water for ap is amsavel
TRANSCRIPT
Water for Pharmaceutical useWater for Pharmaceutical use
Dr. A. AmsavelDr. A. Amsavel
IntIntroductionroduction
• Water is important material like any other Water is important material like any other reagent, itreagent, it
• Quality should conform to PharmacopeiasQuality should conform to Pharmacopeias• Systems must be properly validated / qualified to Systems must be properly validated / qualified to
meet GMP meet GMP • Potential for microbial growthPotential for microbial growth• Water for parenteral use should not be Water for parenteral use should not be
contaminated with pyrogens or endotoxinscontaminated with pyrogens or endotoxins• Specifications and periodic testing are requiredSpecifications and periodic testing are required
Why purify the water?Why purify the water?
• Quality always variable due to seasonal Quality always variable due to seasonal variations, regional variationvariations, regional variation
• Must remove impurities and Must remove impurities and controlcontrol microbesmicrobes to to avoid contaminating productsavoid contaminating products
• Treatment depends on water’s chemistry and Treatment depends on water’s chemistry and contaminants, influencedcontaminants, influenced by, e.g. by, e.g. rainfall, rainfall, erosion, erosion, pollution, pollution, dissolution, sedimentation, dissolution, sedimentation, decompositiondecomposition
Contaminants of waterContaminants of water
There is nThere is no pure water in natureo pure water in nature, as it can contain , as it can contain contaminantscontaminants
Contaminant groups:Contaminant groups:
– IInorganicnorganic compounds compounds
– OrOrgagannic compoundsic compounds
– Solids Solids
– GasesGases
– MicroorganismsMicroorganisms
Contaminants of water (Contaminants of water (22))
Possible Possible mineralsminerals o Calcium, magnesium, cCalcium, magnesium, copper, aluminium, heavy metals, opper, aluminium, heavy metals,
arsenic, lead, cadmium, nitratesarsenic, lead, cadmium, nitrateso Iron, manganese, silicates, carbon dioxideIron, manganese, silicates, carbon dioxideo Hydrogen sulfide , PhosphatesHydrogen sulfide , Phosphates
Microorganisms – Biofilm formationMicroorganisms – Biofilm formationo ProtozoaProtozoa
o CryptosporidiumCryptosporidium
o GiardiaGiardia
o BacteriaBacteria
– PseudomonasPseudomonas
– Gram negative, non-fermenting bacteriaGram negative, non-fermenting bacteria
– Escherichia coli and coliformsEscherichia coli and coliforms
Water requirement and useWater requirement and use
Water is the most widely used substance / Water is the most widely used substance / raw raw materialmaterial
Different grades of water Different grades of water used for different used for different stages:stages:
– Washing, preparation, synthesis, production, Washing, preparation, synthesis, production, formulation, controlformulation, control
Which grade of water is suitable for a Which grade of water is suitable for a particular stage? particular stage? – Consider nature and intended use of intermediate or Consider nature and intended use of intermediate or
finished product, and stage at which water is usedfinished product, and stage at which water is used
Water requirement and useWater requirement and use
Requirements:Requirements: EMEA "Note for guidance on the quality of water EMEA "Note for guidance on the quality of water
for pharmaceutical use“for pharmaceutical use“
USP <1231> Water For Pharmaceutical PurposeUSP <1231> Water For Pharmaceutical Purposess
Guide To Inspections Of High Purity Water Guide To Inspections Of High Purity Water Systems (FDA)Systems (FDA)
WHO guidelinesWHO guidelines
Water for Pharmaceutical use- IP 2007- p576Water for Pharmaceutical use- IP 2007- p576
Water requirements and useWater requirements and use
Control the quality of waterControl the quality of water– ProductionProduction– Storage and distributionStorage and distribution
Contaminants, microbial and chemical qualityContaminants, microbial and chemical quality
Microbial contamination risk and concernMicrobial contamination risk and concern
Water is used on demandWater is used on demand
