Validation of Pharmaceutical Water System:

USP General Chapter <1231>Rostyslaw (Rosty) Slabicky BS Ch E

USP General Chapters – Chemical Analysis Expert Committee

Last Updated: December 2015Antonio Hernandez-CardosoCourse ID: CM-1231-02

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Instructor Name

He also served as a Chairman of the PhRMA Water Quality Committee that proposed the contemporary water standards.

Mr. Slabicky is Director of Regional Quality, Compliance and Audits with Boehringer Ingelheim Pharmaceuticals Inc. since 1986. He earned the degree of Bachelor of Science in Chemicals Engineering from the Polytechnic Institute of New York,

now part of the New York University.

USP Affiliation: USP General Chapters – Chemical Analysis Expert CommitteeTitle: Director of Regional QualityCompany: Boehringer Ingelheim Pharmaceuticals Inc.Education: Bachelor of Science in Chemicals Engineering from the Polytechnic

Institute of New York, now part of the New York University

Rosty Slabicky is a member of the USP General Chapters – Chemical Analysis Expert Committee and serves on several Expert Panels, including Combined Pharmaceutical Waters. He has been involved in developing the contemporary pharmaceutical water standards and associated with USP for over 25 years as advisor, and USP

Pharmaceutical Water expert during three consecutive cycles as a volunteer.

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� Bulk Monographed Waters and Steam

Purified Water Water for Injection

Water for Hemodialysis Pure Steam

� Sterile Monographed Waters

Sterile Purified Water Sterile Water for Injection

Bacteriostatic Water for Injection Sterile Water for Irrigation

Sterile Water for Inhalation

� Test Methods

USP <643> Total Organic Carbon USP <645> Water Conductivity

� General Information Chapter

USP <1231> Water for Pharmaceutical Purposes

USP Pharmaceutical Water Topics

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� General Information Chapter provides guidance to the stakeholders on selection

of water, validation, design and operation, sampling, chemical and microbial

considerations, and specifications:

1. Introduction

2. Source Water Considerations

3. Waters Used for Pharmaceutical Manufacturing & Testing Purposes

4. Validation and Qualification of Water Purification, Storage, and Distribution

Systems

5. Design and Operation of Purified Water and Water for Injection Systems

USP General Chapter: <1231> Water for Pharmaceutical Purposes

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1. Sampling

2. Chemical Evaluations

3. Microbial Considerations

4. Alert and Action Levels and Specifications.

USP <1231> Water for Pharmaceutical Purposes is being revised

Pharmacopeial Forum September / October 2015 41(5) In Process Revision

USP General Chapter: <1231> Water for Pharmaceutical Purposes

(cont’d)

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� Validation is the program of documenting, to a high level of assurance, that a

specific process is capable of consistently delivering product conforming to an

established set of quality attributes. A validation program qualifies and

documents the design, installation, operation, and performance of the system.

Validation Approach

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� Validation boundaries for the water system define the scope of the process and

testing

� Boundary may be at the use point or include the transfer process, hard piped

equipment, or hoses

� Boundaries need to consider how the water is transferred for the actual

consumption

� If the actual water use location is outside the boundary, the transfer process

needs to be validated separately.

� QC sampling is intended to reflect the quality of water at the true point of use

Validation Boundaries

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� Life cycle approach

– Design

– Initial validation

– Life cycle monitoring

– Validation Maintenance

– Change based re-testing

Water System Validation Life Cycle

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USP <1231> Revision Water system validation life cycle

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� Identify:

– Source water attributes and seasonal variability

– Grade of pharmaceutical water required based on use

– Water consumption, instantaneous demand

– Allowable downtime

– Design and unit operations

– System operation, sanitization, monitoring

� URS should be a point of reference throughout the validation life cycle and

verified during the design qualification

Define User Requirements

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� System design is based on source water and product water quality, how water is

used, quantity and maintaining quality

� Design of unit operations

� Process Technologies

� Operating Parameters

� Maintenance of quality, sanitization

� Control Sequences

� Design quality into the water system

� The system design satisfies the User Requirements and is the basis for

validation tasks

System Design

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� Documented review of design and operating strategy for conformance to GMP’s

and meeting user requirements

� Review of the user requirements, system design, components, specifications,

functions, and operations

� Mitigate GMP risks to an acceptable level

� Review may be performed as part of the overall design process or as a separate

DQ.

� Formally documents review process

Design Qualification (DQ)

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� System assembly and testing may include a Factory Acceptance Test (FAT):

– Typically all unit operations are operational

– Water and supporting utilities are not available

– Testing is by simulating control sequences

� FAT increases confidence that water system will function properly when installed

� Limited qualification testing may be performed if:

– Water system design / controls do not change

– Good Engineering Documentation in place

Installation and Commissioning: Factory Acceptance Test

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� Commissioning is the water system project completion.

