presented by john montalto 13 may, 2013 - pharmout q9 10 qrm overview ... • the international...
TRANSCRIPT
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ICH Q8 & Q9
Presented by John Montalto
13 May, 2013
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Slide 2 PharmOut 2013
Guidelines
Please contribute
Please stop me to ask a question
Please relax and enjoy yourself
Phone on silent
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Slide 3 PharmOut 2013
ICH Q8
01 Introduction
02 ICH Quality paradigm
03 Pharmaceutical development
04 QbD
04a QbD case study
05 Control strategy
06 QTPP
07 DoE
08 Process capability
09 Outcomes of Pharmaceutical development
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Slide 4 PharmOut 2013
ICH Q9
10 QRM overview
11 History of QRM
12 QRM resources
13 QRM Regulatory implementation
14 QRM multi-disciplinary teams
15 Risk justifications
16 Risk registers
17 Risk management models
18 Risk management summary
Activity 9-10
Activity 11
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Slide 5 PharmOut 2013
Assessment
Open book assessment
30 minutes
Hand in Assessment and Feedback form.
Thank-you!
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Introduction to Pharmaceutical Development and Quality Risk Management
Presented by John Montalto
13 May, 2013
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Slide 7 PharmOut 2013
John Montalto
I hold a Bachelor of Science degree and a Diploma in Management
16 years industry experience in a variety of roles Facilitator and consultant to various government agencies,
regulators and the United Nations
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Lei Hao
This activity is a getting to know you exercise:
Introduce yourself What is one interesting fact about
you?
5 min/?
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Slide 9 PharmOut 2013
Course structure
Day 1
ICH Q8
Pharmaceutical development
Design space
Day 2
ICH Q9
Implementation of Quality Risk Management (QRM)
Day 3
ICH Q9
QRM models
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Course objectives
ICH Q8
Understand the basic concepts and requirements of Pharmaceutical Development
Understand the concepts and requirements of Quality by Design (QbD)
ICH Q9
Identify critical quality attributes and critical process parameters in a manufacturing process
Integrate QRM into quality management systems
Understand different risk assessment tools
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Activity 1 Pharmaceutical development
With the person next to you, discuss and document the following:
Define the term pharmaceutical development
What does pharmaceutical development mean to you?
What do you expect within pharmaceutical development?
Contribute to the group discussion
WB 1/ 10 mins
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Slide 12 PharmOut 2013
Activity 2 Quality Risk Management (QRM)
With the person next to you, discuss and document the following:
Define the term Quality risk management
What does Quality risk management mean to you?
What do you expect from a QRM system?
Contribute to the group discussion
WB 2/ 10 mins
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Influences on pharmaceutical development and risk management
|1835 | 1960s 1990|1998 | 2000 | 2006 | 2008 2010 | 2011 |2012
first factory mutual insurer
was created
ISO 14971 Medical
devices Application of
risk management to medical
devices published
ICH Q9
Failure Modes Effects
Analyses were used to improve efficiency and run time of
equipment from a
reliability perspective
ICH Q8
ASTM E2500-
07
ASTM E2500-
07
ICH Q10
ICH Q11
ISO 31000 Risk
management principles
and guidelines
ICH established
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Slide 14 PharmOut 2013
Top 10 Most Frequently Cited GMP Deficiencies (PIC/S Member Authorities)(July 2010 June 2011)
1. Documentation on manufacturing
2. Design & maintenance of premises
3. Documentation quality systems elements/procedures
4. Personnel issues training
5. Design & maintenance of equipment
6. Cleaning validation
7. Process validation
8. Product Quality Review
9. Supplier & contractor audit
10.Calibration of measuring & testing equipment
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Top 10 Most SevereGMP Deficiencies (PIC/S Member Authorities)(July 2010 June 2011)
1. Design & maintenance of premises
2. Contamination, potential for (chemical, physical, microbial)
3. Design & maintenance of equipment
4. Sterility assurance
5. Batch release procedures
6. Process validation
7. Cleaning validation
8. Investigation of anomalies
9. Documentation quality systems elements/procedures
10. Regulatory issues noncompliance with marketing authorisation
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Top Ten GMP Deficiencies found by MHRA (UK)(from MHRA web site Aug 2011)
1. Investigation of Anomalies
2. Quality management
3. Quality management (Change Control)
4. Validation Master Plan & Documentation
5. Corrective Action/Preventative Action (CAPA)
6. Complaints and Product Recall
7. Documentation
8. Equipment Validation
9. Quality Management Product Quality Review
10.Investigation of Anomalies - OOS
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Pharmaceutical development and risk management in the future
A greater emphasis on risk registers is one anticipated focus of regulatory agencies
Integration of risk management into the wider quality systems
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The ongoing impact of ICH Quality Guidelines
Within the GMP guides expect an ongoing alignment with:
ICH Q8 Pharmaceutical Development
ICH Q9 Quality Risk Management
ICH Q10 Pharmaceutical Quality System
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EU GMP updates short term
GMP chapter 1 GMP chapter 7 GMP Annex 2
Pharmaceutical Quality System
Q10 alignment
Outsourced Activities
Q9 and Q10 alignment
The MHRA has expressed its desire to better regulate and control biological products, and sees this industry as one of sustained growth and increasing proliferation in the market place
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EU GMP updates mid term
GMP chapter 2 GMP chapter 5
Q9 and Q10 alignment
- Continuous verification of training
The term pedigree and verifying the pedigree of starter materials
- Location- Suppliers- Integrity of supplied product- Inspection and compliance of
suppliers- Raw materials and starter materials
controls- Certification of suppliers
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EU GMP updates long term
GMP chapters 3 and 5
GMP chapter 6 GMP chapter 8 GMP Annex 16
Q9 alignment
Segregated facilities
Q9 and Q10 alignment
Formal considerations for Out Of Specification results and trending guidance
Q9 alignment
Reporting strategies, product shortages, Corrective and Preventative Action systems and root cause analysis
Qualified Persons
Harmonisation and mechanisms for ensuring consistent approaches for Qualified Persons and batch release
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EU GMP proposals
Ongoing regulatory focus
The MHRA anticipate an ongoing adoption of ISO14644 Cleanrooms and associated controlled environments into Annex 1 Manufacture of Sterile Medicinal Products requirements
Blood and tissues The creation of a Good Practice code for blood and tissues is
seen as critical to public safety
Improved clarification on collection and testing stages
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EU GMP proposals
Concept papers
Annex 15 Qualification and Validation Continuous Process Verification will become a formal
requirement of validation methodologies
Annex 17 Parametric Release The rise of new technologies and on line testing technology
will shape annex 17 in the future
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EU GMP proposals
Concept papers
Good Distribution Practice for Active substances
QRM guidelines for excipients handling
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Pharmaceutical development
an opportunity to present the knowledge gained through the application of scientific approaches and quality risk management to the development of a product and its manufacturing process.
