Pharmaceutical Water Systems Monitoring Approaches 16_Tavalsky Bonus.pdf · Pharmaceutical Water Systems –Monitoring Approaches Dawn Tavalsky Sanofi Pasteur and Karen S Ginsbury

Pharmaceutical Water Systems – Monitoring Approaches

Dawn Tavalsky

Sanofi Pasteur

and

Karen S Ginsbury

PCI Pharmaceutical Consulting Israel Ltd

To be discussed…

I. Pharmaceutical Water —Definitions and General Overview

Potable and purified water

Highly purified water

Water for injection

Noncompendial water

General equipment/systems overview

To be discussed…

II. Water System Validation, Monitoring and Annual Reporting Validation requirements for FDA and EMEA Understand your water system design and

available sample points Develop a validation protocol and report Evaluate the financial, resource and schedule

impact of the validation, monitoring and testing plan

Determine alert and action levels Evaluate and troubleshoot trends Implement a monitoring and testing program

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Water in the Pharmaceutical World

Critical component in the manufacture of most drug products:

Raw material

Process ingredient

Cleaning agent

High potential for contamination

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Guidance

FDA Guide To Inspection High Purity Water Systems, 1993

CPMP Notes for Guidance on Quality of Water for Pharmaceutical Use 2002

USP <1231> Water for Pharmaceutical Purposes ITGS WATER FOR PHARMACEUTICAL USE 1986

REVERSE OSMOSIS 1980HEAT EXCHANGERS TO AVOID CONTAMINATION 79

PDA Technical Monograph No.4Design Concepts for the Validation of a Water for Injection System 1980s

ISPE Good practice guide: Commissioning and qualification of pharmaceutical water systems

Standard Methods for the Examination of Water and Waste Water

US FDA 483 Observations, Warning Letters, Recalls

FDA Guide To Inspection of High Purity Water Systemshttp://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074905.htm

Notes for Guidance on Quality of Water for Pharmaceutical Usehttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003394.pdf

USP Water for Pharmaceutical Purposeshttp://pharmacopeia.cn/v29240/usp29nf24s0_c1231.html

USP <1231> Water for Pharmaceutical Purposes

Validation of Water Systems

“A typical program involves intensive daily sampling and testing of major process points for at least one month after operational criteria have been established for each unit operation, point of use, and sampling point”

USP Pharmacopeial Forum Vol. 30 (5) p1773

FDA Inspection Technical Guideshttp://www.fda.gov/ICECI/Inspections/InspectionGuides/InspectionTechnicalGuides/ucm072925.htm

Inspection Technical Guide – Reverse Osmosishttp://www.fda.gov/ICECI/Inspections/InspectionGuides/InspectionTechnicalGuides/ucm072913.htm

Inspection Technical Guide – Heat Exchangers to Avoid Contaminationhttp://www.fda.gov/ICECI/Inspections/InspectionGuides/InspectionTechnicalGuides/ucm072911.htm

PDA Technical Monograph #4:how to validate a WFI system

Five step validation plan:

1. System description, construction, operating considerations and procedures including sanitization schedules

2. IQ

3. OQ

4. PQ

5. Documentation and monitoring program

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Inspectors Technical Guides onWater for Pharmaceutical Use

Documents are old and does not necessarily reflect current thinking

BUT

Provides a useful overview of water systems and FDA’s approach to them

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Inspector’s Technical Guide: Water for Pharmaceutical Use

Covers different types of water used in manufacturing drug product

THE 8 TYPES OF WATER ARE:

1. Non-potable

2. Potable (drinkable) water

3. USP purified water

4. USP water for injection (WFI)

5. USP sterile water for injection

6. USP sterile water for inhalation

7. USP bacteriostatic water for injection

8. USP sterile water for irrigation

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ITG: USP Water

The USP designation means that the water is the subject of an official monograph in the current US PHARMACOPEIA with various specifications for each type

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ITG: Water is a Raw Material

The USP purified water and the USP WFI on the other hand are components or "ingredient materials" as they are termed by the USP, intended to be used in the production of drug products.

