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GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Risk Management: Requirements, Challenges and Impact on GMP Qualification
ACHEMA | VTU Engineering GmbH | Brigitte Gübitz |
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Content
§ Requirements for Quality Risk Management § Risk Management Process and Risk Analysis Tools§ GMP conform Qualification an Validation
₋ Impact of Risk Management § Status Quo in Risk Management § Future Challenges in Risk Management
₋ Object Oriented Risk Management₋ Knowledge-Based Risk Management à
REXS as best practice tool used by VTU
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Content
§ Requirements for Quality Risk Management § Risk Management Process and Risk Analysis Tools§ GMP conform Qualification an Validation
₋ Impact of Risk Management § Status Quo in Risk Management § Future Challenges in Risk Management
₋ Object Oriented Risk Management₋ Knowledge-Based Risk Management à
REXS as best practice tool used by VTU
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Requirements for Quality Risk Management
§ Risk management is required by lawover the entire life cycle of drugs, API´s, medical devices − Medical devices
ISO 13485 – Section 7.1 planning of product realization:the organization shall establish documented requirements for risk management throughout product realization à reference to ISO 14971: RM-standard
− Drugs and drug ingredientsPart III EU-GMP guideline / ICHQ9- Quality Risk Management:implementation of risk management is required over the whole life-cycle of drugs and API´s resp. across the whole enterprise
− ISO 9001:2015 (publication expected end of 2015):one of the key changes in the 2015 revisionà establishment of a systematic enterprise-wide risk-based approach
à including the entire supply chain
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Potential Risks in Distribution
§ As global production grows, so does the risk§ Significant impact on the distribution
− longer supply chains
− seasonal temperature variations
− distribution network is complex and involves many players
§ Differences between countries / continents− availability of expertise, infrastructure and equipment
− for temperature-controlled storage, transport and distribution
à these variables increase quality and safety risks
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Risk Management for Distribution
§ EU GDP Guidelines− medicinal products for human use:
2013/C 343/01 Guidelines on Good Distribution Practice of medicinal products for human use
− API´s for medicinal products: 2015/C 95/01 Guidelines on principles of Good Distribution Practice of active substances for medicinal products for human use
§ US GDP Guidelines− 21CFR211 Subpart H – Holding and Distribution Management
à a risk based approach for wholesale distribution of medicinal products
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Content
§ Requirements for Quality Risk Management § Risk Management Process and Risk Analysis Tools§ GMP conform Qualification an Validation
₋ Impact of Risk Management § Status Quo in Risk Management § Future Challenges in Risk Management
₋ Object Oriented Risk Management₋ Knowledge-Based Risk Management à
REXS as best practice tool used by VTU
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Risk Management Modelaccording to ISO 14971 / ICHQ9
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
§ Tabular form − Failure Mode and Effects Analysis (FMEA)
− Hazard Analysis and Critical Control Point (HACCP)
− Hazard Operability Analysis (HAZOP)
§ Graphical methods− Cause-and-effect-diagram /
Ishikawa Diagram
− Fault Tree Analysis (FTA)
Conventional risk analysis techniques
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
§ Conventional risk analysis techniques − cover risk assessment and risk control§ Risk Review
− continuous review of risk assessments
− based on knowledge from product life cycle and actual risk knowledge
§ Risk communication− Sharing / reuse of risk knowledge
− key factor for successful risk review and for an effective risk management process
− barely exist in most organizations
Risk Analysis Methods
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Content
§ Requirements for Quality Risk Management § Risk Management Process and Risk Analysis Tools§ GMP conform Qualification an Validation
₋ Impact of Risk Management § Status Quo in Risk Management § Future Challenges in Risk Management
₋ Object Oriented Risk Management₋ Knowledge-Based Risk Management à
REXS as best practice tool used by VTU
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Risk Management in Qualification & Validation
§ Risk management is required by law§ EU-GMP guideline annex 15: qualification and
validationDeadline for coming into operation: 1 October 2015
1) scope and extent of qualification and validationshould be based on risk assessments of the facilities, equipment, utilities and processes
2) a quality risk management approach should be applied throughout the lifecycle of a medicinal product.