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Why adopt a risk management approach?
"Two primary principles of quality risk management are:
The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient; and The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk
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Laying the foundations
Understanding the principles of QRM is the foundation for ensuring the process consistently produces a
quality product.
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Activity 3What could go wrong?
WB 3/ 10 mins
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The quality paradigm
Presented by John Montalto
13 May, 2013
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ICH - 20 year process
The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
The ICH was initiated in 1990
Objective of ICH:Technical and scientific harmonisation between Japan, Europe and US. This objective has evolved significantly.
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Quality Paradigm
Paradigm a framework containing the basic assumptions, ways of thinking and methodology that are commonly accepted by members of a scientific community
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Develop a harmonised pharmaceutical quality system applicable across the lifecycle of the product emphasizing an integrated approach to quality risk management and science.
ICH, 2003
Quality paradigm
Pharmaceutical Quality System
Science and knowledge
Quality risk management
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Quality paradigm
ICH Q8 Pharmaceutical Development
ICH Q9 Quality Risk
Management
ICH Q10 Pharmaceutical Quality System
ICH Q11 Development
and Manufacture of
Drug Substances
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Quality paradigm
Science and knowledge should not be isolated, but are dynamic across the lifecycle of the product and process and implemented throughout the quality management systems
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Quality paradigm
Key points
1 Quality must be built in. Quality cannot be tested in.
2 Utilise and rely on science throughout the product lifecycle
3 QRM is a key enabler to be applied across the product lifecycle
4 To assure product quality, a robust pharmaceutical quality system and knowledge management must be in place
5 An integrated approach to quality; including development, manufacturing and quality
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Quality paradigm
Quality must be built in. Quality cannot be tested in.
In process and end product testing are only indicators of product quality
What must be considered:
In process and end product testing
Process reliability and robustness
Controlling variables
More comprehensive assurance of product quality
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Quality paradigm
Utilise and rely on science throughout the product lifecycle
What are the Critical Quality Attributes (CQAs) of a bottle of water?
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Quality paradigm
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Quality paradigm
Utilise QRM to formalise knowledge and establish more reliable communication mechanisms
Utilise QRM to assess and evaluate the impact of variables to the product and process
QRM is a dynamic process that continually evolves
QRM is a key enabler to be applied across the product lifecycle
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Quality paradigm
To assure product quality, a robust pharmaceutical quality system and knowledge management system must be in place:
QRM must be integrated into the quality management system
Knowledge must be:
Acquired Captured Managed
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Quality paradigm
An integrated approach to quality, including:
Stand alone systems will not adequately incorporate knowledge
Information and knowledge from all phases of the product lifecycle must feedback into the quality management system
Development Manufacturing Quality
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ICH Q8
Empirical, minimal approach
Considers only the essential product development requirements
Enhanced approach
Quality by Design (QbD)
Comprehensive understanding of product and process
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Approaches & Outcomes
Minimal Enhanced
Conducted one variable at a time minimum product knowledge
Multivariate experiments extensive product knowledge
Focus on optimization and reproducibility of process
Focus on control strategy and robustness of process
End product testing On line (PAT) tools utilized
Primary control through FPP specifications FPP specifications part of overall control strategy
FPP quality controlled by in-process and end product testing
FPP quality ensured through risk based control strategy since product and process are well understood.
Real time release testing with possible reduction of end product testing
Quality over product life cycle managed through problem solving and corrective action
Quality over product life cycle managed through preventive action and continuous improvement
Satish Mallya, World Health Organisation, 2011
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Quality paradigm
The ultimate aim of quality is to improve patient outcomes
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Good Manufacturing Practice
Pharmaceutical Quality System
Pharmaceutical Development
Technology Transfer
Commercial Manufacturing
Product Discontinuation
Management Responsibilities
Process Performance & Product Quality Monitoring SystemCorrective Action / Preventative Action System
Change Managements SystemManagement review
Knowledge Management
Quality Risk Management
Enablers
PQSelements
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Influences on pharmaceutical development and risk management
|1835 | 1960s 1990|1998 | 2000 | 2006 | 2008 2010 | 2011 |2012
first factory mutual insurer
was created
ISO 14971 Medical
devices Application of
risk management to medical
devices published
ICH Q9
Failure Modes Effects
Analyses were used to improve efficiency and run time of
equipment from a
reliability perspective
ICH Q8
ASTM E2500-
07
ASTM E2500-
07
ICH Q10
ICH Q11
ISO 31000 Risk
management principles
and guidelines
ICH established
-
ICH Q8 Pharmaceutical Development
Presented by John Montalto
13 May, 2013
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Slide 48 PharmOut 2013
Quality
In Brussels, 2008, the ICH made the following statement:
develop a harmonised pharmaceutical quality system applicable across the lifecycle of the product emphasizing an integrated approach to quality risk management and science.
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Pharmaceutical development
The aims of pharmaceutical development include:
The design of a quality product and its manufacturing process
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Pharmaceutical development
Design a quality product and its manufacturing
process
Build quality in to the design of the product and its manufacturing
process
Consistently deliver the intended
performance of the product
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Pharmaceutical development
Research and Development (R&D) activities should not be isolated from the wider business.