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CPMP (Committee for Proprietary Medicinal Products):

Water for Pharmaceutical Use

Different grades of water depend on use

Control of quality of water (in particular microbiological control) is a major concern

Considerable resources devoted to development and maintenance of pharmaceutical water systems

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CPMP: Water for Pharmaceutical Use

European Pharmacopoeia contains grades of water for pharmaceutical use including

WFI (by distillation ONLY; USP allows RO)

Purified Water

Highly Purified Water (Not in USP)

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CPMP on types of Water

Potable Water:

should be tested at the manufacturing site

May be used in chemical synthesis

May be used in early stages of cleaning equipment

Is source water for PW / WFI

WFI

For parenteral formulations

Prepared by distillation ONLY

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Water for Injection: Definition

NOTE: NO ADDED SUBSTANCE

DELIVER TO POINT OF USE –

WATER WHICH CONFORMS TO SPEC

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CPMP: Water used for Cleaning Equipment

Final rinse should use the same quality of water as that used in manufacture of the API or pharmaceutical product

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CPMP on types of Water

Purified Water Used in the manufacture of pharmaceutical

products not required to be sterile Prepared by distillation, de-ionization or any other

suitable method Prepared from potable Water

Highly Purified Water Used for products where high biological quality is

required but don’t need WFI Prepared by double pass RO, UF, DI NOT acceptable as WFI

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ITG: Potable Water

But what about potable water as a component? Is it required to undergo routine sampling and testing before use in production?

It is important to know that potable water may not be used to prepare USP dosage form drug products or for laboratory reagents to test solutions

However, potable water may be used to manufacture drug substances (also known as bulk drugs or bulk pharmaceutical chemicals)[APIs or Active Substances]

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ITG:

Is non-potable water a concern during drug inspections?

It may be present in a plant in the boiler feed water, cooling water for the air conditioning or the fire-sprinkler systems

Look carefully for any cross-connections to the potable water supply. Non-potable water supply lines should be clearly marked as such, especially when adjacent to potable water supply connections.

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ITG: SOURCES OF WATER CONTAMINATION

Piping system defects may cause contamination of clean incoming water

Because of this possibility, point-of-use sampling is indicated, that is, drawing the water sample after it has passed through the piping system.

Microbial contamination of oral liquid and topical drug products continues to be a significant problem, and is usually rooted in the use of contaminated water. Because of the potential health risks involved with the use of contaminated water, particular attention should be paid to deionized (DI) water systems, especially at small, less sophisticated manufacturers.

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ITG: System Sanitization

To minimize this contamination, the USP notes that water systems for pharmaceutical manufacturing should have "corrective facilities.“

By this they mean access to the system for sanitization or introduction of steam, chlorinators, storage at elevated temperatures, filtration, etc.

Inquire about these during your inspection

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ITG: In-Plant Water Treatment Systems

Sand bed filters with or without chlorination equipment are common in larger plants. However, these may be centrally located and the water piped to the pharmaceutical manufacturing site

The operations of these systems should be validated along with any subsequent treatment

If storage tanks are used, determine the capacity, the rate of use, the frequency of flushing and sanitizing the internal surfaces.

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ITG: Use of filters

While depth or membrane type filters are often used in water systems, final filtration as the sole treatment for water purification is generally not acceptable

However, filtration could be acceptable, for example, when used for reducing microbial/particulate loads in potable water used as an ingredient in chemical manufacturing where water need not be sterile

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ITG: Chlorination

Chlorination of potable water is an effective treatment if minimum levels of 0.2mg/liter of free chlorine are attained

Be aware however, that any carbon or charcoal filters in the system will remove this protective chlorine and thus eliminate any inhibitory effect on microbial growth after this point

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ITG on WFI

USP WFI is usually produced in a continuously circulating system maintained at an elevated temperature

The high temperature, maintained uniformly throughout the system by constant circulation, prevents significant microbial growth

A temperature of 80C is commonly used and is acceptable

Lower temperatures may also be acceptable, provided the firm has adequate data to demonstrate that a lower temperature works as intended

If WFI is held at ambient temperature rather than recirculation at elevated temperature, it must be dumped or diverted to non-WFI use 24 hours after being produced

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ITG: Action and Alert Levels

