Effective Qualification of Critical Utilities.pdf

8/19/2019 Effective Qualification of Critical Utilities.pdf

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Effective Qualification of Critical Utilities

Presented By Miguel Montalvo,President, Expert Validation Consulting, Inc.

IVT Validation and cGMP Compliance Forum – San Juan, P.R.

July 12th – 14th, 2011


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April 23, 2013 2

FDA 21st Century Initiative –Effects on Facility and Utilities

Qualifications

! Aseptic Processing Concept Paper from 2002 – Basis for 2004Final Guidance" Goal – !build quality into products using science-based

facility, equipment and systems design.”

" Ensure reliable and robust product protection through

adequate design and control.” " Advantages of Automation and Isolation Concepts - Innovation" Consistent with Agency efforts to harmonize with international

regulatory standards (ISO-14644 Classifications)!

Agency intent to integrate quality systems and risk management approaches into existing programs with the goal of encouragingthe adoption of modern and innovative manufacturingtechnologies


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3

ICH-Q7A - cGMPs for APIManufacturing

! HVAC Systems – These systemsshould be designed andconstructed to minimize risks ofcontamination and cross-

contamination”

! Qualification of Critical Equipment

and Ancillary Systems

" Design Qualification

" Installation Qualification

" Operational Qualification

" Performance Qualification

! Periodical Review of ValidatedSystems


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April 23, 2013 4

Quality Systems Approach toPharmaceutical GMP

s –

Guidance from FDA (9/29/06)! The guidance describes a comprehensive quality systems (QS) model,

highlighting the model's consistency with the CGMP regulatoryrequirements for manufacturing human and veterinary drugs, includingbiological drug products. The guidance also explains how

manufacturers implementing such quality systems can be in fullcompliance with parts 210 and 211.

”

! Implementation of Quality Systems, when coupled with manufacturingprocess and product knowledge, can handle changes without a needfor regulatory submissions - changes in facility, equipment or evenprocesses

! Change Control – managing change to prevent unintended

consequences

! According to CGMP regulations, the QCU has the responsibility ofreviewing and approving all initial design criteria and procedurespertaining to facilities and equipment and any subsequent changes(see 211.22(c))!”


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April 23, 2013 5

Quality Systems Approach toPharmaceutical GMP

s –

Guidance from FDA (9/06)

! Quality by Design Concept:" Quality by design means designing and developing

manufacturing processes during the product development stage

to consistently ensure a predefined quality at the end of themanufacturing process. A quality system provides a soundframework for the transfer of process knowledge fromdevelopment to the commercial manufacturing processes andfor post-development changes and optimization

”

" Quality should be built into the product, and testing alonecannot be relied on to ensure product quality.

”

" A quality system can provide the necessary framework forimplementing quality by design (building in quality from thedevelopment phase and throughout a product

s life-cycle),continuous improvement, and risk management in the drugmanufacturing process. This concept is being developed underthe ICH Q8 Pharmaceutical Development Expert Working

Group.”


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April 23, 2013 6

Effects on Equipment/SystemsQualifications – Quality Systems

Approach

! Design Qualification/Review

! Purchasing Controls

" Vendor/Contractor Selection is Key” to an Effective

Qualification/Project Implementation

! Monitoring and Control – Master Project Plan" It is the responsibility of the designer, construction manager

and plant engineer in charge of the project that all agreed

upon”

design requirements are met during:! During Construction

! Start-Up and Commissioning

" Qualification and Routine Monitoring


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ISPE Efforts and Impact

Baseline Engineering Guides – Volume #5

"

Enhanced DesignReview Concepts

! Structured DesignReview

" System Impact and

Components CriticalityLevels and Applications


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Scope of the ISPECommissioning

and Qualification Guide

Design

Development

Engineering Change Management

Enhanced DesignReview

Scope of Guide

ProcessValidation

IQ & OQ

commissioning PQ

Design for Impact

Impact Assessment

QA Change Control

GEP Contribution

Of Interest to the Regulatory


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ISPE – Impact Concepts andApplication

! FDA cooperation with development of these concepts for new manufacturingfacilities and modifications to existing. It does not mean acceptance by FDA.Guidelines still prevail – Process Validation Guideline from 1987 whichincludes qualification requirements.

! Scope – Facilities, Utilities, Equipment! Key Concepts:

" Direct Impact Systems – impact on product quality

!

Qualification required

" Indirect Impact Systems – not expected to have an impact on productquality

!

Commissioning may be enough (Enhanced Commissioningdocumentation)

" No Impact Systems

! Basis – GEP application, Enhanced Design and Review and Commissioning

! System Impact Assessment is key (Risk) – rationales for decision are fully

understood, documented and endorsed by QA function


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Validation Life Cycle

Design

Verify

Do

Act

Plan

Qualification

Continued System Verification

Discontinuation


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Life-Cycle Phases

!

Design

" User Requirements

" FunctionalRequirements

" Detailed Design

!

Qualification

!

Continued SystemVerification

" Monitoring

" Change Control

" Deviations/OOS

" Maintenance

11

Risk Management is appliedat every phase


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Plan for Compliance

! Application of GEP s during the Design and Construction Phases

! Audits of vendors and suppliers" Proactive Review of Turn-Over Packages/Forms

! Master Project Plan to include" Basis of Design – Process/Product

" User/Functional Specifications

" Definition of Responsibilities

" Scope of Installation

" Cost/time considerations

" Quality Plan to Include:

! Design Review with pre-determined

acceptance criteria

! FAT/SAT Requirements

! Start-Up and Commissioning

! Qualification Requirements

(may be in parallel to VMP)


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Master Project Plan

! Applicable to New Facilities or Major Modifications/Projects

! Project is awarded:

" You may have User Requirements and FunctionalRequirements Specifications

" You may even have a Conceptual Designdocument

! Master Project Plan includes Quality Plan with

Design Review and Change Control processes


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Project Phases


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Process Support Systems orUtilities Requirements – Direct

Impact vs. Indirect Impact

! Direct Impact—raw material,product contact or directimpact on product quality

" Water For Injection

" HVAC System for CleanArea

" Clean Steam

" Clean Compressed Air

! IQ, OQ, and PQ required

! Indirect Impact—noproduct contact but mayhave indirect effect on

product quality" Vessel jacket heating/

cooling

" Potable water forwashing/cleaning –not final rinse

" Vacuum for drying/coating

! IQ and OQ required


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Approval of Suppliers/Vendors

! Approval is granted after all initial approvalrequirements have been met and all

documentation has been gathered and reviewed! Purchasing must not be allowed to enter into a

contract or PO with a supplier/vendor that has notbeen approved – Approved Supplier List (forCritical, Major and Minor class Suppliers)

! Quality Agreement or Contract in place beforefirst order is issued for Critical or Major materials/services


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Quality Agreements/Contracts

! Defined Requirements – specifications and otherneeds

! Communication – changes

! Giver versus Acceptor responsibilities

! Testing/standards/regulations to be applied

! Requirements for Qualification/Certification and impactof deviations/non-conformances

" Number of lots/batches and evaluation process

! Documentation

! Requirements for Sub-Contracting any step/process

! Dispute Resolution


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Quality Agreements/Contracts

! In the technical contract, both parties can agree upon a checklist,in which the company contracting the services lays down all therequirements for the supplier. A checklist with an extreme level of

detail is necessary, and should be an attachment to the technicalcontract. For example, if there is a specific concern for crosscontamination, the list can put special emphasis on air handlingunits, hygienic control, environmental monitoring, etc.

