GMP for Facilities

8/13/2019 GMP for Facilities

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2008 SynertecPABME, 27-29 April

GMP for facilities:

From design through to operationDr Nick Kotlarski

Principle Consultant, Biopharmaceuticals

Synertec Asia Pte Ltd

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Typical Facility

Lifecycle

Time

Decommission

Site selection &Master planning

ConceptDesign

DetailedDesign

Construct

Procurement Commission

Qualify

Validate

Operate

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Expenditure Lifecycle

Time

$ Construct C&Q DecommissionCumulative Cashflow

Facility costs/year


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Context

Facility Lifecycle

Design, Build & License (2-5 years)

Operate (As long a possible - >15 years?) Decommission (Mercifully swift)

Must consider the overall lifecycle

Design for safe & efficient operation

Integrated quality into design

What design practices aid efficient GMPcompliance once in operation?




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1. Facility Design

Good

FastCheap

Goal of design

Make safe product

Sufficient quantity Cost-effective




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Biotech Facilities

Biological processes are complex 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 themanufacturing 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 themost important facility control points

To achieve this:

Fundamental understanding of Products criticalquality attributes is needed (ICH Q8)

Clearly defining a risk-based approach aligns thetasks of facility design through to operationmaximising product safety.




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Facility Design Issues

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 PRODUCTIONSYSTEM

UTILITIES

LAYOUT DESIGNis the key control

SYSTEM DESIGNis the key control

PROCEDURESmaintain control

MONITORINGmaintains control

Operational controls



Cli k H & U d


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Outline of Risk-based

Design to Operation

Quality

Management

System

System Impact

(No/In-/Direct)

Component

Criticality

GEPNo

GEPNo

Risk Ranking

Close-outhigh risks

IQ/OQ/PQValidation

SOP

Design activities:

System impactassessment

Component criticality

Plan how to close-out risks

Testing activities

Follow logically fromthe design planning

Most effort on thehighest risks



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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

Risk assessment is at the core of a methodologyfor aligning resources to achieve maximum safety

Frequency & limitsBasis for sentencing OOS





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Effort Risk

GoodDesign

IndirectSystems

Utilities(No impact)

ValidatedMonitoring

PVPQOQIQCommission

AssessRisk

DirectImpact

Good EngineeringPractice (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

Document templates

Facilitate cross-functional teams, promote the focus onproduct safety

Refer back to this body of knowledge

Share it widely

Keep current

Establish a system for managing a facilitysconfiguration parameters





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Configuration

Management Database

Operating ranges

Planthierarchy

Alarmsettings

Automation controls

Criticality ranking

Design spec

Document versions





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Configuration Management:

Design Benefits

Summary of design requirements

Ready correlation of system, risk-ranking, andperformance specification

Can be cross-referenced during commissioning &qualification to confirm that all design parametershave been met.

Can simplify automatic generation of test protocols Know ledge management

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FacilityBuildCapacity

Decommission

2. Operation

Goal is to maintain the Validated state

As documented in specifications & qualification

WithdrawCommercialManufactureClinicalDiscovery

Operation

ProductLicense

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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

Executed Commissioning Protocols

Executed Qualification protocols (IQ/OQ/PQ)

As-built description Change Management

SOPs for facility (& product) Maintenance, calibration, purchasing

Documented summary

of product knowledge


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Live Design

Documents Once validated, VMP must still be followed

Not restricted to start-up

Not restricted to Consultants that qualifiedfacility

Responsibility of staff, contractors & consultants

When changes are made, the relevantdesign & testing documents should be

revised


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Compliance Complexity

Number of Variables

ContinuedCompliance

Effort

ManualManagementAdequate

Consider Useof Automated

Tools


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Support tools

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


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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.


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Continued Compliance

Configuration Auditreport highlightsdeviations between thePCS and the CMdatabase.

Validation Tool

Comparison

REPORTREPORT


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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 throughto operation

Prevent erosion Efficient dissemination

Influence of design on operation


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Summary

Vision for Design & Operation

Fundamental understanding of manufacturing process

Design control mechanisms

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

proportional to risk


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Contemporary Facility

Lifecycle

Time

Critical QualityAttributes

Design tocontrol risk

Construct

Test Facility

ValidateProcess

Decommission

Operate

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

Continual compliance based on productunderstanding & risk-management

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Questions and Answers



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Contact

Synertec Pty. Ltd.

Level 34,

100 Miller Street

Nth Sydney NSW 2060( +61 2 9922 3233

Synertec Pty. Ltd.

57 Stewart Street

Richmond VIC 3121

( +61 3 9274 3000

Synertec Asia Pte. Ltd.

2 Bukit Merah Central #14-04

Spring Singapore Building

Singapore 159835( +65 6377 0865

[email protected]


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LaunchFilingPhase

IIIPhase

IIPhase

IPre-IND

LeadOpt

Hitto Lead

ScreenDiscovery

Q10: Pharmaceutical

Quality System*

Aims

Achieve Product Registration Establish & Maintain Control

Facilitate ContinuousImprovement

Regional GMPs

ISO 9000

Q9: Quality RiskManagement

Q8: PharmaceuticalDevelopment

Q10: Pharmaceutical QualitySystem

* Draft, May 2007

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ISPE C&Q Baseline*

Parking Facilities

Elevators

Pure Water

Chilled Water

Office A/C

BMS

Production A/C

Autoclave

No Impact

DirectImpact

ProductQuality?

Combination ofdesign andmethod ofoperationdetermines

level of impact

GEP

Validation

ISPE Baseline Guide:Vol 5 Commissioning and Qualification


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Design to Operation*

ProcessValidation

GEP Contribution

Of Interest to Regulators

IQ & OQ

CommissioningEnhanced

Design Review

Design

Development

PQ

Design for Impact Focus testing on Impact

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

VMP

Impact Assessment

System ComponentProtocols


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Example: Utilities

Critical Utilities- Purified Water- Water for Injection- Clean Steam- Process Gasses

- HVAC- CIP/Cleaning- Process Chiller- Process Controls- Critical Power

Non-Critical Utilities- Potable Water- Instrument Air- General HVAC- Plant Chiller

- Electrical Power- Plumbing/Waste

GMPManufacturing

Process


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Example: Purified Water

Component-level assessment Component performance range

Equipment/instrument

Design criteria Operating range

Close-out Tests for IQ/OQ/PQ & annual revalidation

Input to SOP for monitoring, maintenance, calibration,purchasing, out-of-specification & records

en em, tra lai em loi yeu thuong em dem, tra lai em niem tin thang nam qua ta dap xay. Giet


GMP for Facilities

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