� Commissioning assumes that the system will require changes

� Data and inspections during installation support the Installation and Operational

Qualification:

– Water system installation and test data using the final “as installed”

configuration

– Good Engineering Documentation in place

� Microbial controls need to be in place during start up

Installation and Commissioning: Installation and Site Acceptance Testing

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� Verification of Installation, Start up, Acceptance Testing, Tuning of controls

� Part of the IQ may be executed during Factory Acceptance Testing (FAT),

system installation, Site Acceptance Testing (SAT), or Commissioning:

– Data that is used for the IQ must be from the final configuration of the system

– Data generated before the start of IQ must be properly documented

– The data must be reviewed as part of the validation package.

Installation Qualification (IQ)

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� Description of System

� Drawings

– Components (P&ID)

– Slopes

– Sampling Locations

� Manuals, Logs

� Installation Verification

� Configuration (Set points, Alarms)

Installation Qualification (IQ) Activities

� Automated Controls

� Control Sequence

� Equipment

� Materials of Construction

� Preventive Maintenance

� Calibration

� SOP and Methods

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� Tests and inspections to verify that the equipment, system alerts, and controls

are operating reliably

� Appropriate System Alert and Action Levels are established (Alarm set points)

� OQ may overlap with aspects of IQ and PQ

� Part of the IQ may be executed during system installation, Site Acceptance

Testing (SAT), or Commissioning

Operational Qualification (OQ)

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� Operating Parameters

� Set points

� Alarm Functional Check

� Functional Testing of Components

� Control Sequence Tests

� Sanitization

� Cleaning

Operational Qualification (OQ) Activities

� Calibration Results

� Test Instrument Calibration Results

� System Suitability

� Hydrostatic Pressure Tests

� Security, Backup….

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� Identify Critical Process Parameters (CPP)

Temperature Flow Rate

Pressure Sanitization Schema

� Identify Water Attribute Parameters

Conductivity Total Organic Carbon

Microbial Attributes

� Demonstrate control of CPP with all unit operations, maintenance and control

sequences working together to deliver water meeting required water quality

attributes

� PQ is implemented through several phases

Performance Qualification (PQ)

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� Initial increased monitoring to demonstrate system capable of producing and

distributing water of appropriate quality.

� Confirm / Refine Critical Process Parameters and Attributes

� Typically 2-4 weeks of sampling to confirm that quality attributes are achieved

and maintained:

– Chemical attributes are observed in a short time

– Microbial attributes, including biofilm control requires extended time

� Water is not used for production / use is simulated

� Preliminary evaluation of data and decision for use

Performance Qualification: Prospective Phase

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� Continued monitoring at a reduced level from the Prospective Phase to build

data on system operation, control of quality attributes, and performance.

� Develop initial performance trends.

� May use at Risk (batch release after concluding Concurrent PQ).

� Typically 2-4 week sampling duration

� Formal review and release for operational use

Performance Qualification: Concurrent Phase

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� Ongoing routine monitoring frequency of system operation, performance and

quality attributes for the operational life of the system

� Establish reproducibility and reliability of system by trending parameters and

attributes

� Evaluate effects of seasonal changes and longer term maintenance

� Appropriateness of alert and action levels for process control.

Routine Operational Use (Life Cycle Monitoring)

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� Life cycle maintenance activities to ensure a state of control is maintained:

Calibration Instrument Standardization

Manuals and Drawings Maintenance

Change Control Procedures

Monitoring and Trending Deviation Investigations

CAPAs Periodic Review

Training Logbooks / Records

� Programs are is place for the life of the system

Validation Maintenance (Continued Process Verification)

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� Identification, evaluation and follow up of changes (e.g. Unit operations,

components, SOP’s, methods) to ensure a continued state of control

� The impact of the change on process parameters and quality attributes must be

identified, evaluated and remediated.

� This may result in a selective validation activity to demonstrate the ongoing state

of control for the system and ability to maintain water quality attributes.

Change Control

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� Monitor the status of the water during the implementation of the change

� Modifies monitoring and sample plan may be needed

� Not all changes will require validation follow up:

– Minor ones, such as gasket elastomer changes could have an impact on quality attributes.

– Certain calibration and preventive maintenance activities may be considered routine tasks if

they do not impact on system operation or water quality.

Change Control

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� Replacement of components needs to be carefully evaluated:

– Using exact parts generally does not affect system operation or control.

– Using components with similar functional specifications can be performed at risk with the critical specifications (e.g., material of construction, dimensions, flow rate, response factors)

having been evaluated

– Differences determined to be acceptable and documented within the change control system.

Change Control: Component Replacement

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– Original Validation

– Calibration records

– Unit operations

– Deviations / CAPAs

– Cumulative impact of changes

– Process and Quality Trends

� Assurance that the system is operating within the validation

requirements and in a state of control

� Periodic assessment of validation maintenance to determine impact on

the state of control:

Periodic Review

– Maintenance history

– Quality and Process data

– Process variability, alarms

– Drawings, Logbooks

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� May result in adjustments to operating and sanitization processes, monitoring

plans, or maintenance and calibration plans

� May also result in additional testing or repeating certain qualification tasks

(requalification).

� Where another Quality Management program exists to control or review

validation maintenance activities (e.g. Calibration, Preventive Maintenance,

System Suitability Testing):

– The QM Referenced as part of the Periodic Review

– Review of these activities may not have to be repeated

Periodic Review

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