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GMP for facilities: From design through to operation


Dr Nick Kotlarski
Principle Consultant, Biopharmaceuticals Synertec Asia Pte Ltd

PABME, 27-29 April

2008 Synertec

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Typical Facility Lifecycle


Construct Procurement Detailed Design Concept Design Commission Qualify Validate

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Decommission

Operate

Time
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Expenditure Lifecycle
$
Construct C&Q

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Decommission

Cumulative Cashflow

Facility costs/year Time

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Context
Facility Lifecycle
Design, Build & License (2-5 years) Operate (As long a possible - >15 years?) Decommission (Mercifully swift)

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Must consider the overall lifecycle


Design for safe & efficient operation Integrated quality into design

What design practices aid efficient GMP compliance once in operation?


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1. Facility Design
Goal of design Make safe product Sufficient quantity Cost-effective

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Good

Cheap

Fast

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Biotech Facilities
Biological processes are complex

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display inherent variability many process streams favour microbial growth more variable biological analytical techniques

Frequently administered parenterally Handle genetically-modified organisms Quality is directly linked to the manufacturing facility High-risk Product category
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Designing & Operating Facilities

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Regulatory expectation is a risk-based approach to validation for facilities (ICH Q9/Q10) Efficient design directs attention (& cost) to the most important facility control points To achieve this: Fundamental understanding of Products critical quality attributes is needed (ICH Q8) Clearly defining a risk-based approach aligns the tasks of facility design through to operation maximising product safety.
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Facility Design Issues


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Manufacturing process requirements Control of contamination and cross-contamination Containment of hazardous materials Utilities Consider up-front capital + lifecycle

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Design control mechanisms


PEOPLE MATERIALS PRODUCTION SYSTEM

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UTILITIES

LAYOUT DESIGN is the key control PROCEDURES maintain control

SYSTEM DESIGN is the key control MONITORING maintains control

Operational controls
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Outline of Risk-based Design to Operation


System Impact No GEP (No/In-/Direct) Component No GEP Criticality
Quality Management System

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Risk Ranking Close-out high risks

IQ/OQ/PQ Validation
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SOP

Design activities: System impact assessment Component criticality Plan how to closeout risks Testing activities Follow logically from the design planning Most effort on the highest risks
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Risk Management determines balance


Facility Design Control

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Effort ($) invested in controlling the most significant risks Rationale for extent of validation

Facility Operational Controls


Calibration Maintenance On-going testing Revalidation Frequency & limits Basis for sentencing OOS

Risk assessment is at the core of a methodology for aligning resources to achieve maximum safety
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Effort Risk
Utilities
(No impact)

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IQ

Indirect Systems Direct Impact


OQ


PQ


PV


Validated Monitoring

Assess Good Commi Risk Design ssion

Good Engineering Practice (GEP)


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Team-based
QA & Reg. Affairs R&D Production QC (Clinical) (Commercial) Engineering Share responsibility Contract expertise as required Communication

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Document the Teams Rationale


Quality Management System

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Document templates Facilitate cross-functional teams, promote the focus on product safety

Refer back to this body of knowledge


Share it widely Keep current

Establish a system for managing a facilitys configuration parameters


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Configuration Management Database


Plant hierarchy Design spec Alarm settings <User>

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Criticality ranking Operating ranges Document versions Automation controls

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Configuration Management: Design Benefits


Summary of design requirements
Ready correlation of system, risk-ranking, and performance specification

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Can be cross-referenced during commissioning & qualification to confirm that all design parameters have been met. Can simplify automatic generation of test protocols Knowledge management

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2. Operation
Product License

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Discovery

Clinical
Build Capacity

Commercial Manufacture Facility

Withdraw
Decommission

Operation
Goal is to maintain the Validated state As documented in specifications & qualification
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Out-puts from Design & validation


Operating facility
Some stock of registration batches

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Cupboard(s) full of documents Personnel


Maybe a few from the product inception Many recent quality & production hires

High expectations
Supply conforming product Make a return on investment

Start-up support personnel


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Those documents
Validation Master Plan (VMP) Risk assessments
No-, indirect- & direct-impact Component-level

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Documented summary of product knowledge

Executed Commissioning Protocols Executed Qualification protocols (IQ/OQ/PQ) As-built description


Change Management

SOPs for facility (& product)


Maintenance, calibration, purchasing
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Live Design Documents

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Once validated, VMP must still be followed


Not restricted to start-up Not restricted to Consultants that qualified facility Responsibility of staff, contractors & consultants

When changes are made, the relevant design & testing documents should be revised
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Compliance Complexity

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Continued Compliance Effort

Manual Management Adequate

Consider Use of Automated Tools

Number of Variables
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Support tools

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Automated Information Management Systems (AIMS)


Enterprise Resource Planning system (ERP) Manufacturing Execution System (MES) Computerised Maintenance Management Systems (CMMS)

Document Management System Complex task just using these effectively .. Configuration Management System
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Configuration Management
Database information provides content for much of AIMS
Single source
Established at design inception Controlled information

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Add information for operation e.g.