R&D provides an excellent opportunity to learn about the product and its manufacturing process.
This learning and knowledge must be translated into the subsequent life cycle phases.
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Pharmaceutical development
R&D is no longer restricted to developing a pharmaceutical product, it must include the development of a manufacturing process.
One of the greatest variables any product will face is the up scale of a manufacturing process.
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Pharmaceutical development
What can be done with all of this information gained from pharmaceutical development?
1
Establish quality risk management program for the product and its manufacturing process
2
Gain knowledge and establish parameters (design space) where you can verify the consistent manufacture of a product that fulfils its intended purpose
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ICH Q8
ICH Q8 Pharmaceutical Development, is split into two sections:
Part I Pharmaceutical Development details what regulatory
submissions need to include for compliance
Part II Annex to Pharmaceutical Development considers an approach to
realising Pharmaceutical Development
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Pharmaceutical development
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Pharmaceutical development
How does a lack of information impact your business right now?
How does a lack of knowledge impact your quality decisions right now?
Do you know why your product is in the dosage from that it is in?
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Pharmaceutical development
Quality by Design (QbD) is one component of pharmaceutical development:
Manufacturing processes and formulation
Product quality
Process control strategies
Risk based regulatory scrutiny
Patient safety
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Pharmaceutical development
While design space is optional, Control Strategy is never optional
Jacques Morenas, former PIC/S Chair, April 2011.
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US FDA Process Validation stages
Stage 1 Process Design
Stage 2 Process
Qualification
Stage 3 Continued Process
Verification
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US FDA
Stage 1 Identify
sources of variability
Stage 1 Identify
sources of variability
Stage 2 Control of
variability
Stage 2 Control of
variability
Stage 3 Statistical
evaluation of data
Stage 3 Statistical
evaluation of data
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Pharmaceutical developmentQuality by Design
Design space
Establishing product and process performance parameters
Testing, Design of Experiments, verification of product and process performance parameters
Stress testing
Understanding the impact of variables on your product and process
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Pharmaceutical development
Understanding the impact of variables on your product and process.
Quality risk management approach
Understanding and controlling variability to deliver consistent products that fulfil their label claims
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What drives your process?
Product understanding is required to design the process.
Critical Quality Attributes define the process.
Product
Process
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CQA and CPP
A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality
Drug substance, excipients, intermediates
Critical Quality Attribute
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CQA and CPP
A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality
Critical Process Parameter
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Pharmaceutical development
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Pharmaceutical development
Risk Assessment
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Activity 4ICH Q8 Pharmaceutical development
Activity 4.1
Read and review section 2 to section 2.2.3
Summarise the main points in your workbook
Work in pairs or individually
Contribute to group discussion
WB 4.1/ 45 mins
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Pharmaceutical development
Considerations should include:
Drug substances
ExcipientsContainer closure
Manufacturing processes
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Pharmaceutical development
Organisations may want to fulfil the minimum requirements for product development.
This may be a false economy because enhanced science based knowledge may result in more flexibility from regulators.
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Drug product components
Drug substance considerations:
Physiochemical and biological
properties
Consider pharmacopeia requirements
manufacturability
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Characterisation
What are the potential impurities of the drug substance?
What are the sources of each impurity?
Are impurities a result of degradation or process failure?
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Drug product components
Drug substance considerations:
What is the drug substance specification? For each test in the specification, what is the justification for
the acceptance criteria?
For each test in the specification, provide a summary of analytical methods.
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Drug product components
What are the storage conditions and the retest/expiry period for the drug substance?
The structure of stability studies must be considered
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Drug product components
Excipients:
The excipients chosen and the justification for selection
Compatibility with the drug substance and other excipients must be considered
manufacturability
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Drug product components
Excipients:
What are the components and composition of the final drug product on both a per unit dose and %w/w basis?
How does each excipient work in the product?
For example, does any excipient exceed the FDA inactive ingredient database limit for this route of administration
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Drug product
Formulation development:
Which attributes are critical to the quality of the drug product?
What is the therapeutic benefit of the product?
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Drug product
Overages:
The preference is to eliminate overages due to degradation of the product over time.
This in itself is an excellent demonstration of pharmaceutical development where a key attribute must be designed to be robust and repeatable and not have to compensate for lack of capability.
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Drug product
Physiochemical and biological properties:
What impacts safety, performance and manufacturability of the product?
Aseptic products will pose different challenges and greater attention on process capability may be required.
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Manufacturing process development
What is the manufacturing process utilised and how will the process be controlled?
What manufacturing processes are available and what adaptation is required?
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Manufacturing process development
The manufacturing process development programme or process improvement programme should identify any critical process parameters that should be monitored or controlled (e.g., granulation end point) to ensure that the product is of the desired quality.
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Methods of manufacture (MoM)
The EU guide to Process Validation provides some detail relevant to methods of manufacture.
Non-standard MoM
Specialised dose forms
New technology in conventional processes
Highly specialised or highly complex processes
Non-standard methods of sterilisation
Highly specialised or highly complex
Includes processes such as lyophilization and aseptic manufacture, real time release (parametric release)
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Standard or Non-standard MoM:
Needs to be justified on a case-by-case basis considering the appropriate development data or by reference to similar products.
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Manufacturing process development
What is the existing or proposed control strategy for the manufacturing process?
How are critical attributes monitored?
How will data gathered during development studies be analysed?
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Manufacturing process development considerations
What is the rationale for selecting this manufacturing process for the drug product?
What process development studies, were conducted and at what scale?
(the EMA Guideline on Process Validation refers to a scale up factor of less than 10)
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Manufacturing process development
What is the process map listing input material attributes, process parameters, and output material quality attributes for all of the unit operations in the manufacturing
process?
How will the robustness of the process be measured?
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Container closure system
Based on the intended use of the product, the container closure system should be justified.
Considerations should include:
Primary packaging materials
Consideration of the product supply chain
Materials of construction and
product compatibility
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Container closure system
Dosing devices must be able to consistently deliver the required dose.