! Process knowledge is also critical. Manufacturers must

characterize all processes, monitor process variables (in real-time if possible), and anticipate how product and process willbehave in this multivariate environment

18


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Traceability Matrix Model

User RequirementsSpec

DesignSpecs

System Build

Installation Qualification

Functional Specs OperationalQualification

PerformanceQualificationVerifies

Verifies

Verifies

Design Review


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April 23, 2013 20

Specifications Purpose

! User Requirements – Describe clearly and preciselywhat you need the system to do? It must be driven by

the business process needs.! Functional Requirements Specifications – How the

system will achieve the User Requirements in terms offunctionality characteristics?

! Design Specifications – What are the specific (detailed)

attributes/characteristics for the system to be able tomeet the functions and user requirements?


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April 23, 2013 21

Traceability Matrix Application/Relation to Design Qual./Review

! User Requirements Specifications – basis for theFunctional Requirements Specifications – basis

for the Design Specifications and Drawings

! Design Qual./Review verifies the flow from one setof specifications to the next has been effective/complete and that all criteria/requirements are

met by the design


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April 23, 2013 22

Design of a Process SupportSystem or Utility – Plan for

Compliance

! Clear Design Specifications: User Requirements andFunctional Requirements

!

Process Requirements – determine what are therequirements for your specific application (asepticconditions vs terminally sterilized products)

! Risk analysis.

! Facility Location – environment conditions and seasonal

changes. Evaluate facility location in terms oftemperature/humidity worst case conditions

! Feed (if applicable)


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April 23, 2013 23

Design of a Process SupportSystem or Utility – Plan for

Compliance (Cont.)

! Initial Cost vs. Maintenance Costs – evaluate the options in terms oforiginal investment vs. maintenance costs.

!

Other aspects to be considered – reliability, future growth/flexibility! Average and Upper (peak) demand for utilities and environmental

conditions

! Critical Parameters – set-points, alert and action limits

! Methods of Measurement, control, monitoring and documentation ofparameters

! Automation Control Costs – how much automation is desiredcompared to operating and initial cost


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Process Requirements andConsiderations

! Potential for Contamination"

Feed, Make-up air

" Equipment/Personnel

" Materials/Components

" Room Finishes

"

Other Products! Effects of exposure to extreme

conditions - temperature,humidity

! Filtration requirements

! Safety Considerations

! Product requirements – sterile,

particulate levels/classifications


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April 23, 2013 25

Design Qualification/ReviewApplication

! New Facilities or Major Modifications to ExistingFacilities

" Direct Impact Systems – primary focus

" Indirect Impact – may select systems based on levelof impact

" Typical Direct Impact Systems – HVAC for ClassifiedEnvironments, Purified Water, Manufacturing

Equipment/Systems


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What is Design Review?Is it the same as DesignQualification or Enhanced

Design Review”

?


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April 23, 2013 27

ISPE Baseline EngineeringGuide #5 – Section 7 on EDR

! Enhanced Design Review (EDR) – “a documented review of the

design, at an appropriate stage in the project, for conformance to

operational and regulatory expectations.”

"

“It is in the interests of all to reveal design or specificationproblems through a rigorous , structured and appropriate

review process early in the project, rather than discover themlater !where a remedy might involve significant delay and

expense.”

" Avoiding the use of the term DQ

! EDR provides audit trail from conception of the project up to thecompletion of the detailed design


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April 23, 2013 28

ISPE Baseline EngineeringGuide #5 – Section 7 on EDR

! EDR aims to capture (organize) the design documents witha formal index and a process for their archival

! “EDR should be described in the Validation Master Plan

(VMP) indicating intention, process to be followed,responsibilities of persons involved, and position of EDR

with reference to GEP and Qualification Practices.”

" Master Project Plan with a Quality Plan Section instead

of the VMP

! Impact and complexity of the design will influence the depth

of the review process.


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April 23, 2013 29

EDR Rationale

! To be included in Plan:

" What will be reviewed

" What method will be used – supporting data

" Who will be involved

" When?

" How will be documented?

! Could be in a standard procedure


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Steps in a Design Review

! Define scope and objectives of thereview, the methods to be followedand the outputs (SOP)

! Who will be involved (SOP)

! Identify and evaluate any potentialareas or items of noncompliance(checklist)

! Review the design documents anddrawings against the user/functional specifications and otherrequirements identified on thechecklist above

! Ensure that designs are modified toeliminate noncompliant features

! Prepare a brief report thatsummarizes the design-review process and

obtain appropriateapprovals, includingquality assurance.

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April 23, 2013 31

When Should ChangeControl Be Implemented?

! Need a policy for Change Control Management which willinclude applications at different points

! Define application for new and/or modifications to facilities,utilities, equipment and systems

! Formal QA Change Control procedures MUST be implementedupon completion of the Qualification / Validation

! Implement change control for all Direct and Indirect Impactsystems – level of detail/depth of impact determination will becommensurate with the impact level of the system/process

! Once the system / equipment is identified and specified

(approved documents), it falls under some level of changecontrol


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April 23, 2013 32

Change Control Levels early inProjects – Impact Determinations and

Application of Risk

! Direct Impact Systems – more documentation requiredand a formal risk assessment done for changes

! Indirect Impact Systems – basic procedure and form to

be completed. No need for formal risk assessment aspart of the change impact analysis.

! Responsibilities must be defined for each project

phase! User functions to be involved – Quality (at a defined

level)

R l ti hi b t D i


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April 23, 2013 33

Relationship between DesignReview and Change ControlManagement during Design

! Team for Design Review is normally same teamthat will evaluate changes

! Documentation of Design Review will serve to

document changes and their verification ofimplementation.

! The DQ process/meetings will provide theopportunity to complete any Change Control

documentation required for the changes to DirectImpact and Indirect Impact Systems.


