GMP For Facilities

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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
Decommission
Operate
Time
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PABME, 27-29 April
2008 Synertec
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Expenditure Lifecycle
$
Construct C&Q
MELBOURNE SYDNEY
Decommission
Cumulative Cashflow
Facility costs/year Time
PABME, 27-29 April
2008 Synertec
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Context
Facility Lifecycle
Design, Build & License (2-5 years) Operate (As long a possible - >15 years?) Decommission (Mercifully swift)
MELBOURNE SYDNEY
Must consider the overall lifecycle

Design for safe & efficient operation Integrated quality into design
What design practices aid efficient GMP compliance once in operation?

PABME, 27-29 April 2008 Synertec
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1. Facility Design
Goal of design Make safe product Sufficient quantity Cost-effective
MELBOURNE SYDNEY
Good
Cheap
Fast
PABME, 27-29 April
2008 Synertec
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Biotech Facilities
Biological processes are complex
MELBOURNE SYDNEY
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
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

MELBOURNE SYDNEY
Manufacturing process requirements Control of contamination and cross-contamination Containment of hazardous materials Utilities Consider up-front capital + lifecycle
PABME, 27-29 April
2008 Synertec
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Design control mechanisms

PEOPLE MATERIALS PRODUCTION SYSTEM
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
Risk Ranking Close-out high risks
IQ/OQ/PQ Validation
PABME, 27-29 April
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
2008 Synertec
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Risk Management determines balance

Facility Design Control
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)
MELBOURNE SYDNEY

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
MELBOURNE SYDNEY
PABME, 27-29 April
2008 Synertec
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Document the Teams Rationale

Quality Management System
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>
Criticality ranking Operating ranges Document versions Automation controls
PABME, 27-29 April
2008 Synertec
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Configuration Management: Design Benefits

Summary of design requirements
Ready correlation of system, risk-ranking, and performance specification
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
PABME, 27-29 April
2008 Synertec
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2. Operation
Product License
MELBOURNE SYDNEY
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
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
MELBOURNE SYDNEY
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
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
MELBOURNE SYDNEY
Continued Compliance Effort
Manual Management Adequate
Consider Use of Automated Tools
Number of Variables
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Support tools
MELBOURNE SYDNEY
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
Add information for operation e.g.

Compatible products
Specific operating conditions Validated cleaning methods
Trained operators
PABME, 27-29 April
2008 Synertec
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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)
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.
PABME, 27-29 April
2008 Synertec
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Continued Compliance
Validation Tool
Comparison
MELBOURNE SYDNEY
Configuration Audit report highlights deviations between the PCS and the CM database.
PABME, 27-29 April
REPORT REPORT
2008 Synertec
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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
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
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
PABME, 27-29 April
2008 Synertec
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Summary
MELBOURNE SYDNEY
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
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
PABME, 27-29 April
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Questions and Answers
MELBOURNE SYDNEY
PABME, 27-29 April
2008 Synertec
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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
PABME, 27-29 April
2008 Synertec
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Q10: Pharmaceutical Quality System*

Discovery Screen Hit to Lead Lead Opt PreIND
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
MELBOURNE SYDNEY
Product Quality?
Combination of design and method of operation determines level of impact
Validation
Pure Water
Direct Impact
PABME, 27-29 April
ISPE Baseline Guide: Vol 5 Commissioning and Qualification
2008 Synertec
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Design to Operation*
Impact Assessment
System Component
MELBOURNE SYDNEY
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
PABME, 27-29 April
*Adapted from ISPE Baseline Guide (Vol. 5, Mar 2001)
2008 Synertec
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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
PABME, 27-29 April
MELBOURNE SYDNEY
Non-Critical Utilities
- Potable Water - Instrument Air - General HVAC - Plant Chiller - Electrical Power - Plumbing/Waste
2008 Synertec
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Example: Purified Water

Component-level assessment
MELBOURNE SYDNEY
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
PABME, 27-29 April
2008 Synertec

GMP For Facilities

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