Repeated use verification may should consider real life product conditions
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Microbiological attributes
Microbiological attributes may include:
Microbial limits testing and the relevance of this
Preservative systems and the justification for these systems
For aseptic products, maintaining integrity of the container closure system
Antimicrobial preservative effectiveness
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Novel product considerations
Use pharmaceutical development studies to supplement clinical trial information:
Pharmaceutical development advantages
Know what your product and process can tolerate
Understand how various parameters influence product quality
Knowing and not guessing, whats important to patient safety and product quality
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Legacy product considerations
Design space is considered optional, but control strategy is not optional.
Advantages
Formal product and process knowledge
Clear communication from product development through to manufacture of what impacts product and process quality
Regulatory flexibility
Disadvantages
The cost of establishing a non compulsory item
The payback is too difficult to quantify
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ICH tripartite integration
Q8 Q9 Q10
Quality Target Product Profile (QTPP)
Clinical and non clinical studies on drug substance
Risk efforts to evaluate patient needs and product risks
Knowledge management; previous knowledge and experiments
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ICH tripartite integration
Q8 Q9 Q10
Processdevelopment
Characterisationof processDesign of Experiments (DoE)
Determine failure modes
Identify potential product parameters that impact quality
Batch records
Technical transfer
Supplier identification and selection
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ICH tripartite integration
Q8 Q9 Q10
Commercial manufacture
Commercial process design
On line technology implementation
Analysis and trending of data
Develop control strategy
Manage risks
Standard Operating Procedures
ValidationProcess
Monitoring and establishing alert and action limits
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Acknowledgements
Jennifer A. Maguire, Ph.D & Karen A. Bernard, Ph.D CMC Reviewers, Office of Generic Drugs, US Food and Drug Administration
US FDA Process Validation Guidance for Industry, 2011 EMA Guideline on Process Validation, 2012
ICH
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Quality by Design
Presented by John Montalto
13 May, 2013
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Quality by Design (QbD)
A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management
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QbD
The company that fails is the company that comes to us and says Just tell us what to do and we will do it.
The company that succeeds is the company that says to us Here is what we did and why we think it is appropriate.
Dr. Phillip Minor National Institute of Biological Standards and Control
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FDA
Pharmaceutical GMPs for the 21st Century
Science & Risk based regulation
FDAs New Initiative on Drug Product QualityJanet Woodcock, MDDirector, Center for DrugEvaluation and ResearchFood and Drug AdministrationOctober 25, 2002
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Impact of Risk
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The impact of Science
QbD
ICH Q8, Q9 Q10 and Q11
Other documents Case studiesPDA & FDA
GMPsEUUS FDAPIC/S
Design space
Risk
Quality Targeted Product ProfilesQTPP
Control strategy
Design of experiments
DOE
Critical Process
ParametersCPP
Critical Quality
Attributes(CQA)
Product Lifecycle
ICH Tripartite
EU - Voluntary
EU - Mandatory
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Who is driving QbD?
US FDAs Lawrence Yu, Deputy Director for science and chemistry in the Office of Generic Drugs
As weve said many, many times, FDA Office of Generic Drugs expects QbD applications starting January 2013.
You heard right, full implementation of QbD in January 2013.
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Where does QbD start?
QbD is a lifecycle concept
FDA Process Validation - 3 stages
1. Process Design = Quality by Design 2. Process Qualification 3. Continued Process Verification
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What is QbD?
The quality by design (QbD) principle can be simply stated as follows:
Once a system has been tested to the extent that the test results are predictable, further testing can be replaced by establishing that the system was operating within a defined design space.
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What is the goal?
Focus of FDA PV GuidelineVariable or variability - Mentioned 19 times
Control - Mentioned 62 times
Statistics - Mentioned 15 times
Inputs and Outputs
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FDA PV Stages
Stage 1 Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities.
Stage 2 Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.
Stage 3 Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.
[FDA Guidance for Industry Process Validation: General Principles and Practices, Jan 2011]
Identify Variability
Control of Variability
Statistics
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Design space
The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality.
Working within the design space is not considered as a change. Movement out of the design space is considered to be a change
and would normally initiate a regulatory post approval change process.
Design space is proposed by the applicant and is subject to regulatory assessment and approval (ICH Q8).
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Design space
A design space can be dynamic and updated as knowledge and experience with the process are acquired.
Operating within the design space is part of the control strategy.
Design space is generally part of R&D and the risks associated with scale up must be identified and controlled.
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Design space
Consider the design space for a single unit operation i.e get participants to design an ideal packing line.
Link to CQAs
Upstream and downstream interfaces
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Design space
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Design space
In developing design spaces for existing products, multivariate models can be used for retrospective evaluation of historical production data.
The level of variability present in the historical data will influence the ability to develop a design space, and additional studies might be appropriate.
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Design space
Capturing development knowledge and understanding contributes to design space implementation and continual improvement.