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Construction

! Construction shall comply withdesign drawings andspecifications

! Changes shall be documented inaccordance to a change controlprocedure (defined in QualityPlan)

! Cleaning procedures and criteriafor acceptance of the work must

be pre-defined! Security and access procedures

must be defined

F t A t


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35

Factory AcceptanceTesting (FATs)

!

FATs are standard tests that areexecuted at the factory to verifyproper operations before thesystem leaves the plant.


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Start-Up and Commissioning

! Adequate Installation/Construction Documentation - as per GEP s:

" Design Concepts

" Design Schematics

" As Installed drawings

" Instrumentation Calibrations

" Test records

" Operation and Maintenance Manuals

" Statutory inspection Reports

" Material Certificates, FATs

" Duct Installation and Cleaning documentation

" Changes are properly managed

and documented during construction

" Training of personnel


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April 23, 2013 37

$ $

Design Purchasing

Construction

Installation

Start-up

Validation

V

Project Phases

C i i i L d


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April 23, 2013 38

Commissioning Leadsto IQ/OQ for Indirect and

Direct Impact Systems" Documents created and collected during

Commissioning are incorporated into thevalidation package

" During construction, a review of current status

of installed equipment and walk through canhelp ensure validation criteria are kept on target—avoid unnecessary delays

" Start-up/field testing may address the needs of

IQ/OQ criteria

Key Question:


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April 23, 2013 39

Key Question:Is Commissioning going to beconsidered part of Validation

Effort?! Yes!

" Define Commissioningprocess and documentationin Project/Quality Plan andin Master Validation Planand how they will relate tofurther qualification of

systems

! No

" CompleteCommissioning

" Will need to repeatsome tests forQualification

" Still need to describe

Commissioningrequirements inPlans


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April 23, 2013 40

Commissioning as part ofMaster Validation Plan

! Advantages:" Pre-qualification determination if system is reliable/

operates according to specifications

" Avoid redundancy

! Requirements:" Pre-defined/documented test requirements

" Training of personnel executing the tests

" Adequate documentation practices

" Quality review


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April 23, 2013 41

Equipment Qualification Levels

! Historical:

" Installation

Qualification" Operational

Qualification

" PerformanceQualification

!

Suggested – applying Risk Assessment/Analysis:" Direct Impact System:

! Product Failure Hazard Level:

– Level I – Sterile/Biological/Critical MedicalDevices! Installation – more detail

! Operational Qualification – basic operational

functions, controls, alarms, Challenge ParameterRanges and Worst Cases – extremes

– Level II – Oral Solid/Liquids! Installation – adequate detail

! Operational Qualification – Basic OperationalFunctions, Controls, Critical Alarms

" In-direct Impact System:! Installation – not detailed

!

Basic Operational Functions - only those which couldimpact the product quality

" No Impact – Enhanced CommissioningDocumentation

! PQ – no change. Only for critical direct

impact systems.


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April 23, 2013 42

Questions to be Answered

! Which sections of a system need to be qualified?

! Which parameters to test and at what level – Does

an OTC/Cosmetic system/equipment/facilityneeds to test all systems at Worst case” or theextreme parameter limits?

! How many runs/tests?

! Decisions on criteria - equipment specificationsversus process needs?

R i t f I t ll ti


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April 23, 2013 43

Requirements for InstallationQualification – In-direct Impact

System! Main Components Verification – critical components only

" Base decision on risk assessment

! Drawings Verification

! Utilities Verification! Availability of Support Documentation – Manuals, Specifications,

Design Review Documents, PO’s, Commissioning Documents

! Procedures and corresponding training – Operation, Maintenance,Cleaning

! Calibrations – critical instruments

" based on risk assessment

! Hardware/Software Configuration and Set-up Information

! Filter Verification (if applicable)

R i f I ll i


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April 23, 2013 44

Requirements for InstallationQualification – Direct Impact

System (Level II – Oral Solid/Liquids)! Main Components Verification as per design/drawings including controls/

instrumentation" Base list of main components on risk assessment

! Drawings Verification to be As-Built

! Materials of Construction – product contact only! Lubricant List! Utilities Verification – Electrical, Water, Compressed Gases

! Review Support Documentation – Manuals, Specifications, FAT reports,Design Review Documents, PO

s, Commissioning Documents

! Procedures and corresponding training – Operation, Maintenance,

Cleaning! Calibrations – critical instruments

" Base list of instruments on risk assessment

! Hardware/Software Configuration and Set-up Information! Input/Output Loop Verification


Requirements for Installation


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April 23, 2013 45

Requirements for InstallationQualification – Direct Impact System

(Level I – Sterile/Biological/

Critical Medical Devices)! Main Components Verification as per design/drawings including controls/

instrumentation" Base list of main components on risk assessment

! Drawings Verification to be As-Built! Materials of Construction – product contact only! Lubricant List and Spare Parts List

! Utilities Verification – Electrical, Water, Compressed Gases! Review Support Documentation – Manuals, Specifications, FAT reports, Design

Review Documents, PO

s, Commissioning Documents! Procedures and corresponding training – Operation, Maintenance, Cleaning! Calibrations – critical instruments

" Base list of instruments on risk assessment

! Hardware/Software Configuration and Set-up Information – applicable procedures

for back-up, restore

! Input/Output Loop Verification! Construction completion documentation such as:

" Piping pressure and leak testing" Pipe slope verification" Pipe insulation" Instrument loop checks


R i t f O ti l


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April 23, 2013 46

Requirements for OperationalQualification – In-direct Impact

System

! Verify the basic Operational Functions - only thosewhich could impact the product quality" Functional Tests – critical parameters at nominal values

and verifying only critical responses or characteristics" Controls Verification" Motor verification

" Sequence Verification (if applicable)

! Select the parameters from risk assessment/analysis–select number of tests for each

! Select the responses or resulting characteristics to beverified from risk assessment/analysis

R i t f O ti l


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April 23, 2013 47

Requirements for OperationalQualification – Direct Impact

System (Level II – Oral Solid/Liquids)! Verify the basic Operational Functions including critical

alarms" Functional Tests – parameters at operational limits and

verifying critical responses or characteristics" Controls Verification" Motor verification" Sequence Verification (if applicable)" Critical Alarms – verification and reporting

! Select the parameters to be challenged from risk

assessment/analysis – select number of tests for each! Select the responses or resulting characteristics to be

verified from risk assessment/analysis

Requirements for Operational


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April 23, 2013 48

q p

Qualification – Direct Impact System (Level I – Sterile/Biological/

Critical Medical Devices)

! Verify the operational functions and critical alarms.Challenge Parameter Ranges and Worst Cases – extremes

" Functional Tests – parameters at operational extreme limits and

verifying critical responses or characteristics" Controls Verification – more detailed

" Motor verification

" Sequence Verification (if applicable)