Compatible products
Specific operating conditions Validated cleaning methods

Trained operators

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CM applied to Process Control System (PCS)


Configuration database contains
All equipment systems, set points
Often only documented in qualification packages (if at all)

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Expected operating ranges & alarms

Reference PCS to configuration database


Avoid duplication/transfer of information Provide real-time feedback to verify against the configuration database = continuous verification.

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Continued Compliance
Validation Tool
Comparison

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Configuration Audit report highlights deviations between the PCS and the CM database.
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REPORT REPORT

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Configuration Management: Operational Benefits


Single source of facility parameters
Based on design requirements Change control to capture as-built state Referenced by AIMS

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Additional control over system configuration


Reduced risk of unknown, uncontrolled changes
Instruments Set-points, controller tuning parameters

Deviations discovered early

Streamline revalidation documentation generation


Single point of change for configuration information
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Alignment of design for operational excellence

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Sharing & management of critical parameters needs to be consistent between departments


Sharing across AIMS Essential tools for complex biotech facilities

Managing knowledge from facility design through to operation


Prevent erosion Efficient dissemination Influence of design on operation

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Summary

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Vision for Design & Operation Fundamental understanding of manufacturing process Design control mechanisms proportional to risk Test to confirm control Maintain this control with continuous improvement Key steps Document & share critical quality attributes Align systems
Continue risk-based approach during operation

Central database of attributes is a useful tool


Especially those critical to quality
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Contemporary Facility Lifecycle


Construct Test Facility Validate Process Design to control risk

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Decommission

Operate Control Critical Quality Attributes Aligned systems Risk-Assessments Effective support tools

Time

Critical Quality Attributes

Continual compliance based on product understanding & risk-management


2008 Synertec

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Questions and Answers

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Contact
Synertec Asia Pte. Ltd. 2 Bukit Merah Central #14-04 Spring Singapore Building Singapore 159835 ( +65 6377 0865 Synertec Pty. Ltd. 57 Stewart Street Richmond VIC 3121 ( +61 3 9274 3000

MELBOURNE SYDNEY

Synertec Pty. Ltd. Level 34, 100 Miller Street Nth Sydney NSW 2060 ( +61 2 9922 3233

nick.kotlarski@synertecasia.com www.synertec.com

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Q10: Pharmaceutical Quality System*


Discovery Screen Hit to Lead Lead Opt PreIND

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Phase I

Phase II

Phase III

Filing

Launch

ISO 9000 Q9: Quality Risk Management Q8: Pharmaceutical Development

Regional GMPs Q10: Pharmaceutical Quality System Aims Achieve Product Registration Establish & Maintain Control Facilitate Continuous Improvement
2008 Synertec

Draft, PABME, 27-29*April

May 2007

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ISPE C&Q Baseline*


GEP Parking Facilities No Impact
Elevators Office A/C Chilled Water BMS Production A/C Autoclave

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Product Quality?

Combination of design and method of operation determines level of impact

Validation

Pure Water

Direct Impact

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ISPE Baseline Guide: Vol 5 Commissioning and Qualification

2008 Synertec

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Design to Operation*
Impact Assessment
System Component

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Protocols

Design Development VMP


Enhanced Design Review

Commissioning

PQ

Process Validation

IQ & OQ Design for Impact Focus testing on Impact Of Interest to Regulators GEP Contribution

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*Adapted from ISPE Baseline Guide (Vol. 5, Mar 2001)

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Example: Utilities
GMP Manufacturing Process Critical Utilities
- Purified Water - Water for Injection - Clean Steam - Process Gasses - HVAC - CIP/Cleaning - Process Chiller - Process Controls - Critical Power
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Non-Critical Utilities
- Potable Water - Instrument Air - General HVAC - Plant Chiller - Electrical Power - Plumbing/Waste

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Example: Purified Water


Component-level assessment

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Component performance range Equipment/instrument Design criteria ben em, tra laiem loi yeu thuong em dem, tra lai em niem tin thang nam qua ta dap xay. Gio php.net Operating range

Close-out
Tests for IQ/OQ/PQ & annual revalidation Input to SOP for monitoring, maintenance, calibration, purchasing, out-of-specification & records

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