– not subjected to testing and batch or lot release before not subjected to testing and batch or lot release before use, therefore has to meet specification "on demand" use, therefore has to meet specification "on demand" when usedwhen used
– Micro test results require incubation periodsMicro test results require incubation periods
Water quality specificationsWater quality specifications
Types of water:Types of water: Drinking water / potable waterDrinking water / potable water
Purified water (PW)Purified water (PW)
Highly Purified Water (HPW)Highly Purified Water (HPW)
Water for Injection (WFI)Water for Injection (WFI)
Other……Other……
Drinking water / potable waterDrinking water / potable water
Comply Comply with specification (WHO, ISO and with specification (WHO, ISO and national or regional agencies) – regular national or regional agencies) – regular testing neededtesting needed
Supply under continuousSupply under continuous positive pressure positive pressure
Defect free plumbing system to prevent Defect free plumbing system to prevent contaminationcontamination
Could be from public water supply system or Could be from public water supply system or natural sourcesnatural sources
Source water quality influences the treatment Source water quality influences the treatment requiredrequired
Purified water Spec as per IPPurified water Spec as per IP
Parameter Limit
Nature
Clear, Colourless, Odourless and tasteless
Acidity or Alkalinity Conform to the test
Ammonium NMT 0.2 ppm
Ca and MgConform to the test0.5ml of 0.01M EDTA
Heavy Metals (2.4.8) NMT 0.1 ppm
Chloride Conform to the test
Nitrates NMT 0.2 ppm
Conductivity ( at 25° C ) NMT 5.1 µS/cm µS/cm (EP)
Purified water Spec as per IPPurified water Spec as per IP
ParameterParameter LimitLimitSulphates Conform to the test
Oxid. Substances Conform to the test
Res. on Evaporation NMT 0.001%
Aluminium NMT 10ppb
Bioburden (2.6.12) NMT 100 cfu/ml
NMT 80 cfu/ml (alert limit)
Endotoxins (2.6.14) < 0.25 EU/ml
Purified Water (PW)Purified Water (PW)
Prepared from potable water sourcePrepared from potable water source
Meet pharmacopoeia specification for chemical Meet pharmacopoeia specification for chemical and microbial purityand microbial purity
Protected from recontaminationProtected from recontamination
Protected from microbial proliferationProtected from microbial proliferation
Quality of water Quality of water Purified Water (USP)Purified Water (USP)
Conductivity Conductivity ≤ 1.3 µS/cm @ 25º C ≤ 1.3 µS/cm @ 25º C 2.1 µS/cm2.1 µS/cm Total Organic Carbon (TOC) ≤ 500 ppbTotal Organic Carbon (TOC) ≤ 500 ppb Microbial ≤ 100 cfu/mlMicrobial ≤ 100 cfu/ml No endotoxin requirementNo endotoxin requirement
Water for Injection (WFI)Water for Injection (WFI)
Conductivity Conductivity ≤ 1.3 µS/cm @ 25º C≤ 1.3 µS/cm @ 25º C Total Organic Carbon (TOC) ≤ 500 ppbTotal Organic Carbon (TOC) ≤ 500 ppb Microbial ≤ 10 cfu / 100 mlMicrobial ≤ 10 cfu / 100 ml Endotoxin requirement < 0.25 EU/mlEndotoxin requirement < 0.25 EU/ml
Purified water Spec USP/EPPurified water Spec USP/EP
Parameter Limit
NatureClear, Colourless,
Odourless
pH 5 - 7
Conductivity ( at 25° C )NMT 2.1 µS/cm µS/cm (USP)NMT 5.1 µS/cm µS/cm (EP)
TOC < 0.5 ppm
NO3 NMT 0.2 ppm
NO2 Conform to the test
Heavy Metals (2.4.8) NMT 0.1 ppm
Acidity or Alkalinity Conform to the test
Oxid. Substances Conform to the test
Purified water Spec USP/EPPurified water Spec USP/EP
ParameterParameter LimitLimitChloride Conform to the test
Sulphate Conform to the test
Ammonium NMT 0.2 ppm
Ca / Mg Conform to the test
Res. on Evaporation NMT 0.001%
Bioburden (2.6.12) NMT 100 cfu/ml
NMT 80 cfu/ml (alert limit)
Endotoxins (2.6.14) < 0.25 EU/ml
TOC < 0.5 ppm
Water purification methodsWater purification methods
Manufacturer to select appropriate method of Manufacturer to select appropriate method of purification and sequence of purification stepspurification and sequence of purification steps
Basis;Basis;
– Water quality specificationWater quality specification
– Yield (efficiency) of the systemYield (efficiency) of the system
– Feed water qualityFeed water quality