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Control strategy tableDrug Substance CQA (3.2.S.2.6) / Limit In Drug Substance
In process Controls (Including In-process testing and process parameters)
Controls on material attributes (raw materials / starting materials / intermediates)
Impact of Manufacturing Process Design
Is CQA tested on drug substance / Included in Drug Substance specification (3.2.S.4.1)
Organic Purity
Impurity XNMT 0.15%
Impurity Y
NMT 0.20%
Any individual unspecified impurity
NMT 0.10%
Design space of the reflux unit operation composed of a combination of % water in Intermediate E and the reflux time in step 5 that delivers Intermediate F with Hydrolysis Impurity 0.30% (3.2.S.2.2)
Process parameters step 4 (3.2.S.2.2)
P(H2) 2 barg
T
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Activity 4ICH Q8 Pharmaceutical development
Activity 4.2
Read and review section 2.3 to section 2.6 Summarise the main points in your
workbook
Work in pairs or individually Contribute to group discussion
WB 4.2/ 45 mins
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Extracted from the FDA IM release worked example
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdf
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Lifecycle Approach Example
Le
ve
l o
f Q
C L
ab
Te
sti
ng
Time / Process Knowledge
ProcessDesign
PV(PPQ)
CommercialManufacturing
Could vary
based on approach Variability
Estimate Established
Post Periodic Review Signal
Change introduced /
CAPA
PAT Implemented
Monitoring
QC Testing
Control Strategy is dynamic over the lifecycle
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Quality By QC
Sampling Sampling Errors Introduction of variables
through sampling interventions
Testing How accurate is the test
method? Is the sensitivity of the
test known What is the incidence of
false positives
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Sampling
n+135+1 = 6
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Sampling
First 6
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Sampling
Random 6
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Sampling
Stratified
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Sampling
Systematic
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Sampling
Targeted
First
Last
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Sampling
Knowledge / Risk
First
Last
Morning Tea
Lunch
Shift Change
Afternoon Tea
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Slide 126 PharmOut 2013
Holistic Approach
Continued Process Verification
Process Qualification
Process Design
Continued Process Verification
Process Qualification
Process Design
Continued Process Verification
Process Qualification
Process Design
Extensive product and process design efforts can lead to streamlined efforts in later stages of product lifecycle
-
Slide 127 PharmOut 2013
Lifecycle Approach Example
Le
ve
l o
f Q
C L
ab
Te
sti
ng
Time / Process Knowledge
ProcessDesign
PV(PPQ)
CommercialManufacturing
Could vary
based on approach Variability
Estimate Established
Post Periodic Review Signal
Change introduced /
CAPA
PAT Implemented
Monitoring
QC Testing
Control Strategy is dynamic over the lifecycle
-
Slide 128 PharmOut 2013
What is the Process Validation Shift in Emphasis?
FDA Guidance for Industry, Process Validation: General Principles and Practices, January 2011.
Process validation is defined as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products.
Old definition:
Objective understand and control input variability impact and manufacturing process to assure consistent product quality and reliable supply
Concern about recent quality issues and drug shortages
New definition:
-
Quality by Design case study
Presented by John Montalto
13 May, 2013
-
Slide 130 PharmOut 2013
Activity 5.1- The perfect Cappuccino!
Inputs
Raw Materials
Milk
Sugar
Water
Chocolate Powder
Coffee Beans
Equipment
Cup-saucer-spoon
Grinder
Espresso Machine
Barista
Outputs
QTPP
Taste
Temperature
Appearance
Aroma
Texture
WB 5.1/ 5 mins
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Slide 131 PharmOut 2013
Activity 5.2 - QbD Case StudyThe perfect cappuccino
Complete a risk assessment for making a cappuccino
Risk rate each process stage against the inputs
Low (L), Medium (M), High (H)
Work in groups
WB 5.2/ 40 mins
E.g. Raw Material
-
Slide 132 PharmOut 2013
Risk Assessment
Processing stage Mil
k
Su
ga
r
Wa
ter
Ch
oco
late
Co
ffe
e b
ea
ns
Cu
p,
Sa
uce
r,
Sp
oo
n
Gri
nd
er
RM QC & QA Low Low Low Low High Low Low
Grinding Low Low Low Low High Low Low
Brewing Low Low High Low Low Low Low
Frothing Med. Low Low Low Low Low Low
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Slide 133 PharmOut 2013
Design of Experiment (DOE)
Extent of coffee grind is critical to quality, but how much is enough?
What other variables need to be considered in the DOE process?
Grinder, Grinding time, Fineness. How can these variables be tested?
-
Slide 134 PharmOut 2013
Activity 5.3 - QbD Case StudyThe perfect cappuccino
What controls would you put in place in order to reduce the risk?
(Establish a control strategy)
WB 5.3/ 5 mins
-
Slide 135 PharmOut 2013
The perfect Cappuccino!Inputs
Raw Materials
Milk
Sugar
Water
Chocolate Powder
Coffee Beans
Equipment
Cup-saucer-spoon
Grinder
Espresso Machine
Barista
Outputs
CQA
Taste
Temperature
QA
Appearance
Aroma
TextureThermometer
Vendor Assurance
Screening
Controls
-
Slide 136 PharmOut 2013
Activity 5.4 - QbD Case StudyThe perfect cappuccino
Repeat the risk assessment for making a cappuccino assuming the control strategy is in place.
Risk rate each process stage against the inputs
Low (L), Medium (M), High (H)
Work in groups
WB 5.4/ 10 mins
E.g. Raw Material
-
Slide 137 PharmOut 2013
Risk Assessment
Processing stage Mil
k
Su
ga
r
Wa
ter
Ch
oco
late
Co
ffe
e b
ea
ns
Cu
p,
Sa
uce
r,
Sp
oo
n
Gri
nd
er
RM QC & QA Low Low Low Low Low Low Low
Grinding Low Low Low Low Med. Low Low
Brewing Low Low Low Low Low Low Low
Frothing Med. Low Low Low Low Low Low
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Slide 138 PharmOut 2013
Identifying variables
Quality Target Product Profile (QTPP)
Appearance Temperature Aroma Texture Taste
Sweetness
Bitterness
Aftertaste
Critical Quality Attributes(CQA)
Taste Temperature (Safety)
-
Slide 139 PharmOut 2013
Controlling Variables
Critical Quality Attributes(CQA)
Temperature
Critical Process Parameters(CPP)
Thermometer Acceptance criteria
Taste Coffee beans Source control Auditing Acceptance criteria
Grinding How much grinding
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Slide 140 PharmOut 2013
Control StrategyInputs
Raw Materials
Milk
Sugar
Water
Chocolate Powder
Coffee Beans
Equipment
Cup
Spoon
Coffee Machine
Barista
Outputs
CQA
Taste
Temperature
QA
Appearance
Aroma
Texture
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Slide 141 PharmOut 2013
Control Strategy
Planned set of controls, derived from current product and process understanding that assures process performance and product quality
A control strategy can include, but is not limited to the following:
Material attributes (raw materials, starting
materials, intermediates, reagents, primary
packaging materials)
Controls are implicit in the design of the
manufacturing process
In-process controlsControls on drug
substance
-
Control Strategy
Presented by John Montalto
13 May, 2013
-
Slide 143 PharmOut 2013
Control strategy
A planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. (ICH Q10)
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Slide 144 PharmOut 2013
Control strategy
Control strategies are designed to ensure product quality, consistently.