" Critical Alarms – verification and reporting

! Select the parameters to be challenged from riskassessment/analysis – select number of tests for each

! Select the responses or resulting characteristics to beverified from risk assessment/analysis


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April 23, 2013 49

Additional Areas to be coveredduring the qualification

! Process Parameters vs. Equipment Design -Verify that the equipment is capable ofoperating at the desired process parametersindependently of the equipment design

! Flexibility, Reliability, Future Growth

H d i lifi i


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April 23, 2013 50

How to determine qualificationrequirements - Steps

! Procedure/Policy to describe the evaluation processand documentation requirements

! Impact Assessment – ISPE Baseline Engineering Guide

Volume #5 Commissioning and Qualification concepts! Hazard Level determination for Direct Impact systems

! Risk Assessment on system parameters andspecifications

! Protocol development including results from Risk

Assessment and rationale for decisions


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April 23, 2013 51

Protocol Requirements –General Outline

! Approvals

! Objective/Purpose

! Scope/Boundaries

! System Description

" Overview

" Basis of Design

" Flow Diagrams

! Qualification Approach:policies, procedures,references

! Responsibilities

! Pre-Requisites

! Definitions

! Test requirements

" Record of Signatures

" Test Instruments –Calibrations

" Qual. Tests

! Acceptance Criteria

! Documentation/ Handlingof deviations or exceptions

! Attachments


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April 23, 2013 52

Integrated PLC Qualification

! Qualification should encompass all aspectsthat could affect the operation of a system

" Program code

" Wiring

" Labeling

" Instrument enclosures

" Transmitters

" Recorders

" Monitors

" Final control elements


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April 23, 2013 53

PLC IQ/OQ

! Review of Program Code

! Display/Graphics/ControlPanel Verification

!

Operator InterfaceChallenges

! Review of SoftwareDevelopment proceduresand Test Protocols

! Design review of allperipheral equipment

! Tests to verify that all wireshave been correctlyterminated

! Reports Accuracy

! Verification that the systemhas been installed andlabeled in accordance withthe Process and

Instrumentation drawings! Review of security features

! Fault tree analysis toidentify unwantedoperations activities

! Review of all anticipated

operation activities andmaintenance activities

! Control SoftwareBack-up/Recovery Test


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April 23, 2013 54

BMS, DCS or SCADA(Supervisory Control and Data

Acquisition)! Stand-Alone Systems that provide additional tools:

" Recipe Manager (Specification, Stages, Alarms limits)" Reporting Tools"

Screen Builders" Software Package Design Constraints" Data usually acquired without operator action" Data available for later retrieval, reporting, analysis, and

archiving" Communication with the PLC"

Program timing


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April 23, 2013 55

BMS, DCS and SCADA

Validation Issues! Field Device Calibration

! Field Device Maintenance

! Cabling Changes! PLC Maintenance (HW&SW)

! Software and Hardware Upgrades

Legacy Systems Key


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April 23, 2013 56

Legacy Systems – KeyQuestions

! How much documentation is available fromoriginal purchase/design/installation?

! Change Control System – How good is it?

Have changes to the system beendocumented and tested properly?

! How critical is my system to the operation?


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April 23, 2013 57

Legacy Systems - IQ

! Documentation Available:" Similar to new equipment in

terms of Specifications,drawings, manuals, PO

s.

" Verify history of changes

" Inspect/Verify calibrations,utilities installations, majorcomponents, materials ofconstruction

" Required SOP s and training

" Software/Hardwareinstallation, configuration

! Documentation not available:"

Need to create specifications forsystem as installed.

" Verify drawings are created and/or up-to-date.

" Create/review operational andmaintenance procedures.

Document history of equipmentoper. and maintenance. Verifytraining on those procedures.

" Inspect/Verify calibrations,utilities installations, major

components, materials ofconstruction

" Software/Hardware installation,configuration


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April 23, 2013 58

Legacy Systems - OQ

! Parameter Ranges – in the absence ofspecifications, use actual operationalparameters

! Testing to be done similar to new system.

! Retrospective is not a concept for

equipment qualification. Limitations andrisks are much higher for trying to defendthis position(History, Quality of Operationaland Maintenance Documentation, ChangeControl)


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Performance Qualification(PQ) – Direct Impact Systems

! Test quality at use points fora pre-determined period

! Criteria as per specifications

! Verify/document operational

data during the test period

! Operational and PM SOP sare effective and followed

Qualification Summary


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Qualification SummaryReports - Outline

! Approvals

! Objective

! Data Summary

! Analysis of Deviations orExceptions

" Cause

" Effect on Study

" Conclusion

" Approval By QualityFunction

! Conclusions

Facilities


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FacilitiesRequirements – New

! Electrical supply system

! Terminations—walls,ceilings, floors, drains

! Access controls! Pest controls

! Usually handled through afacilities protocol

Design of an HVAC System


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April 23, 2013 62

Design of an HVAC System –Plan for Compliance

! Clear Design Specifications:" User Requirements" Functional Requirements

! Process Requirements – determine what are the

requirements for your specific application:" Potential for Contamination: Make-up air, Equipment/Personnel,

Materials/Components, Room Finishes, Other Products

" Effects of exposure to extreme conditions - temperature,humidity

" Filtration requirements

" Safety Considerations

" Product requirements – sterile, particulate levels/classifications

Design of an HVAC System


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April 23, 2013 63

Design of an HVAC System –Plan for Compliance

! Facility Location – Evaluate in terms oftemp./humidity worst case conditions

! Automation Control Costs – how muchautomation is desired compared to operatingand initial cost

! Initial Cost vs. Maintenance Costs – originalinvestment vs. maintenance costs.

! Other aspects to be considered – reliability,

future growth/flexibility! Average and Upper (peak) demand for

utilities and environmental conditions


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April 23, 2013 64

Design Specifications

! General Purpose of Areas, Operations to be Carried out,Constraints, Specified Occupancy

! Layout and configuration of the installation

! Required Air Quality for each area! Critical Parameters – set-points, alert and action limits. Worst case

conditions

! Contamination Control Concept for each area/room/zone

! Controls/Instrumentation/Automation – Failure protection devices,

alarms for critical parameters, BMS, documentation of parameterdata

! Dust Collection Systems (if applicable)

! Material/Equipment/Personnel Flow to minimize possibilities ofcontamination

Premises for Classified/


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Premises for Classified/Clean Rooms

! Surfaces must be smooth,impervious and unbroken inorder to minimize theshedding or accumulation of

particles or microorganismsand to permit the repeatedapplication of cleaningagents!No uncleanablerecesses

”

– EU Annex 1

! Sealed false ceilings

!