à NEW
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Risk Management in Qualification & Validation
§ Risk management is required by law§ EU-GMP guideline annex 15: qualification and
validationDeadline for coming into operation: 1 October 2015
1) scope and extent of qualification and validationshould be based on risk assessments of the facilities, equipment, utilities and processes
2) a quality risk management approach should be applied throughout the lifecycle of a medicinal product.
à NEW
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Scope and Extend of Qualification
Validation MasterplanVMP
ValidationPlanning
Process Validation Cleaning Validation
Validation of Analytical Methods
Master Validation ReportValidation
MonitoringMaintenance
Change- Control
Re-ValidationCont. VerificationDQ
IQ
OQ
PQ
Qualification Master Report
URSQualification
Impact Assessment
Scope of Qualification
RA Testing:Extend of
Qualification
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Scope of Qualification: Impact Assessment
§ Definition according ISPEInternational Society for Pharmaceutical Engineering)− Impact assessment is the process by which the impact of a system on
product quality is evaluated and the critical components within those systems are identified.
§ Is system GMP / GDP critical?− system has direct contact with the product / product components?− system can be a source of contamination?− system can affect cleaning-, sterilization process?− system maintain the correct temperature conditions?− system can affect adequate turnover?− system assures a safe and secure storage?− …….
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Impact Assessment
§ Impact AssessmentA. system has direct contact with the product / product components ?B. system can be a source of contamination?C. system can affect cleaning-, sterilization process?D. system assures a safe and secure storage / transport
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Risk Management in Qualification & Validation
§ Risk management is required by law§ EU-GMP guideline annex 15: qualification and
validationDeadline for coming into operation: 1 October 2015
1) scope and extent of qualification and validationshould be based on risk assessments of the facilities, equipment, utilities and processes
2) a quality risk management approach should be applied throughout the lifecycle of a medicinal product.
à NEW
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Activities in Risk Management
1. Step
Risk Identification
3. Step
Risk Evaluation
4. Step
Risk Control; Risk Acceptance
5. Step
Risk Review
2. Step
Risk Analysis
V
V
VV
V
V
Process-Development
Product-Development
Process-Engineering
Scale Up & Process Optimization
Implementation in production
Manufacturing & Application
à over the whole Product Life Cycle
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Status Quo in Risk Management
§ Risk Management = performing risk assessments and implementing defined measures
§ Risk assessments are performed „isolated“
§ Efficient risk communication is still a challenge
§ Lifecycle-based risk management is required but rarely implemented in daily practice
− lifecycle-approach for risk management is hardly described in the literature
− there are barely any lifecycle-oriented reference-models for risk management in GMP- environment
à Future Challenges: Implementation of Lifecycle-RM and Risk Communication
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Content
§ Requirements for Quality Risk Management § Risk Management Process and Risk Analysis Tools§ GMP conform Qualification an Validation
₋ Impact of Risk Management § Status Quo in Risk Management § Future Challenges in Risk Management
₋ Object Oriented Risk Management₋ Knowledge-Based Risk Management à
REXS as best practice tool used by VTU
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Implementation of Lifecycle-RM:Easy by using existing Object
§ Risk assessments are always performed for products, equipment and processes or their combinations
à Object Oriented Risk Assessments
§ Products are − Final drug products, medical devices, intermediates− Row materials, product components, process media, packaging material§ Processes are
− Production processes− Associated processes (change management, supplier selection, maintenance,
qualification/validation, …)§ Equipment is
− Production facilities, laboratory equipment, IT-systems, …
FFF
FU
Lifecycle of Objects defines à Lifecycle of Risk Management
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Lifecycle Phases of Objects
§ Phases in the lifecycle of a drug / a medical device
I.Product-Development
II:Process-Development Laboratory-scale
III:Process-Engineering (Prototype I)
IV:Scale Up & Process-Optimization (Prototype II)