Some considerations for control strategies include:
In process controls
Input material control
Container closure controls
-
Slide 145 PharmOut 2013
Control strategy
The focus of control strategies must be, initially on critical process parameters.
Remember, critical process parameters are translated from critical quality attributes.
Critical process parameters must be measurable and quantifiable.
-
Slide 146 PharmOut 2013
Control strategy
The aims of pharmaceutical development are to minimise sources of variability and to build knowledge of product and process.
Understanding your product, process and variables facilitates the development of adequate control strategies.
-
Slide 147 PharmOut 2013
Control strategy
Risk transfer is an appropriate control strategy:
Can you implement controls at another stage of the process?
Is there an opportunity to minimise the reliance on end product testing?
-
Slide 148 PharmOut 2013
Control strategy
ICH diagramatic example of real time feed back loop
NEEDS A DIAGRAM FROM JOHN
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Slide 149 PharmOut 2013
Control strategy
Control strategy inclusions:
Control of input materials and attributes
Product specifications
Controls for unit operations
Monitoring and measuring CQAs during processing
An ongoing monitoring program
-
Slide 150 PharmOut 2013
Control strategy
Control strategy is a continuum of controls, as opposed to one discrete control for one parameter
-
Slide 151 PharmOut 2013
Linking ICH Q8, Q9 and Q10 to develop a control strategy
Identify all quality attributes based on current process and product understanding
Risk assessments identify Critical Quality Attributes (CQAs)
Control Strategy design, develop and implement
Continual improvement
Dynamic process as
product knowledge and
process understanding
increase
-
Slide 152 PharmOut 2013
Control strategy
-
Slide 153 PharmOut 2013
Risk assessment identify Critical Quality Attributes (CQAs)
Appearance Performance Comfort Stopping Heating/Cooling
Transmission
Severity (impact on quality)
L H L H L L
Probability(risk likelihood)
L M M M L M
Detectability H M H M H H
Total L H L H L L
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Slide 154 PharmOut 2013
Risk assessment identify CQAs
Appearance Performance Comfort Stopping Heating/Cooling
Transmission
Colour
Brake assembly
Acceleration
Suspension
Seat covering
Tyres
Fuel type
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Slide 155 PharmOut 2013
Developing Control Strategy
Stopping
Brake assembly
Stopping
Vehicle gradually stops by application of a foot peddle at 10m/s/s
Control Strategy
Qualification of manufacturing equipment
Assembly Process Validation
Control Strategy
Raw materials, lubricants and oils
Feedback
Maintenance Life Plans - Brake pressure switch calibration, inspection regime
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Slide 156 PharmOut 2013
How would you use control strategies to verify your validation efforts?
An ongoing process
-
Slide 157 PharmOut 2013
An ongoing process
While design space is optional, Control Strategy is never optional
Jacques Morenas, PIC/S Chair, April 2011
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Slide 158 PharmOut 2013
CQA and CPP
A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality
Drug substance, excipients, intermediates
Critical Quality Attribute
A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality
Critical Process Parameter
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Slide 159 PharmOut 2013
CQA and CPP
Checks performed during production to monitor and if appropriate, adjust the process
In-process control
Tests which may be performed during the manufacture of either the drug substance or drug product, that may be outside of routine in-process tests
In-process tests
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Slide 160 PharmOut 2013
Quality Risk Management
Product knowledge drives Process development
Develop Control Strategy
Continual improvement
-
Slide 161 PharmOut 2013
An ongoing process
It is a requirement of GMP that manufacturers identify what validation work is needed to prove control of the critical aspects of their particular
operations.
Annex 15, PIC/S Guide to Good Manufacturing Practice for Medicinal Products Annexes, January, 2013
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Slide 162 PharmOut 2013
Control strategy
The controls may include parameters that apply to:
Drug substance
Drug product materials
Components
Facilities and equipment parameters
In process controls
Finished product specifications
-
Slide 163 PharmOut 2013
Control Strategy is not
Is not a new concept Your products and processes already have control strategies
Is not just a list of specifications for QC testing requirements
Is NOT optional
-
Slide 164 PharmOut 2013
Implement Control Strategy
Every process and product has an associated control strategy:
Overall strategy for a product
Discrete control strategy for an
operation
-
Slide 165 PharmOut 2013
Various approaches
In-process testing
Real time release testing
End-product testing
Control strategy
approaches:
Controls on raw and starting material attributes, intermediates and reagents
Sequence of purification steps
Order of addition of reagents
Training and personnel matters
Gowning and clean room behaviours
Localised Control strategy
approaches
-
Slide 166 PharmOut 2013
Batch release
Control Strategy and batch release decisions are separate
Control Strategy is not the only consideration when batch release decisions are determined
-
Slide 167 PharmOut 2013
Defining the control strategy
What are the quality criteria
(QTPP)?
Rely on knowledge -including the design of the product and
process
Risk based approach to
identify critical process
parameters
Ongoing knowledge and
continual improvement
-
Slide 168 PharmOut 2013
Control strategy within the lifecycle
The control strategy requires continual improvement.
How can you build knowledge? The more you know about your product and performance
the more ability you will have to control.
-
Slide 169 PharmOut 2013
Traditional approach
Emphasis on end-product testing
Operating ranges set on observed process data
Generally narrow target range
Process capability (or lack of capability)
-
Slide 170 PharmOut 2013
In process approach
In process determination that a CQA is within an appropriate range or limit.
Remember validation requires a high degree of assurance.
Documented evidence
In the not so distant future technology will change control strategies.
Process Analytical Technologies (PAT) Real Time Release Testing (RTRT)
-
Slide 171 PharmOut 2013
Different points of view
Industry Regulators
Analytical testing sensitivity Has risk been adequately identified and controlled?