Walls/ceiling/floorterminations – seamless androunded corners

! Utilities installations – norecesses, unsealed openings anddifficult to clean surfaces

! Pressure differential – warningsystem

! Changing rooms with physicalbarrier between class levels

! Air locks with interlocks

! Layout of equipment – considerergonomics and personnelcomfort and ease of movement

! Flow of personnel – limit entries

and exits and the amount ofpersonnel

! Limit the activities/interventionsinto the aseptic processing area


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Decisions on Parameters

Parameter Suggested Values/Limits from Reg.Guidelines

Industry Suggestions(PDA, Others)

Air Velocity –HEPA Filters

90ft/min is no longer required. It is suggested. FDAstatement is at a velocity sufficient to sweep particlesaway from the filling/closing area and maintain

unidirectional airflow during operations.”

EU stillincludes a range at working level of 0.36-0.54 m/s as a

guidance value”

.

No limit established - Optimumair velocity is highly dependenton the configuration of the HVAC

system and the productionfacilities.

Air ExchangeRates

FDA - 20 Room Air Changes for Class D (ISO #8) zoneswould be typically acceptable.

”

EU has no suggestions.No specific number. Standardpractice NLT 50 for Class A/B(ISO 5/6) and 20 for Class D (ISO

8)

Pressure

Differentials

FDA - at least 12.5 Pa (0.05 inches water gauge) should

be maintained between classified and un-classifiedareas and between the aseptic processing room and

adjacent rooms.

EU - guidance values”

of 10-15 Pa between areas ofdifferent classifications

PDA - Pressure Differentials

between 0.03-0.05 inches ofwater are effective.

Temperature andRH%requirements

FDA and EU – no suggestions (comfort)

Additional Tests to be Included


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April 23, 2013 67

Additional Tests to be Includedin Commissioning

! Static tests – installation of systemcomponents

! Dynamic tests – verification of fan

volumes, checking heating/cooling coilperformance

! System Balance and Testing

" Including room pressure/air flowverifications

" Room Air Changes Calculations

! HEPA filter certification tests

Q lifi i R i


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April 23, 2013 68

Qualification Requirementsfor an HVAC System

! Installation, Operational and PerformanceQualification of the HVAC System including IntegratedControl Systems (such as PLC

s)

! Separate protocols for Stand-Alone Systems such as a

BMS or other supervisory control systems

! Basic Documents – protocol, report for each segmentor combined if appropriate (IQ and OQ into one IOQ

protocol)

R i t f I t ll ti


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April 23, 2013 69

Requirements for InstallationQualification of the System

! Main Components Verification as per design/drawingsincluding controls/instrumentation

! Drawings Verification to be As-Built

!

Materials of Construction! Utilities Verification – Electrical, Chilled Water, Steam/Hot

Water

! Review Support Documentation – Manuals, specifications,FAT reports, Design Review/Qual. Documents, PO

s, DuctCleaning Documents, Commissioning Documents

! Procedures and corresponding training – Operation,

Maintenance, Cleaning

! Calibrations

! Filter Verification

Requirements for Operational


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April 23, 2013 70

Requirements for OperationalQualification of the System

! Controls/Alarms Verification

! Sequence of Operation

! Interlocks testing

! Reports

! System Security/Data Retrieval

! Temperature/Humidity Control Verification – minimum offive days for continuous monitoring. Longer for frequentchecks during the day.

! Power Loss and Recovery Testing! Sterile Operations – Air velocity, Pressure Differentials, Air

Flow/Laminar Flow Verification as per design. PressureDifferentials for five days if continuous or longer forfrequent checks during the day.


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71

Performance Qualification

! System operating under normalconditions (SOP

s are effectiveand monitoring is in place) Thisincludes cleaning andsanitization procedures.

! Particulate Counts – three timesper location (twice per shift –

beginning and end of operation)during a week period for eachcondition

! Viable Counts – air, surface.Three results in a week for eachcondition. Aseptic areas require

testing per shift.! Static vs. Dynamic Conditions

! Challenge is for EnvironmentalControl System – not only theHVAC


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Water System Design andSpecifications

72

Guide to Inspections of High


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PurityWater Systems, FDA 1993

! System Design" Application based – type of product. UF as an option for Biotech WFI

" Loop Temperature (70-80ºC) versus sanitization – cost vs risk

" Quality level – risk. Reliability of the system.

! Microbial Limits – sample of 100ml minimum for WFI

" Specific contaminant versus counts

" Biofilm

! Water for Injection Systems

" Pretreatment – monitoring of feed water

" Still, Heat Exchangers, Holding Tanks(Vent Filters), Pumps, Piping(Steel vs PVDF), Reverse Osmosis

" Proper Operation and Maintenance

Guide to Inspections of High


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PurityWater Systems, FDA 1993

! Purified Water Systems

! Process Water

!

Inspection Strategy" Data review – micro

! Investigation reports and actions

" Maintenance records

" System Drawing

" System Validation

! Description, Specifications, Documentation, Drawings

! Procedures – operation, cleaning, flushing, sanitization, sampling/testing

74


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Variety of PharmaceuticalProducts

! Potable Water: Manufacture of substances and initialcleaning of equipment

! Purified Water: For use onsite in manufacture ofingredients of official preparations; not for parenterals

! WFI: For use onsite in manufacture of parenterals

! Internal Specification and Quality Requirements for

specific needs


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What else does FDA expect?

! Feed water must meet EPA Drinking Water Standards

" May use WHO standards for international

applications

! Microbial expectationsPurified Water NMT 100 cfu/ 100 mLWFI NMT 10 cfu/100 mL

Sample size


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Industry References

! ISPE Baseline Engineering Guide – Volume 4

! PDA Technical Reports and additional references

!

ASTM Standards! ASME Standards – Bioprocessing Equipment

! Books:

" Pharmaceutical Water: System Design, Operation

and Validation”

by William V. Collentro" Pharmaceutical Water Systems” by Theodore A.

Meltzer

77

ISPE Baseline Engineering


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ISPE Baseline EngineeringGuide – Volume 4 Water and

Steam Systems

! Pre-Treatment Options

! Final Treatment Options

! Instrumentation

! Storage/Distribution

! Qualification/Validation

! Appendix

78

F d Ch t i ti


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Feed Characterization

! Ground Water vs

Surface Water! Chemical and

MicrobiologicalLoads

! Seasonal Variations! Volume and effects

of peak usage

Zero In On User Requirements


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Zero In On User Requirements – System Planning

! Multi-DisciplinaryTeam Approach

!

