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PQ and Monitoring of WaterPQ and Monitoring of Water SystemsDawn TavalskyDeputy Director Cleaning Validation

Water in the Pharmaceutical World

Critical component in the manufacture of any drug product:

R i lRaw materialProcess ingredientCleaning agent

High likelihood to be source of contamination:

All life needs waterMi b ith littl t i t

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Microbes can grow with little nutrient encouragement, as long as there is water

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Where to turn for Validation Guidance?

USP <1231> Water for Pharmaceutical PurposesFDA Guide to Inspection of High Purity Water SystemsWater SystemsParenteral Drug Association Technical Report No. 4 titled, "Design Concepts for the Validation of a Water for Injection System."ISPE Good practice guide Commissioning and qualification of pharmaceutical water and steam systems40CFR141 Total Coliform RuleStandard Methods for the Examination of

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Standard Methods for the Examination of Water and Waste WaterUS FDA 483 Observations, Warning Letters, Recalls

USP <1231> Water for Pharmaceutical Purposes

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Validation of Water Systems

“A typical program involves intensive daily sampling and testing of major process points for at least one month after

ti l it i h b t bli h d f h itoperational criteria have been established for each unit operation, point of use, and sampling point”

USP Pharmacopeial Forum Vol. 30 (5) p1773

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Validation of Water Systems

IQ

OQ

PQPQ is executed by intensively monitoring the system over a period of 1 year and is typically structured into 3 phases Before

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period of 1 year and is typically structured into 3 phases. Before starting the PQ, the operational ranges and sanitizing cycles must be fixed based on the results of the OQ and then verified in the subsequent PQ.

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Validation of Water Systems

Sample Sites During PQRaw water and water immediately after the production system must be testedmust be tested. Sampling points after critical stages of production for qualification purposes must be considered, based on the system configuration and risk assessment. To prove effectiveness, samples are typically taken after carbon filters, deionizers, and before and after UV units.Well water must be tested and comply with drinking water regulation

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regulationThe Points of Use must be sampledAny additional System Monitoring Sites must be sampled

Validation of Water Systems

Performance Qualification Phase 1PQ Phase 1 is intended to demonstrate that the system operates within predetermined operating ranges and delivers water of the p p g grequired quality.

PQ Phase 1 usually lasts over a time period of 2 weeks to 4 weeks with daily sampling (representing worst case usage condition) for 10 to 20 working days at every monitoring point. Samples must be tested for the required microbiological and physicochemical parameters. All additional online-recording of TOC and Conductivity must be assessed in the respective validation report.

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Water produced during this period must not be used for regular production purposes.

The formal provisional release of the water system must be performed after the review and assessment of all available results obtained during this phase.

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Validation of Water Systems

Performance Qualification Phase 2The second phase is intended to demonstrate that the system consistently operates within predetermined operating ranges andconsistently operates within predetermined operating ranges and delivers water of the required quality, when it runs in accordance with the SOPs with consumptions representing production usage.

The sampling is performed daily in the same manner as in PQ Phase 1 for another period of 2 to 4 weeks with daily sampling for at least 10 to 20 working days at every monitoring point.

Water produced during PQ Phase 2 may be used for regular production purposes, provided that PQ Phase 1 was assessed

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p p p pand documented by QO to be successful and authorized for use.

If critical operating parameters (e.g. sanitization conditions) need to be changed during phases 1 and 2, consideration must be given to their possible repetition.

Validation of Water Systems

Performance Qualification Phase 3The PQ Phase 3 demonstrates that the water system, which is operating in accordance with the SOPs over a long period of timeoperating in accordance with the SOPs over a long period of time (at least 44 to 48 weeks), will consistently produce water of the required quality.

Microbiological sampling is performed (working) daily at a minimum of one monitoring point, with all monitoring points tested at least weekly. Physicochemical sampling is performed at least weekly from a selected monitoring point representing the whole system (e.g.

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the return to the tank). The PQ of the water system is completed, when data for a full year are obtained.

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Validation of Water Systems

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The validation of WFI systems must follow the approach as given in the table above. For PW and HPW Systems the approach shown above is highly recommended but may be adapted according to site usage and risk analysis assessment particularly in terms of sampling point frequencies.

ISPE Guide with Respect to WFI

Phase 1 and 2 (the first month)For the first month of sampling you test every point every dayday

Phase 3 (for the rest of the first year)"For WFI systems, the FDA Guide recommends sampling daily from a minimum of one point of use, with all points of use tested weekly."

After Phase 3No formal frequency recommendation, But, the agency

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would be looking for testing similar to Phase 3 unless you had a very good record and justification to reduce the sampling.

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Developing the Sampling Scheme

Begin with end in mindThere is no “one size fits all”fits all

Each situation is uniqueTaylor the analytical techniques to the final use of the water in the manufacturing process

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Microbial Water Validation Considerations

Most waterborne contaminants are Gram negative bacteria.We want quantification and qualification.E t i ti f lt i t f lt lExogenous contamination: faulty air vents, faulty seals, human interactionEndogenous contamination: colonization in resins, carbon beds, filter membranes, dead legs.Biofilm formation: microbes adaptation to survival in low nutrient environment.

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Sampling captures “planktonic” organisms shed from biofilm upstream.

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Sampling Considerations

How do I develop a sampling scheme that minimizes risk without “overdoing” it?

First – know the regulations/site policiesSecond – Evaluate the time and cost involved with additional samplingThird – Weigh the risk of getting a failing sample

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You HAVE to be a little strategic!!

Review Printed Time Estimation Sheet

Note: It takes more time than you might think when you y g yadd up all of the “minutes”

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Example List of Sample Sites

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Example Sample Scheme

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Example Sample Scheme

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Example Sample Scheme

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Sampling Instruction Considerations

Proper sampling equipmentDocument training of samplersFl hi ?Flushing?Do not spray alcohol prior to samplingTransfer hose?Refrigerate after 30 minutes, test within 24 hoursOOS? Not always the lab’s fault.

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Sampling Instruction Considerations

Include specific details on how to sample – photos are also often very helpful

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Example List of Sample Containers

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Example List of Sample Equipment

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Example Sample Instructions

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Example Sample Instructions

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Example Testing Specifications

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Heavy Metals?

USP justifies:NPDWR specs are very tightContemporary water systemconstruction materials do not leach heavy metalsNo failures in previous tests

Washington Post Article:1Questions veracity of local water authority testsOld infrastructure in old distribution systems leach lead

European Pharmaceopeia:Retains heavy metal requirement

Instrumentation

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InstrumentationAA or ICP allows for higher sensitivity.

Should at least document absence during commissioning.

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How long should microbial monitoring continue?

A water purification system is dynamic and changingI l fInternal factors:

Aging resinAging filtersAging UV lightsMaintenanceLeaksDead legs

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Biofilm formationProduction shifts

How long should microbial monitoring continue?

Seasonal VariationsW li h i hWater quality changes with seasonsAffected by temperatureDrought, flood

Wisconsin Cryptosporidium outbreak 1993:50 people died4000 people hospitalized403 000 people became ill

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403,000 people became illIneffective filtration failed to remove oocystsTurbid feed water slows disinfection

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What is a biofilm?

Unwanted adhesion of bacteria or other organisms onto surfaces of solution handling systemsN t il if i & tiNot necessarily uniform in space & timeMay contain significant amounts of inorganic materials held together by the polymeric matrix

(Charackis & Marshall, Biofilms, 1990)

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Biofilms

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Biofilms

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Biofilms

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Biofilms

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Biofilms

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