Vortrag BGü Bucaresti 2015 02 Brigitte - Tarus Mediatarusmedia.ro/wp-content/uploads/2015/09/Brigitte_Kubitz.pdf · 2013. 9. 25. · GDP & GMP 2015 | VTU Engineering GmbH | Brigitte


Content

ß Requirements for Quality Risk Management ß Risk Management Process and Risk Analysis Toolsß GMP conform Qualification an Validation

₋ Impact of Risk Management ß Status Quo in Risk Management ß Future Challenges in Risk Management

₋ Object Oriented Risk Management₋ Knowledge-Based Risk Management ‡

REXS as best practice tool used by VTU


Requirements for Quality Risk Management

ß 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 ‡ 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 revision‡ establishment of a systematic enterprise-wide risk-based approach

‡ including the entire supply chain


Potential Risks in Distribution

ß As global production grows, so does the riskß Significant impact on the distribution

− longer supply chains− seasonal temperature variations− distribution network is complex and involves many players

ß Differences between countries / continents− availability of expertise, infrastructure and equipment − for temperature-controlled storage, transport and distribution

‡ these variables increase quality and safety risks


Risk Management for Distribution

ß 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

ß US GDP Guidelines− 21CFR211 Subpart H – Holding and Distribution Management

‡ a risk based approach for wholesale distribution of medicinal products


Content






Risk Management Modelaccording to ISO 14971 / ICHQ9


ß Tabular form − Failure Mode and Effects Analysis (FMEA)

− Hazard Analysis and Critical Control Point (HACCP)

− Hazard Operability Analysis (HAZOP)

ß Graphical methods− Cause-and-effect-diagram /

Ishikawa Diagram

− Fault Tree Analysis (FTA)

Conventional risk analysis techniques


ß Conventional risk analysis techniques − cover risk assessment and risk controlß Risk Review

− continuous review of risk assessments− based on knowledge from product life cycle

and actual risk knowledgeß 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


Content






Risk Management in Qualification & Validation

ß Risk management is required by lawß 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.

‡ NEW


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


Scope of Qualification: Impact Assessment

ß 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.

ß 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?− …….


Impact Assessment

ß 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


Extend of Qualification: FMEA


Risk Management in Qualification & Validation

ß Risk management is required by lawß 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.

‡ NEW


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

‡ over the whole Product Life Cycle


Status Quo in Risk Management

ß Risk Management = performing risk assessments and implementing defined measures

ß Risk assessments are performed „isolated“

ß Efficient risk communication is still a challenge

ß 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

‡ Future Challenges: Implementation of Lifecycle-RM and Risk Communication


Content






Implementation of Lifecycle-RM:Easy by using existing Object

ß Risk assessments are always performed for products, equipment and processes or their combinations

‡ Object Oriented Risk Assessments

ß Products are − Final drug products, medical devices, intermediates− Row materials, product components, process media, packaging materialß Processes are

− Production processes− Associated processes (change management, supplier selection, maintenance,

qualification/validation, …)ß Equipment is

− Production facilities, laboratory equipment, IT-systems, …

FFF

FU

Lifecycle of Objects defines ‡ Lifecycle of Risk Management


Lifecycle Phases of Objects

ß 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


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

I: Product-Development

II: Process-Development (Lab)


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


Lifecycle of Risk Analysis

I: Product- DevelopmentII: Process- Development (Lab)


VI: Manufacturing / Distribution/ Application V: Implementation in Production

III: Process-Engineering (Prototyp I)

Manu-facturing

Quality-ControlDistributionApplication

RA

RARA

RARA

RA RA

RA

RA


Lifecycle of Risk Analysis

I: Product- DevelopmentII: Process- Development (Lab)


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


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:


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


Content






Path to Knowledge-Based Risk Management at VTU

ß primary barrier to risk management = ineffective risk communication

ß effective risk communication :

1. implementation of a Life-Cycle risk management process

2. Innovative Software for risk managementREXS


Queries

ß Customized search queries − Sites− Risks− RA-Documents− Actions

ß Question of the experts: − which risk assessements

for a „clean room“ were already performed?


Suggestions during risk analysis

ß Question of the experts:− Which failures can occur in a production room with fermentation of cell

cultures?F

FF

FU


Suggestions for risk evaluation

ß Question of the experts: − How is the probabiltiy of

occurence?

ß Former ratings are indicated¸ Less time is required for discussion¸ Consistent results


Benefit with REXS at VTU

ß Faster preparation of risk analysesß Consistency across departments and sitesß Easy management of actionß “getting the right information to the right people at the right

time”


Content






Any Questions?