Although there are no absolute microbial standards for water (other than water intended to be sterile), the CGMP regulations require that appropriate specifications be established and monitored

The specification must take into account the intended use of the water; i.e., water used to formulate a product should contain no organisms capable of growing in the product

Action or alert limits must be based upon validation data and must be set low enough to signal significant changes from normal operating conditions

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Chemical vs Micro Quality

It is relatively easy to obtain the chemical quality required:

pH, Total Organic Carbon, Conductivity

It is extremely difficult to maintain the required microbial quality:

NO Pathogens

Low microbial counts

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The Solutions

High quality starting water

System designed to allow for no standing water (always a source of contamination)

Provisions for sanitization at each step of the system

Initial validation of the design

Ongoing monitoring

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Control of Microbes

Artiss 1978

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The key to the problem

Artiss 1978

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System Design

Consider Chem and Micro Specs

Consider validation requirements

Prepare SOPs for maintenance, operation and sanitization

Consider capacities and your company’s capabilities and needs

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System Design: From PDA monograph

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Capacities

Cost - Budget

Hourly usage (routine / peak)

Daily usage

Maximum daily capacity

Number of users

What happens if start working shifts!!

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Specifications - USP / Ph. Eur.

Chemical - TOC, conductivity, other

Microbiological:PW: alert / action / release?

25 cfu / ml40 50 for release?

Historical data? Don’t have for new system

WFI: 10 cfu / 100ml

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Pre-Treatment Systems

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Problems with Sand Filters:

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Problems with Deionizers

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Carbon Filter

Must be either disposable - no use for large capacities

or STEAM sterilizable100C IS NOT ADEQUATE

A CARBON FILTER WILL EVENTUALLY ALWAYS CAUSE CONTAMINATION!!

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Problems with Carbon Filter

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Bacterial Contamination of RO (from ITG)

1. certain naturally occurring Gram- negative bacteria can multiply in relatively pure RO water

2. thorough periodic disinfection of the entire RO system is essential in producing water with acceptable bacterial counts

3. stagnant water in pipes down stream of the membrane is the major source of bacteria and endotoxin in the product water

4. the efficiency of a membrane in rejecting bacteria is better in continuous operation than in intermittent use

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Quality Water in = Q. Water out

Amount of dissolved solids in water produced by reverse osmosis is approximately a constant percentage of those in the feed water

E.g. feed water contains 300 ppm TDS, product water may have 15 to 30 ppm (95% and 90% rejection ratio respectively)

RO system design is based on a certain range of feed water TDS, the percentage of rejection and percentage of recovery desired

For a given system, the higher the percentage of recovery or the lower the percentage of rejection, the poorer the quality of product water becomes

RO system with deionizer and/or several modules in series can produce water with less than 0.1 ppm TDS (resistivity about 1 megohm-cm)

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Mixed Bed Deionizer - Polisher or CDI

Mixed Bed Deionizer- ideally single use resin with high change frequency

CDI - continuous deionization:fairly new technology: maintenance? Sanitization?

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UV?

Advantage can knock down counts

Disadvantage: some bacteria sunbathe on them

High maintenance

Poor maintenance leads to failure

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WFI - Distillation

Commerical units effectively off the shelf

Make sure you use a reputable company

Piping must be totally sanitary

Steam sterilizable I.e. withstands pressure and sloped for drainage

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Problems with Stills

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Before Validation Begins

Construction change control

Update P&ID / Isometrics

Clean and passivate

Calibrate

Debug / fine tune

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System Validation

A chance to get to know the system: Installation Qualification

Were all components correctly installed Drawings match system on site

Instruments calibrated

Air breaks with drains

……

Operational Qualification Routine operation, alarms challenges, SOPs for cleaning,

maintenance, sanitization and monitoring

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System Validation 2

Performance Qualification The system provides Purified Water USP / Ph. Eur.

That repeatedly and reliably meets your company’s pre-determined specifications: chemical and microbial quality

Means daily sampling from points before and after each installation and from storage tanks and from each use point for 30 days + continue for a year on reduced plan

UNDER fixed operational, sanitization and maintenance procedures i.e. must have SOPs in place and personnel trained up

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What to do with Results

Why are you sampling

What is a specification

If you have a specification and bother to sample and test….

