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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 ?