Slide1 : Water for Pharmaceutical Use
Part 1: Introduction and treatment Supplementary Training Modules on Good Manufacturing Practice WHO Technical Report Series No 929, 2005. Annex 3
Slide2 : 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
Slide3 : 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
Slide4 : 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
Slide5 : 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 Water for Pharmaceutical Use
Slide6 : 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 Water for Pharmaceutical Use
Slide7 : 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
Slide8 : Contaminants of water (2)
Problem minerals
Calcium, magnesium, copper, aluminium, heavy metals, arsenic, lead, cadmium, nitrates
Iron, manganese, silicates, carbon dioxide
Hydrogen sulfide
Phosphates Water for Pharmaceutical Use
Slide9 : Contaminants of water (3)
Microorganisms – Biofilm formation
Protozoa
Cryptosporidium
Giardia
Bacteria
Pseudomonas
Gram negative, non-fermenting bacteria
Escherichia coli and coliforms Water for Pharmaceutical Use
Slide10 : Biofilm formation
Free-swimming aquatic bacteria use polymucosaccharides to colonize surfaces
Complex communities evolve which shed microcolonies and bacteria Water for Pharmaceutical Use
Slide11 : 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
Slide12 : 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
Slide13 : 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.
Slide14 : 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.
Slide15 : 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.
Slide16 : 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.
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 Water for Pharmaceutical Use
Slide18 : 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.
Slide19 : 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.
Slide20 : 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
Slide21 : 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.
Slide22 : Complete the table
Water for Pharmaceutical Use
Slide23 : 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
Slide24 : 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
Slide25 : 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
Slide26 : Pre-treatment steps
Primary filtration and multimedia filter
Coagulation or flocculation
Desalination
Softening Water for Pharmaceutical Use
Slide27 : Water for Pharmaceutical Use
Water for Pharmaceutical Use :
Water pre-treatment complex in a pre-treatment room
Water for Pharmaceutical Use
Slide29 : brine and salt tank brine drain by pass valve Water Softener – schematic drawing Water for Pharmaceutical Use
Slide30 : 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 Water for Pharmaceutical Use
Slide31 : 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
Slide32 : 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
Slide33 : 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
Slide34 : 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
Slide35 : Water treatment purification stages downstream of the pre-treatment system may include:
Filtration
Disinfection
Reverse osmosis (RO) or deionization (DI)
Distillation or ultrafiltration Water for Pharmaceutical Use
Slide36 : Water for Pharmaceutical Use
Slide37 : Reverse osmosis (RO) theory Water for Pharmaceutical Use
Slide38 : Water for Pharmaceutical Use
Slide39 : 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
Slide40 : 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
Slide41 : 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
Slide42 : 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
Slide43 : 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
Slide44 : 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