ACT on the results

High counts indicate a problem with the system and REQUIRE CORRECTIVE ACTION

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What to do with results - 2

Need to: Look at earlier and later results (not

retests but do give a trend)

Investigate

Check maintenance and production activities around the time of the problematic results

Perform sanitization or other corrective action if identified as appropriate

Document: esp. effect on product

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VALDIATION

Validation is worthless without SOPs for ongoing operation, maintenance, sanitization and monitoring

Validation is worthless if results that fail to meet acceptance criteria are accepted anyway

Validation is supposed to demonstrate beyond doubt that the system works…always

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Performance Qualification PQ

Intensive sampling

Before and after every installation

(Did your design take this into account?)

What about user loops? Do you sample every user point

Frequency? Every day / once a week

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PQ - tests

Chemical

Microbiological

LAL Endotoxin

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PQ Acceptance criteria

As for routine monitoring?

What about locations that aren’t sampled usually

What about pathogens

What about repeat high counts

Day after day

Sporadic

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Performance Qualification

Day after day water is within specs

Can’t accept a new system which “mostly” meets the requirements

“isolated” incidents in the first thirty days mean things go downhill from now.

INVESTIGATE problems and RESOLVE

UNDERSTAND the causes

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PQ

First Week

First month

System in routine use

First year: seasonal fluctuations

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System Monitoring

Which locations are to be routinely sampled?

Frequency: all weekly / monthly / dailyor a combination of the above

What about if results are above pre-determined levels?

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Change Control / Critical Work Orders

Sudden contamination

Resin changes

RO membranes, 5 / 10 micron filters

UV fails

Other

Carbon filter

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Ongoing Verification

Annual review of system function

Use computer reports to follow important parameters: TOC, conductivity, other

Periodically reverify tagging and P&ID

Periodically perform increased sampling?

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Inspectional Findings 1

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Inspectional Findings - 2Change Control

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RECALL

RECALLS AND FIELD CORRECTIONS: DRUGS -- CLASS III

PRODUCT Epinephrine Mist Kit, Epinephrine Inhalation Aerosol, USP, 5.5 mg/mL 1/2 Fl. Oz.,

Kit contains nebulizer/actuator packaged with vial. Recall # D-221-2. Epinephrine

Mist-Epinephrine Inhalation Aerosol USP Refill, 5.5 mg/mL, packaged in 0.5 ounce plastic

coated glass vials, 1 vial per box, 24 boxes/carton. Recall # D-222-2. CODE Kit with Inhaler

(1/2 oz)

Lot Number Expiration Date RB0166 28-Feb-02 RB0170 28-Feb-02 RB0171 31-Mar-02

RB1200 31-Jan-03 RB1201 31-Jan-03 RB1204 28-Feb-03 RB1205 28-Feb-03 RB1207

28-Feb-03 RB1208 28-Feb-03 RC0176 30-Apr-02 RC1209 28-Feb-03 RC1213 31-Mar-03

RD0178 30-APR-02 RD0180 31-Mar-02 RD0182 30-Mar-02 RD0183 30-Mar-02 RF1414

30-Mar-03 RH0543 30-Jun-02 RH0544 31-Jul-02 RH0547 31-Jul-02 RH0548 31-Jul-02 RJ1669

30-Jun-03 RJ1671 30-Jun-03 RJ1672 30-Jun-03 RK0551 31-Aug-02 RK0552 31-Aug-02

RK0553 31-Aug-02 RK0689 30-Sep-02 RK1676 31-Jul-03 RK1677 31-Jul-03 RK1680

31-Aug-03 RL0690 30-Sep-02 RL0691 30-Sep-02 RN0698 31-Oct-02 RN0699 31-Oct-02

RN0700 31-Oct-02 RP0834 31-Oct-02 RP0835 31-Oct-02 RS0840 31-Jan-03 RS0841 31-Jan-03

Refill (1/2 oz) Lot Number Expiration Date RB0167 28-Feb-02 RB0168 28-Feb-02 RB0169