– Reliability and robustness of treatment systemReliability and robustness of treatment system– Location and design of sampling pointsLocation and design of sampling points– Appropriate instrumentation for measurementsAppropriate instrumentation for measurements
– maintenance and operation maintenance and operation
Water system requirementsWater system requirements
Design, installation, commissioning, qualification / Design, installation, commissioning, qualification / validation, operation, performance and maintenance validation, operation, performance and maintenance to to ensure reliable, consistent production of water of ensure reliable, consistent production of water of required qualityrequired quality
Operate within design capacityOperate within design capacity
Prevent unacceptable microbial, chemical and Prevent unacceptable microbial, chemical and physical contamination during production, storage and physical contamination during production, storage and distributiondistribution
Quality Assurance involved in approval of use after Quality Assurance involved in approval of use after installation and maintenance workinstallation and maintenance work
Water system requirementsWater system requirements
Monitoring of water sources regularlyMonitoring of water sources regularly
– Chemical and microbiologicalChemical and microbiological
– Endotoxin level where relevantEndotoxin level where relevant
Monitoring of system performance, storage Monitoring of system performance, storage and distribution systemsand distribution systems
Records of results, and action takenRecords of results, and action taken
Validated sanitization procedure followed on a Validated sanitization procedure followed on a routine basisroutine basis
Typical water storage and distribution schematicTypical water storage and distribution schematic
Water must be kept
circulating
Spray ball
Cartridgefilter 1 µm
Air breakto drain
Outlets
Hygienic pump
Optionalin-line filter
0,2 µm
UV light
Feed Water from
DI or RO
Heat Exchanger
Ozone Generator
Hydrophobic air filter& burst disc
Sampling of purified waterSampling of purified water
– There must be a sampling procedure, planThere must be a sampling procedure, plan
– Sample integrity must be assuredSample integrity must be assured
– Sampler trainingSampler training
– Sample point Sample point
– Sample sizeSample size
– Sample container Sample container
– Sample labelSample label
– Sample storage and transportSample storage and transport
– Arrival at the laboratory Arrival at the laboratory
– Start of testStart of test
USP testsUSP tests
<643> Total Organic carbon <643> Total Organic carbon
<645> Water Conductivity <645> Water Conductivity
<791> pH<791> pH
<645> Water Conductivity <645> Water Conductivity The instrument must have a minimum resolution of 0.1 µS/cmThe instrument must have a minimum resolution of 0.1 µS/cm
Stage 1 Stage 1
Determine the temperature of the water and the conductivity Determine the temperature of the water and the conductivity
The measured conductivity should not be greater than the The measured conductivity should not be greater than the table value,table value,
If the conductivity is higher than the table value, proceed with If the conductivity is higher than the table value, proceed with Stage 2. Stage 2.
Temp (°C)
Conductivity Requirement
(µS/cm)
Temp(°C)
Conductivity Requirement
(µS/cm)
15 1.0 30 1.4
20 1.1 35 1.5
25 1.3 50 1.9
<645> Water Conductivity <645> Water Conductivity
Satge-2Satge-2
Transfer a sufficient amount of water (100 mL or Transfer a sufficient amount of water (100 mL or more) and stir. more) and stir.
Adjust the temperature, to 25 ± 1°C, agitate and Adjust the temperature, to 25 ± 1°C, agitate and periodically observe the conductivity. (change in periodically observe the conductivity. (change in conductivity (due to uptake of COconductivity (due to uptake of CO22) is less than ) is less than 0.1 µS/cm per 5 minutes, note the conductivity.0.1 µS/cm per 5 minutes, note the conductivity.
Conductivity must not greater than 2.1 µS/cm, Conductivity must not greater than 2.1 µS/cm,
If it is greater, proceed with Stage 3. If it is greater, proceed with Stage 3.
