High Potent Drugs & Containment Technology

Technology Overview & Quality Risk-Based Design Selection

Holger FabritzHead of Quality & Validation Assurance

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Part 1

Definition High Potent Drugs, OEL & hazardous classification

Brief description of isolator and RABS technologies

Isolator/RABS versus Clean room operation

Technology & process examples

Part 2

Risk Analysis –Tool of design evaluation & QM

Risk Analysis –Standards, Workflow, Methods

Project Management

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Definition High Potent Drugs = Active Pharmaceutical Ingredients (HP-APIs)*

1. Highly selective pharmacologically active ingredients thatbinds to specific receptors or enzymes and/or could cause cancer,mutations, developmental effects or reproductive toxicity at low doses.

2. Pharmacologically active ingredient with biological activity at approx. 15 micrograms per kilogram of body weight or below in humans.Equivalent to a therapeutic dose at approx. 1 mg.

3. Active ingredient with an OEL at or below 10 - 20 micrograms per m3 air as an eight hour time weighted average.

*Biological agents like a bacterium, virus, prion or fungus which may cause infection, allergy, toxicity or otherwise create a hazard to human health are not covered in this presentation

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Source:

Definition

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Hazardous Classification

Max. hazardous potential

Min. hazardous potential

Class Physical Condition0 GASES

1 AEROSOL (liquid / air)

2 POWDER (micronized)

3 LYOPHILISAT

4 POWDER (API)

5 POWDER (API + Excipient)

6 LIQUIDS (API)

7 POWDER (humidified)

8 SUSPENSION

9 SOLUTION (org. solvents)

10 SOLUTION (aqueous)

Definition

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Typical HP-API substances

* Source: Shilpi Mehrotra, GBI Researchchemica aggi / Chemistry Today - Vol .28 n 5 September / October 2010

Cytostatica (approx. 59%)*

Hormones

Antibiotics

Narcotics

Radio pharmaceuticals

Products like e. g. Botulinum Toxin (Botox®)

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Commercial value of HP-API

* Source: Shilpi Mehrotra, GBI Researchchemica aggi / Chemistry Today - Vol .28 n 5 September / October 2010

Global market value was at around $ 7.5 billion (2009)* representing approx. 10% of the overall API marketCytostatica (approx. 59%)*

Estimated market growth rate till 2015 is 8.4% per year*

Market split of annual sales within the world regions (2009)*:- North America: 46% (USA represents 94%)- Europe: 36% - Asia: 10% (fastest growing market)

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HP-API facility design

Building

Building utilities

Equipment

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Available cleanroom technologies

Conventionalcleanroom

IsolatorClosedRABS (cRABS)

Open RABS

Open SystemNo operator / environmental

protection*

Local containmentOperator / environmental

protection

* Operator and environmental protection can be achieved by local measures

* Operator and environmental protection can be achieved by local measures

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Conventional clean room

Conventionalcleanroom

IsolatorClosedRABS (cRABS)

Open RABS

Open SystemNo operator / environmental

protection*

Local containmentOperator / environmental

protection

* Operator and environmental protection can be achieved by local measures

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Open Restricted Air Barrier System (RABS)

Conventionalcleanroom

IsolatorClosedRABS (cRABS)

Open RABS

Open SystemNo operator / environmental

protection*

Local containmentOperator / environmental

protection

* Operator and environmental protection can be achieved by local measures

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Closed RABS

Conventionalcleanroom

IsolatorClosedRABS (cRABS)

Open RABS

Open SystemNo operator / environmental

protection*

Local containmentOperator / environmental

protection

* Operator and environmental protection can be achieved by local measures

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Isolator

Conventionalcleanroom

IsolatorClosedRABS (cRABS)

Open RABS

Open SystemNo operator / environmental

protection*

Local containmentOperator / environmental

protection

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Isolator & Process Equipment

Example: Weighing & Compounding

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Example: Weighing & Compounding

Isolator & Process Equipment

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Quality is not only a matter of technology.

The circumstances at point of process need to be designed in detail.

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Example: Optimization of filling process

VIDEO VIDEO

Quality is not only a matter of technology.

The circumstances at point of process need to be designed in detail.

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Why Risk Analyses ?

Systematic analysis of risksin order to identify adequate measures / tests

Abstract analysis prior to the real performance(the opposite of „trail and error“)

Risk-based guidance to clear technical requirements

Method to filter out the essential („right“) requirements

Systematic decision making

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Damage without Risk Analyses

Design requirements are not respected or forgotton

Technical solutions are developed without clear requirements

Tests (Qualification/Validation) are not complete

Tests are performed although not necessary

Conflicts may arise from not involving all competente persons

Expensive solutions do not meet the major aims.

„Unforeseen“ conflicts

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Fields of application

SafetyEnvironmental protection, health, safety at work (EHS)SecurityOperations with high hazard potential (Aviation and aerospace industry, medicine, radioactivity,….)

EconomyDecision for investments (prospects and risks)Optimisation of costs (quality aims vs. costs)Readiness for delivery / time-management vs. costs

QualityQuality ManagementDesign evaluationChange Management

Quality controlInspection of incoming goodsGMP Compliance:Equipment qualification, process validation, cleaning validation

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EC Guide to Good Manufacturing Practice Annex 1 (Sterile Manufacturing),Annex 15 (Qualification and Validation),Annex 20 (Quality Risk Management) (2008) / ICH Q9 (2005)

ISPE-GAMP5

ISPE Baseline® Vol.1-Active Pharmaceutical Ingredients (2nd Edition, 2007)

ASTM E2500-7 Standard

ISO 14971(2007): Application of risk management to medical devices

International regulations concerning GMP Risk Analysis in the pharmaceutical & medical device industry

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GMP Risk Analysis Workflow

Method & formal framework is traceable and agreedupon within the team

The scope of Risk Analysis is be determined

Project documentation on current status is available

Interdisciplinary team of experts & process owners

Unstressed workshop / meeting atmosphere

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Source: ICHQ9 – Quality Risk Management (since 2008 Annex 20 of the EC-GMP-Guide)

RiskIdentification

RiskAnalysis

RiskEvaluation

RiskReduction

RiskAcceptance

Risk Assessment Risk Control

GMP Risk Analysis Workflow

Risk Assessment: Risks should be identified & not been solved

Risk Control: measures and tests should be practicable

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Risk Analysis MethodFMEA / FMECA (Example)

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Risk Analysis MethodDetermination of technical solutions / design by Risk Analysis (Example):

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Producer /Client

Engineering /ServiceSupplier

Equipment-Manufacturer

GMP Risk Analysis & Project Management

Roles of project members

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Project ManagementProduction ManagementQuality AssurancePurchasingProject ManagementProcess TechnologyInfra StuctureArchitecturePiping ConstructionCADInstallation ManagementGMP ComplianceEquipment Manufacturer 1Equipment Manufacturer 2Equipment Manufacturer 3

GMP Risk Analysis & Project Management

Roles of project members

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? Questions ?