V:Implementation in Production
VI:Manufacturing/ Application
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Lifecycle of Objects
I: Product-Development
II: Process-Development (Lab)
IV: Scale Up & Process-Optimization (PT II)
VI: Manufacturing / Application
V: Implementation in Production
III: Process-Engineering ng(Prototyp I)
Goods Receipt
Manu-facturing
Quality-Control
Transport / StorageApplication
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Lifecycle of Objects
I: Product-Development
II: Process-Development (Lab)
IV: Scale Up & Process-Optimization (PT II)
VI: Manufacturing / Application
V: Implementation in Production
III: Process-Engineering ng(Prototyp I)
Goods Receipt
Manu-facturing
Quality-Control
Transport / StorageApplication
Lifecycle of Objects defines the
Lifecycle of Risk Assessments
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Lifecycle of Risk Analysis
I: Product- DevelopmentII: Process- Development (Lab)
IV: Scale Up & Process-Optimization (PT II)
VI: Manufacturing / Distribution/ Application V: Implementation in Production
III: Process-Engineering (Prototyp I)
Manu-facturing
Quality-ControlDistributionApplication
RA
RARA
RARA
RA RA
RA
RA
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Lifecycle of Risk Analysis
I: Product- DevelopmentII: Process- Development (Lab)
IV: Scale Up & Process-Optimization (PT II)
VI: Manufacturing / Distribution/ Application V: Implementation in Production
III: Process-Engineering (Prototyp I)
Manu-facturing
Quality-ControlDistributionApplication
RA
RARA
RARA
RA RA
RA
RA
Continuous Improvement Change Control, Deviation Management, New Products,…..
From Risk Analysis to Life Cycle Risk Management
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Extension of Model to Risk Management
Object Level
Improvement Level
Compliance-/ Regulatory-Impact Assessment
Change: manufacturing process 1
Re-Qualification/ Re-Validation
CAPARA route cause
analyses
complaint product 1
• RA Product 1• RA Product 2
Phase I:• RA Equipment 1 & 2• RA Process 1 & 2• RA Safety
Phase IV:• RA Qual. Equipment 1 & 2• RA Val. Process 1 & 2
Phase V:
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Extension of Model to Risk Management
Object Level
Improvement Level
Compliance-/ Regulatory-Impact Assessment
Change: manufacturing process 1
Re-Qualification/ Re-Validation
CAPARA route cause
analyses
complaint product 1
• RA Product 1• RA Product 2
Phase I:• RA Equipment 1 & 2• RA Process 1 & 2• RA Safety
Phase IV:• RA Qual. Equipment 1 & 2• RA Val. Process 1 & 2
Phase V:
Regulatory(RA´s Regulatory)
Quality Management
QM / GxP Level
Technik• RA Maintenance
Equipment 1 & 2
QM• RA Change
Process 1 & 2
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Content
§ Requirements for Quality Risk Management § Risk Management Process and Risk Analysis Tools§ GMP conform Qualification an Validation
₋ Impact of Risk Management § Status Quo in Risk Management § Future Challenges in Risk Management
₋ Object Oriented Risk Management₋ Knowledge-Based Risk Management à
REXS as best practice tool used by VTU
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Path to Knowledge-Based Risk Management at VTU
§ primary barrier to risk management = ineffective risk communication
§ effective risk communication :
1. implementation of a Life-Cycle risk management process
2. Innovative Software for risk managementREXS
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Queries
§ Customized search queries − Sites− Risks− RA-Documents− Actions
§ Question of the experts: − which risk assessements
for a „clean room“ were already performed?
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Suggestions during risk analysis
§ Question of the experts:− Which failures can occur in a production room with fermentation of cell
cultures?F
FF
FU
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Suggestions for risk evaluation
§ Question of the experts: − How is the probabiltiy of
occurence?
§ Former ratings are indicatedü Less time is required for discussionü Consistent results
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Benefit with REXS at VTU
§ Faster preparation of risk analyses§ Consistency across departments and sites§ Easy management of action§ “getting the right information to the right people at the right
time”
GDP & GMP 2015 | VTU Engineering GmbH | Brigitte Gübitz|
Content
§ Requirements for Quality Risk Management § Risk Management Process and Risk Analysis Tools§ GMP conform Qualification an Validation
₋ Impact of Risk Management § Status Quo in Risk Management § Future Challenges in Risk Management
₋ Object Oriented Risk Management₋ Knowledge-Based Risk Management à
REXS as best practice tool used by VTU
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