<645> Water Conductivity <645> Water Conductivity
Stage-3Stage-3
Add a saturated potassium chloride solution to the same Add a saturated potassium chloride solution to the same water sample (0.3 mL per 100 mL ), and determine the pH water sample (0.3 mL per 100 mL ), and determine the pH to the nearest 0.1 pH unitto the nearest 0.1 pH unit
Stage 3—pH and Conductivity Requirements Stage 3—pH and Conductivity Requirements
determine the conductivity limit at the measured pH value. determine the conductivity limit at the measured pH value. Should meet requirements. Should meet requirements.
If either the measured conductivity is greater than this 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 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. does not meet the requirements of the test for conductivity.
<645> Water Conductivity <645> Water Conductivity
pHpH Conductivity Conductivity Requirement (µS/cm)Requirement (µS/cm)
5.05.0 4.74.7
5.5 2.8
6.0 2.4
6.5 2.2
6.6 2.1
6.8 3.1
7.0 4.6
Water system ValidationWater system Validation
Phase-1 (2 - 4 Weeks)Phase-1 (2 - 4 Weeks)
Phase-2 (2 - 4 Weeks)Phase-2 (2 - 4 Weeks)
Phase-3 (52 Weeks)Phase-3 (52 Weeks)
Phase- I; ValidationPhase- I; Validation
To demonstrate production and delivery of To demonstrate production and delivery of produced water of the required quality and produced water of the required quality and quantity. quantity.
Develop and finalize operating, cleaning, Develop and finalize operating, cleaning, sanitizing and maintenance procedures.sanitizing and maintenance procedures.
Chemical and microbiological testing as Chemical and microbiological testing as per plan.per plan.– feed-water daily to verify its quality.feed-water daily to verify its quality.
– each step in the purification process daily.each step in the purification process daily.
– each point of use and at other pointseach point of use and at other points
Phase- I; ValidationPhase- I; Validation
Outcome of Phase –IOutcome of Phase –I
Use and or refine the SOPs for operation, Use and or refine the SOPs for operation, maintenance, sanitization procedure and maintenance, sanitization procedure and acceptance criteria to be finalized.acceptance criteria to be finalized.
Verify alert and action levels.Verify alert and action levels.
Develop and refine test-failure procedure.Develop and refine test-failure procedure.
Phase- II; ValidationPhase- II; Validation
The approach should:The approach should: To demonstrate consistent operation within To demonstrate consistent operation within
established ranges; andestablished ranges; and To demonstrate consistent production and To demonstrate consistent production and
delivery of water of the required quantity and delivery of water of the required quantity and quality, when operated according to SOPs.quality, when operated according to SOPs.
To demonstrate the water is meets the To demonstrate the water is meets the established acceptance criteria.established acceptance criteria.
Use same sampling scheme as in phase 1.Use same sampling scheme as in phase 1. Water can be used for manufacturing purposes Water can be used for manufacturing purposes
during this phase.during this phase.
Phase- III; ValidationPhase- III; Validation
To demonstrate extended reliable To demonstrate extended reliable performance to ensure that seasonal performance to ensure that seasonal variations are evaluated to meet the variations are evaluated to meet the established acceptance criteria are met for established acceptance criteria are met for a period of one year.a period of one year.
The sample locations, sampling The sample locations, sampling frequencies and tests should be reduced frequencies and tests should be reduced as per routine monitoring & testingas per routine monitoring & testing
Control and monitoringControl and monitoring Ambient temperature PW systems are susceptible to Ambient temperature PW systems are susceptible to
microbiological contamination – especially when static and microbiological contamination – especially when static and periods of low or no demandperiods of low or no demand
Controls may include:Controls may include:
– Maintain flow at all timesMaintain flow at all times
– Control temperature in the system ( <25 degrees Control temperature in the system ( <25 degrees Celsius)Celsius)
– UV disinfectionUV disinfection
– Water treatment components that can be thermally Water treatment components that can be thermally sanitizedsanitized
– Chemical sanitization (e.g. with ozone)Chemical sanitization (e.g. with ozone) chemical and microbiological attributes & trend chemical and microbiological attributes & trend
analysis.analysis. Appropriately controlled, monitored & maintain records Appropriately controlled, monitored & maintain records Regeneration and sanitizationRegeneration and sanitization