Define User Needs:" Water Quality

" Use PointsRequirements

" System Criteria

Water System Design


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Water System Design

! Water Quality Specifications - related to the typeof product to be manufactured

! Clear Design Specifications: User Requirementsand Functional Requirements

! Water Source Quality and Characteristics

" Private Well, Public Well or City Potable Water

" Seasonal variations

" Location of Well (if applicable)

! Quality and Performance Criteria for each

component of the system including capacity

Water System Design


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Water System Design

! System Operational and Maintenance Costs - SanitizationFrequencies, Cleaning, Filter Replacement among others

! Facility Location – environment conditions and seasonal changes

! Evaluate facility location in terms of temperature/humidity worstcase conditions

! Industry Common Practices and Regulatory Input

! Recirculation Loop – Hot or Cold

" Hot loop reduces sanitization requirements – beware of heat

exchangers

" Sanitization for cold loops – daily?

Water System Design


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! Initial Cost vs. Maintenance Costs – evaluate the options in termsof original investment vs. maintenance costs

! Other aspects to be considered – reliability, future growth/

flexibility! Average and Upper (peak) demand for utilities and environmental

conditions

! Critical Parameters – set-points, alert and action limits

! Methods of Measurement, control, monitoring and documentation

of parameters

! Automation Control Costs – how much automation is desiredcompared to operating and initial cost

Water System Design

Additional Requirements and


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Additional Requirements andConsiderations

! Potential for Contamination

! Remove higher level ofcontamination first

!

Keep residual chlorine in as long aspossible – how to eliminate whennecessary

" Carbon filtration versus sodiumsulfite injection or UV

! Dead legs and slope to drain

! Keep distribution system simple

! Filtration requirements

! Safety Considerations

W t S t


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Water Systems

! Entire water systems needs to be considered

" Source (Feed) Water

" Production method – How much water will be used?

" Sampling and Testing – data to be collected

" SOPs

" Pre-treatment steps designed based on actual feed

water evaluation! Softener and carbon filter location will depend on

organic content of incoming water

W t S t D i


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Water System Design

! Pre-Treatment

" Multimedia Filter

" Softener

" Carbon Filter

" Cartridge Filters

" DI Columns

" RO Units

" UV Lamps

! Storage and Distribution

! Instrumentation

" TOC – On-Line

" Resistivity/Conductivity Meters

" pH

Pre-Treatment


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Specifications

! Required quantity and quality of treated water for thefinal treatment process

! Temperature and microbial control approach

! Considerations for added substances” – chlorine,sulfite, acid

! Final treatment selected – cost vs risk of failure

!

Quality of the feed water – need to consider spikes andseasonal variation (worst cases)

! Operational, maintenance, safety, validation, location/space, environmental and other requirements

Impact on Final Treatment


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pCaused by Impurities

Fouling -particulates

Scaling –hardness andminerals

Corrosion -chlorides

Degradation -chlorines

RO Large Large None Large - Membranedependent

Other MembraneProcess

Large - Moderate Large - Moderate None Large - Membranedependent

Single Effect Still Moderate Moderate Moderate-Large Large

Multi-Effect Still Large - Moderate Large - Moderate Moderate-Large Large

VaporCompression Still

Moderate Moderate Small Large

88

Micro Control in


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Pre-Treatment

! Micro Control Agent

! Periodic sanitization (heat or chemical)

!

UV Lights! Avoiding dead legs and stagnation

! Removal of control agent:

" Chlorine – simple (Carbon)

" Chloramines – much more complex (requiresseveral steps). Typically, RO is recommended beforeStill with pH controls/adjustments and sulfiteinjection to assure removal of chloramines and CO2

Final Treatment


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Final Treatment

" Significant shift from Ion Exchange basedsystems to membrane based systems forPW production (90% systems are RO basedtoday) due to costs, ease of operation/maintenance and quality of end product

90

P-8

Standard Conventional Purified Water System Design


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Multi-Media

Softener

Carbon

RO CDI/EDIP-7

Storage Tank

PumpHeat Exchanger

Typical Options for Purified


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Typical Options for PurifiedWater

! System A – Pre-treatment followed by off-site regenerated IX (ionexchange) – separate beds or mixed beds(Cations and Anions) orother configurations

" Feed Water analysis is key – focus on meeting Conductivity/TOC levels

" On-site handling of bulk regeneration chemicals – not desired

! System B – Pre-treatment followed by RO (single or double pass)and off-site regenerated IX for ionic polishing

" RO means more pre-treatment

! System C – Similar to B with CEDI replacing IX (no chemical

regeneration)

! System D – pretreatment followed by distillation (meets WFI)

" Higher capital versus less downtime and maintenance (reliability)

! Sanitization considerations (heat resistance) or additional steps –UV or microbial filtration

92

System C


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System C

93

Recommended “HP" Purified Water System

Design


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Multi Media Carbon Softener

RO

Storage Tank

Pump

Virgin Ion Exchange

Mixed Beds

Final filter TOC

UV

g

Nitrogen Blanket

R

R

F

Totalizing Flow Meter

WFI – Purified Water as a


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feed to Still

! Pre- treament for Still is critical

! Will ease the operation/maintenance

! Reduce the possibility of contaminations andendotoxins in the product WFI

! Typical high volume systems will have RO as partof pre-treatment for Still

95

Still Design


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Still Design

! Volume and temperature driven

! Instrumentation and controls

! Materials of construction

! Vendor selection

96

Single Effect Multi-Effect VC

Capacity Range(GPH) 1-100 25-3000 100-6000

WFI Temperature

Range (ºC)

80-100 37-100 - Ambient

- 80-100

- Combination (hot/

cold loops)

Design Table – Technology


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Options for ME Still

97

For VC, RO or UF as Steps 5 and 6 is optional.

Key Factors for Storage


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and Distribution

! Designed tomaintain waterquality and

deliver to usepoints attemperature andflow required

! Capacity! Continuous flow/

movement

! Minimize Cost

98

Materials of Construction


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! Non compendial:

" Polyvinyl Chloride (PVC)

"

Polypropylene (PP)" Polyvinyldene flouride (PVDF)

! Compendial water

" 316 stainless is preferred but PVDF is an option

! Sanitary Fitting

! Consistent diameter where possible

! Orbital welding is preferred

Other Considerations


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Other Considerations

!

Points of Use Design – application ofZero Dead Leg

”

Sanitary Valves

! Sloped to drain

!

Maintained at positive pressure -constant

! Circulating Loop at 3 ft/second

Microbial Controls


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Microbial Controls

! Ozone – periodically or continuously and UV toremove it

! Temperature Controls

! UV Lights for Microbial control – beware of issuesregarding UV such as cleaning/maintenance,intensity monitoring, flow vs contact time andtypical flora/bacteria present

! Filtration on Distribution System – microfiltrationor ultrafiltration

101

Qualification Pre-Requisites


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Qualification Pre-Requisites

! Well defined system and components specifications/functional requirements and drawings

! Well defined quality specifications

! Well defined sampling/testing procedures

! Training of personnel for water sampling/testing

! Operational and maintenance procedures (Draft)

Qualification Documents


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! Installation Qual. – Pre-Requisites

" System description stating design intent

" Schematic drawing of the system (P&ID)

! Location and number of welds

! Relative elevation

! Slope of lines

! Point(s) of drainage

" System specifications

!