Equipment limitations Quality Management System adequacy to support the Control Strategy
Cost Compliance with Annex 15?
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Slide 172 PharmOut 2013
Summary
Product Quality and Process Performance Monitoring:
Ensure a state of control is
maintained (control inter and intra
batch variability)
Plan and execute a system for
monitoring CQAs and CPPs
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Slide 173 PharmOut 2013
Summary
Use QRM to establish Control Strategy
Control Strategy facilitates timely feedback/feed forward and appropriate CAPA
Provide tools for measurement and analysis of parameters and attributes within Control Strategy
Identify sources of variation affecting process performance and product quality focus continuous improvement here
Use internal and external feedback
Provide and manage knowledge to enhance process understanding
-
Quality Target Product Profile (QTPP)
Presented by John Montalto
13 May, 2013
-
Slide 175 PharmOut 2013
QTPP
A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.
ICH Q8
-
Slide 176 PharmOut 2013
QTPP
Establish Quality Target Product Profile
(QTPP)
Identify Critical Quality Attributes (CQA) of the FPP
Investigate quality attributes of the API
and formulation ingredients
Select an appropriate manufacturing
process and establish the Critical Process Parameters (CPP)
Outline control strategies
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Slide 177 PharmOut 2013
QTPP
The QTPP is a cornerstone of design for the development of the product
QTPP considerations
Intended clinical use of the product
Dosage and dosage forms
Container closure systems
Therapeutic indication, release and delivery
Drug product quality criteria
-
Slide 178 PharmOut 2013
QTPP
-
Slide 179 PharmOut 2013
QTPP considerations
ParacetamolQuality Target Profile (QTPP)
RequirementsTranslation into Critical Quality Attributes
(CQAs)
Dose 500 mg tablet Identity, Assay, Content Uniformity
Container Plastic blister, foil backing All blisters filled, correct number of strips in pack, Unit Integrity and other characteristics
Subjective properties Identity, Appearance, colour, uniformityTaste, odour
Appearance and other characteristics
Absence of defects
Patient safety chemical
purity
Impurities and / or degradation products below ICH or to be qualified
Acceptable degradation product levels at release, appropriate manufacturing environment controls
Input raw material quality
Degradation controlled by packaging, protected from light & heat & oxygen
Patient safety biological
purity
Free from pathogens,
Free from yeast or moulds or below the specified limit
Input raw material quality
Quality of direct impact services and utilities
Clean manufacturing environment and equipmentChemical and drug product
stability : 3 year shelf life
Degradation products below ICH or to be qualified and no changes in bioperformance over expiry period
Acceptable impurity levels at release
appropriate manufacturing & environmental controls
Pharmacopoeial Compliance Meets pharmacopoeial requirements for tablet dosage forms
Meets requirements of TGO 78 (Aust.)
Pharmacopoeial tests and specifications
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Slide 180 PharmOut 2013
Activity 4ICH Q8 Pharmaceutical development
Activity 4.3
Read and review Part II: Pharmaceutical development Annex Section 2 to 2.3
Summarise the main points in your workbook Work in pairs or individually Contribute to group discussion
WB 4.3/ 45 mins
-
Quality by Design considerations
Presented by John Montalto
13 May, 2013
-
Slide 182 PharmOut 2013
Quality by Design
Establishing quality by design can take many different forms:
Consider single or multi-variate analysis
Usually some time of experimentation will feature to establish product and process tolerances
-
Slide 183 PharmOut 2013
Design of Experiments (DoE)
Quality Risk Management recognises that formal efforts are not always appropriate and that informal justifications can provide adequate information.
Consider a summary table of factors and ranges reviewed and the conclusions drawn
-
Slide 184 PharmOut 2013
Design of Experiments (DoE)
DoE can be utilised to establish design space considerations:
What was the criteria used to select variables?
How were ranges for the variables established?
The interaction of variables may also need careful attention
-
Slide 185 PharmOut 2013
Design of Experiments (DoE)
Raw material variability may have an impact on DoE.
The handover of information from process development to commercial manufacture may include raw material suppliers
-
Slide 186 PharmOut 2013
Design of Experiments (DoE)
Constants:
Listing of the parameters that would be kept constant during the DoEs and their respective values, including predictions on the impact of scale on these parameters
-
Slide 187 PharmOut 2013
Design of Experiments (DoE)
The type of experimental design:
People may use predictive models to anticipate outcomes Models can provide great value but the models chosen must be
analysed and evaluated for potential weaknesses in data
-
Slide 188 PharmOut 2013
Design of Experiments (DoE)
Scale dependant factors:
Scale up is a great source of variability for any process and the control of scale up work and the impact of scale up must be adequately managed
-
Slide 189 PharmOut 2013
Design of Experiments (DoE)
Results and statistical analysis of DoE data showing the statistical significance of the factors and their interactions, including predictions made from DoE studies relevant to scale and equipment differences Considerations need to include
statistically significant data sizes
Multiplication and extrapolation of data is complex and may demand subject matter expertise
-
Slide 190 PharmOut 2013
Design of Experiments (DoE)
For organisations with QMS, design of experiments should be based on data:
Perform an analysis on the available data
Allow the date to guide your single variate and multi-variate experiments
-
Process Capability
Presented by John Montalto
13 May, 2013
-
Slide 192 PharmOut 2013
Process Capability
Medicinal products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorisation or product specification.
-
Slide 193 PharmOut 2013
A Capable Process?
Sufficient knowledge & understanding about critical product and process parameters and quality attributes
Control Strategy in place Process in a State of Control Knowledge & understanding gained
over time
Process Design
Process Qualification
Continued Process
Verification
-
Slide 194 PharmOut 2013
US FDA stance on Process Capability
We recommend that a statistician or person with adequate training in statistical process control techniques develop the data collection plan and statistical methods and procedures used in measuring and evaluating process stability and process capability.
-
Slide 195 PharmOut 2013
US FDA stance
Production data should be
collected to evaluate process
stability and capability.
