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