Performance criteria

! Design parameters

!

System boundaries

" Detailed design drawings



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! Installation Qual. – Pre-Requisites

" Vendor manuals and drawings

" Field inspection and test reports

!

Cleaning procedures and records

! Passivation procedures and records

! Weld parameter documentation and inspection reports

!

Slope verification

!

Verification of absence of dead-legs

"

System commissioning test results!

Reported as related to acceptance criteria

!

Verification of automated functions

!

Verification of temperature controls

!

Verification of distribution system velocity

! Initial water quality determination

Installation Qualification


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Documents

! System/Components/Equipment Installation Qualification

" Incoming components specifications and inspection

" Installation verification

" Utilities installation

" Critical instrumentation calibration

" Software Configuration

" PM procedures

" As installed system drawings

" SOPs

" Summary report and conclusion



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! Operational Qualification

" Operational Verification

! Sequences – System/components cleaning/sanitization/flushing/regeneration proceduresand frequency

! Critical parameters – data collection

" Procedures may be in draft or operational



107/148



" Sampling points

! Source water

!

After each critical step in the purification process

! Storage tank (temperature profile and water quality)

!

Circulation loop (temperature profile only)

! At each POU (temperature profile and water quality)

" Sampling procedures

" Testing requirements

" Testing methods

" Acceptance criteria



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" Documentation

" Summary report and conclusion



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!

Performance Qualification" Critical instrumentation calibration

" Operational Data Review – System is operating under approved

SOP

s" Sanitization/Cleaning/Regeneration/Flushing data review

" Sampling plan

" Sampling points

!

Source water initially, then weekly

! After each critical step in the purification!

Storage tank (temperature profile and water quality

!

Recirculation loop (temperature profile only)

! At each POU (temperature profile and water quality)



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! Performance Qualification

" Sampling procedures

" Testing requirements

" Testing methods

" Acceptance criteria

" Documentation

" Summary report and conclusions

Sampling Plan


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Sampling Plan

! Phase 1 (OQ):

During the initial phase the operational parameters and cleaning/sanitation procedures and frequencies will be developed.Sampling should be daily after each step in the purification

process and at each point of use for two to four weeks. Thesampling procedures for point of use should reflect how they aretaken, e.g. use of hose, and time for flushing. At the end of thetwo (2) to four (4) weeks of sampling, the firm should havedeveloped its SOPs for operation and maintenance of the water

system." Develop operating ranges

" Develop and finalize operating, cleaning, and maintenanceprocedures

" Demonstrate production and delivery of in-spec water

Sampling Program


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Sampling Program

!

Phase 2 (PQ – Phase 1):

The second phase of the water system validation is to

demonstrate that the system will consistently produce thedesired water quality when operated in conformance withSOPs. The sampling is performed as in the initial phase andfor the same period . At the end of this phase the datashould demonstrate that the system will consistently

produce the desired quality of water." Demonstrate consistent operation within established

ranges

" Demonstrate consistent production and delivery ofquality water

Sampling Program


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Sampling Program

!

Phase 3 (PQ – Phase 2):

The third phase of validation is designed to demonstrate that

when the water system is operated, in accordance with theSOPs, over a long period of time it will consistently producewater of desired quality. Any variations in quality of thefeedwater, that could affect the operation and ultimately thewater quality, will be noticed during this phase of thevalidation.

" Demonstrate extended performance" Evaluate seasonal variation

" For Water for Injection systems samples should be takendaily from a minimum of one point of use, with all pointsof use tested weekly.

Sampling Program


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Sampling Program

!

FDA Requirements:

" The validation of the water system is completedwhen the firm has collected data for a full year.

" The FDA states that while the above validationscheme is not the only way a system can bevalidated, it contains the necessary elements forvalidation of a water system.

”

Microbiological/Chemical Limits


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Chemical Limits

Tests Potable

Water

Purified

Water

Water for Injection

pH N/A 5.0 - 7.0 5.0 - 7.0

TOC N/A 500 ppb C/liter 500 ppb C/literConductivity N/A 1.3 S/cm @ 25ºC

1.1 S/cm @ 20ºC

1.3 S/cm @ 25ºC

1.1 S/cm @ 20ºC

Bacteria 500 cfu/mL 100 cfu/mL 10 cfu/100mL

Endotoxins N/A Not Specified 0.25 EU/mL

cfu; = Colony Forming Units

USP Limits

Water Systems CriticalQuality Attributes (CQA s)


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Quality Attributes (CQA

s)

! TOC

! Conductivity

! Temperature

! Flow

! Pressure

! Rapid Microbiological Enumeration and ID – off-line

! On-Line Microbial rate of growth – laser technology! On-line Endotoxin (Future)


117/148

Design and Qualification ofOther Utilities

Specific Requirements—C S


118/148

April 23, 2013 118

Clean Steam

!

Design Aspects:" Stainless steel boiler

" Deionized water feed

" Sufficient blowdown level

" Diaphragm valves not recommended

Specific Requirements—Cl St


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119

Clean Steam (cont d)

! Clean steam:" IQ:

! Control valves andsteam traps checked

! Flushing, cleaning,passivation logs/records reviewed

" OQ:! Temperature/pressure

" PQ:!

Pure steam condensate= USP WFI

CLEAN STEAMSPECIFICATIONS


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120

SPECIFICATIONS

Table: Microbiological/Chemical Limits

Tests Clean Steam

pH 5.0 - 7.0

TOC 500 ppbConductivity USP 2? Specifications/

method

Bacteria 10 cfu/100mL

Endotoxins 0.25 EU/mL

cfu; = Colony Forming Units

Specific Requirements—


121/148

121

Compressed Gases

! Compressed gas use as:

" Oxygen supply forbioreactors

"

Nitrogen purge toremove oxygen

" Clean air for asepticoperations

! Quality must meet product

specifications

Specific Requirements—C d G


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April 23, 2013 122

Compressed Gases (cont d)

! Product contact air:" Filtered at points of

use" Supplied by oil-free

compressor" Dried (to -40ºF)

! Filter list" Air intake filter

(protect thecompressor)

" Prefilter on desiccantdryer

! Filter list (cont d) " After filter (for

retention of desiccantparticles)

" Carbon bed"

Point of use filter(s)with integritycertification

! Controls andinstrumentation w/calibration check

" Pressure relief valve

" Temperature andpressure gauges

Specific Requirements—C G


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April 23, 2013 123

Compressed Gases (cont d)

! OQ:

" SOPs for operation and maintenance

" Proper operation of controls and indicators(compressor start or tank—bank switching)

" Alarms and interlocks

" Line pressure (throughout distribution piping)

"

Air temperature

PQ: Process (Clean)C d Ai


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124

Compressed Air

! Dew point

! Hydrocarbons! Viable/non-viable

particulates

COMPRESS GAS SYSTEMSTEST PROGRAM


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April 23, 2013 125

TEST PROGRAM

! Sample Site and FrequenciesDetermination

" For compress gas systemssamples should be taken daily froma minimum of one point of use,with all points of use tested weekly.

