pharmaceutical Use 5.5


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