28-Feb-02 RB1202 28-Feb-03 RB1203 28-Feb-03 RB1206 28-Feb-03 RC0172 31-Mar-02

RC0173 03-Jan-00 RC0177 28-Feb-02 RC1210 31-Mar-03 RC1211 31-Mar-03 RC1212

31-Mar-03 RC1214 31-Mar-03 RD0179 31-Mar-02 RD0181 30-Mar-02 RD0410 31-Mar-03

RD1405 30-APR-03 RD1406 31-May-03 RD1407 31-May-03 RD1408 31-May-03 RD1409

31-May-03 RF1410 31-Mar-03 RF1412 31-Mar-03 RF1413 31-Mar-03 RH0542 30-Mar-02

RH0545 31-Jul-02 RH0546 31-Jul-02 RH0549 31-Aug-02 RH0550 31-Aug-02 RJ1670

30-Jun-03 RJ1674 30-Jun-03 RK0554 31-Aug-02 RK0555 31-Aug-02 RK0688 31-Aug-02

RK1675 31-Jul-03 RK1678 31-Jul-03 RK1679 31-Aug-03 RL0692 30-Sep-02 RL0693

30-Sep-02 RL0694 30-Sep-02 RL0695 31-Oct-02 RL1977 31-Aug-03 RN0696 31-Oct-02

RN0701 31-Oct-02 RP0833 31-Oct-02 RP0836 30-Nov-03 RP0837 30-Nov-03 RP0838

31-Jan-03 RS0839 31-Jan-03 RS0841 31-Jan-03 RS0841 31-Jan-03 RS0842 31-Jan-03 RS0843

31-Jan-03.

RECALLING FIRM/MANUFACTURER Recalling Firm: Alpharma USPD, Baltimore, MD,

by letter on February 26, 2002. Manufacturer: Armstrong Laboratories, Inc., West Roxbury, MA.

Firm initiated recall is ongoing.

REASON Failure to test Purified Water ingredient for all microbial specifications.

VOLUME OF PRODUCT IN COMMERCE 4,333,356 units.

DISTRIBUTION Nationwide.

/70

Inspectional Findings - 3High Counts…no investigation

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Performance Qualification Phase 1 to demonstrate that the system operates within

predetermined operating ranges and delivers water of the required 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.

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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Performance Qualification Phase 2 intended to demonstrate that the system consistently

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 and 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.

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Performance Qualification Phase 3 Phase 3 demonstrates that the water system,

which is operating 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. 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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The validation of WFI systems should 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 frequency

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ISPE Guide with Respect to WFI

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

point every day

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 3 No formal frequency recommendation, But,

the agency 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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Microbial Water Validation Considerations

Most waterborne contaminants are Gram negative bacteria.

We want quantification and qualification. Exogenous contamination: faulty air vents,

faulty seals, human interaction Endogenous contamination: colonization in

resins, carbon beds, filter membranes, dead legs.

Biofilm formation: microbes adaptation to survival in low nutrient environment.

Sampling captures “planktonic” organisms shed from biofilm upstream.

77

Review Printed Time Estimation

Sheet

Note: It takes more time than

you might think when you

add up all of the

“minutes”

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Example List of Sample Sites

79

Example Sample Scheme

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Sampling Instruction Considerations

Proper sampling equipment

Document training of samplers

Flushing?

Do not spray alcohol prior to sampling

Transfer hose?

Refrigerate after 30 minutes, test within 24 hours

Not always the lab’s fault.

83

Sampling Instruction Considerations Include specific details on how to sample – photos

are also often very helpful

84

Example List of Sample Containers

85

Example List of Sample Equipment

86

Example Sample Instructions

87

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Example Testing Specifications

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Heavy Metals?

USP justifies: NPDWR specs are very tight

Contemporary water system

construction materials do not leach heavy metals

No failures in previous tests

Washington Post Article:1 Questions veracity of local water authority tests

Old infrastructure in old distribution systems leach lead

European Pharmaceopeia: Retains heavy metal requirement

Instrumentation AA 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 changing Internal factors:

Aging resin Aging filters Aging UV lights Maintenance Leaks Dead legs Biofilm formation Production shifts

91

What is a biofilm?

Unwanted adhesion of bacteria or other organisms onto surfaces of solution handling systems

Not necessarily uniform in space & time

May 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

95

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