CLEAN AIRSPECIFICATIONS


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126

SPECIFICATIONS

Table: Microbiological/Chemical Limits

Tests Compress Gas

Dew Point < -10

o

CHydrocarbon as Oil

Mist

< 1 ppm

Gas Content USP 23 Specifications/

method for Purity

Bacteria < 0.1 CFU/ft3

Non-Viable Particulate: Room Classificationcfu; = Colony Forming Units


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Maintaining a Compliant System

127

Monitoring Program


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!

Critical Parameter(s) Controls/Alarms

" Reports verification and review (procedure)

" Alert and Action Limits

" Handling of Alarms

" Process Deviations/Failure investigations

! Laboratory testing:

" Data handling

" Analysis of Trends (Quarterly?)

" Alert Limits and Action Limits

" Outside Limit Conditions/Failure Investigations

Alarms


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129

! Critical parameters –temperature, RH%, PressureDifferential, Velocities/Filter

Pressure Drop! Critical to Program

Adequate Alarm Limits andDelays

! Procedural Action Plan for

Alarm Conditions

Reports Verification and Review(Procedure)


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April 23, 2013 130

(Procedure)

! Operations must review the data(recommendation – weekly)

" If system performs a review/trend and includes alarm

reports, this is simpler" If not, manual review is necessary

! Procedure requirement for review, documentationand archival (hard-copy or electronic)

Process Deviations/FailureInvestigations


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April 23, 2013 131

Investigations

! If Action Limits are exceeded, need a ProcessDeviation or similar form/documentation

! Procedure must indicate form, process, review,

approvals and f/up.! Risk Based Interpretation/Possible Effects -

are the system controls working effectively?

Data Handling/Review/Approval


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April 23, 2013 132

Approval

! Documentation: Forms, rules, review/approval ina procedure

! Critical for Bioburden-based sterilization cycles

! Frequencies/samples need to be adjusted basedon actual results

! Product Release Criteria for Aseptically FilledManufacturing

Training of LaboratoryPersonnel


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April 23, 2013 133

Personnel

! Sampling Techniques

! Sample handling and testing

! Incubation Controls

! Media selection:" Incubation conditions

" Growth promotion tests

Analysis of Trends


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April 23, 2013 134

! Statistical Analysis – Control Charts with Alertand Action Limits

! Report to Responsible Management – Operations

! More critical for higher classifications

Alert and Action Limits


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April 23, 2013 135

! Not specifications

! Alert – potential drift from normal operational conditions

" Based on historical information

" Include a documented f/up investigation

" May require corrective action and testing plan changes

! Action Limits – when exceeded, requires immediate f/upand corrective action

! Both levels should be re-examined at a defined frequency

! References:

" PDA Technical Report #13 (Revised) Fundamentals of an

Environmental Monitoring Program” Sept./Oct 2002" ISO-13048-1, Aseptic Processing of Health Care Products –

Part 1: General Requirements”

August, 1998! Alert and Action Levels should be derived from and consistent

with results obtained during the aseptic process validation.Historical data from routine monitoring may also be

appropriate!”

Outside Alert/Action LimitsConditions/Investigations


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April 23, 2013 136

Conditions/Investigations

! Include review of:

" Area maintenance, Cleaning, SanitizationProcedures/documentation

" Operational Parameters

" Training of personnel in area

!

Corrective Action may include:" Training enforcement

" Additional testing/frequencies

" Additional Sanitization

" Additional product testing

" ID of Microbial Contamination and possible source

" Re-assess current procedures

" Revalidation


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Training Program forMaintenance

d O ti P l


138/148

and Operating Personnel

!

cGMP

s

! DocumentationPractices

!

Test Comprehension

! Change Control is Key

Calibration ofInstrumentation


139/148

!

NIST Traceability

!

Calibration procedures pertype of instrument

!

Control software/hardwaremaintained as per procedures

Change Control


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! Pre and Post Approvalof Change

! Impact of Change

determined

! Documentation ofresults and modified

documents anddrawings included inpackage

! Quality review

! Training is Key forEffective Change Control

! Typical Changes affecting

a Water System:

" Operational Procedures

" Sanitization/Cleaning

Procedures" Sampling/Testing

Procedures

Revalidation –Is it required?


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Is it required?

! DO NOT ESTABLISH TIME-BASEDREVALIDATION

! Base decision to revalidate on change control and

monitoring procedures and controls (trending)

141

Auditing for Compliance


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!

Internal Audits

" Risk analysis for

audit observations" Remediation Plans

and Closure

!

Gap Analysis for

Legacy Systems

142

Exercise : Variance andDeviations Investigations


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! Carbon tank, 2 mixed bed resin tank, single effect still. Systemrequirement is for Purified Water. Action limit is TOC does notexceed 300 ppb. POU measurement is 1X/week. Successive weekslook like this:

Week 1 100

Week 2 155

Week 3 95

Week 4 200

Week 5 290

Week 6 250

Week 7 275

Week 8 280

Week 9 270

Exercise : Variance andDeviations Investigations


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!

No specification have been exceeded.

!

What does this data tell you?

!

Is it time to investigate?

! What questions should be asked?

! Should any batches of product beinvestigated?


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Interactive Exercise:

Based on a critical utility system descriptionto be provided, the participants will list thekey protocol requirements and tests for theOQ and PQ of these systems.

Conclusions


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146

Conclusions

! Facility and Utilities Design is dependent onseveral factors including feeds and desiredspecifications

! Design must also consider costs, flexibility,reliability. Options for system components are

numerous

! Design Review for major systems is an FDAexpectation

! Validation must be considered early in theproject

! Sampling, routine monitoring and analysis of

the data to determine system consistency is key

! Change Control is critical to maintain thesystem integrity and documentation for the FDA

Questions?


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147

THANK YOU!!!


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Contact Info.:

Miguel Montalvo

Expert Validation Consulting, Inc.Mobile Phone +1(407) 587-6540

Email: [email protected]

www.expertvalcon.com

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