If properly carried out, these efforts can identify variability in the process and/or signal potential process improvements.
Both quality and business benefits
-
Slide 196 PharmOut 2013
Process Capability
Two Assumptions:
The process is in statistical control. The distribution of the process considered
is Normal. Sources of variation well understood and detectable The impact of variation on the process and on product
attributes clearly defined
The variation must be controlled in a manner commensurate with the risk it represents to the process and product
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Slide 197 PharmOut 2013
What is normal?
Normal distributions are symmetrical with a single central peak at the mean (average) of the data.
The shape of the curve is described as bell-shaped (Gaussian) with the graph falling off evenly on either side of the mean.
50% of the distribution lies to the left of the mean and 50% lies to the right of the mean.
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Slide 198 PharmOut 2013
Normal distribution
Area under the curve =100%
~68% of the area falls within 1 StDev.
~ 95% of the area falls within 2 StDev.
~ 99.7% of the area falls within 3 StDev.
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Slide 199 PharmOut 2013
Process Capability Analysis
Process capability analysis compares the performance of a process against its specifications.
Two parts of Process Capability: 1) Measure the variability of the output of a process
2) Compare that variability to its specification (USL and LSL)
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Slide 200 PharmOut 2013
Process Capability Index
Process Capability Index or Process Capability Ratio is a statistical measure of process capability: the ability of a process to produce output within specification limits.
Process capability indices measure how much "natural variation" a process experiences relative to its specification limits and allows different processes to be compared with respect to how well they are controlled.
There are several statistics that can be used to measure the capability of a process. We will look at Cp and Cpk.
Generally, need 50 independent data values.
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Slide 201 PharmOut 2013
Process Capability Index (Cp)
Cp = Estimates what the process is capable of producing if the process mean were to be centred between the specification limits. Assumes process output is approximately normally distributed
-
Slide 202 PharmOut 2013
Process Capability Index (Cpk)
Cpk = Estimates what the process is capable of producing, considering that the process mean may not be centred between the specification limits (2-sided specification)
-
Slide 203 PharmOut 2013
Process Capability Indices
If group of darts off the bullseye, but grouped tightly= good Cp, or good process capability, but not good Cpk.
If the group of darts are closer to the bullseye, that is good Cpk.
If Cp=Cpk the process is centred at the midpoint of the specification limits.
If Cp>Cpk the process is off-centre.
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Slide 204 PharmOut 2013
Process in control & capable?
Need to evaluate overall process variation over time
-
Slide 205 PharmOut 2013
A more realistic process
Intra and inter batch variation over time
-
Slide 206 PharmOut 2013
Special Cause Variation
-
Slide 207 PharmOut 2013
Data analysis
Control Charts used to assess whether or not a process is in statistical control
These charts (e.g. XbarR, Xbar-S, I-MR) are sensitive to detecting shifts in the process.
Numerous statistical packages (standalone and embedded in automation software) that assist with these calculations
If the Normal distribution assumption is not appropriate, yet capability indices are recorded, one may seriously misrepresent the true capability of a process.
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Slide 208 PharmOut 2013
Data gathering
Select the critical parameters to measure Understand the sources of variation and
their magnitudes-special or common cause?
Collect the correct data-needs to be reliable source, to the correct number of significant digits and in the correct time order
Clear procedures and instructions in place-a systematic procedure for determining the capability of the process
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Slide 209 PharmOut 2013
Process Capability Analysis-Minitab
-
Slide 210 PharmOut 2013
Process Capability Analysis-Minitab
Anderson-Darling (AD) Normality test shows that data does not follow a Normal distribution.
This is due to the fact that the p-value for the A-D test is
-
Slide 211 PharmOut 2013
Process Capability Analysis-Minitab
Histogram indicates spread of data and the USL and LSL
In this case, all samples met specification, but if the target is a result of 99, the process is running high.
May drift above USL in future? A number of results could be
outliers and may prompt an investigation
Results close to the USL
?
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Slide 212 PharmOut 2013
Process Capability Analysis-Minitab
Cp of 1.56 indicates that the data is within the LSL and USL
Cpk of 0.62 indicates that the process is not centred or off target
The plot also shows that the process is off-target
Within and Overall results shown
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Slide 213 PharmOut 2013
Process Capability Analysis-Minitab
Xbar-R or Xbar-S charts are used when data is collected in subgroups.
Individuals and Moving Range (I-MR) chart is used when there are no subgroups.
The I chart is sensitive to non-normal data.
The moving range (MR) chart shows variability between one data point and the next.
Reason for data shift? Outlier?
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Slide 214 PharmOut 2013
Process Capability Analysis-Minitab
Graph detailing the Last 25 Observations or results.
Can visually show if data is trending any particular direction
Can be useful, in addition to the other tools previously discussed
-
Slide 215 PharmOut 2013
Process Capability Analysis
Many more useful statistical tools available
Non-normal data can be transformed before calculating the process capability indices using the transformed data-requires knowledge to use the correct method of transformation
-
Slide 216 PharmOut 2013
Activity 4ICH Q8 Pharmaceutical development
Activity 4.4
Read and review Part II: Pharmaceutical development Annex Section 2.4 to 2.4.6
Summarise the main points in your workbook Work in pairs or individually Contribute to group discussion
WB 4.4/ 45 mins
-
The outcomes of Pharmaceutical Development
Presented by John Montalto
13 May, 2013
-
Slide 218 PharmOut 2013
Continual improvement of the product
InputsInputs
Manufacturing experience
Deviations/CAPA Performance
monitoring Complaints Management reviews Variability
Product lifecycle adjustment
Adjustments based on routine feedback loops
Ongoing process and facility design to improve on the original models
Continual improvement
Knowledge library expands
Control strategyFeed forward/back
-
Slide 219 PharmOut 2013
Continual improvement of the process
InputsInputs
PQS processes Outsourced activities Self inspection External inspection Regulatory
considerations Your business
PQS adjustment
Allocation of resources
Learning and training Updates to quality
policies and objectives Documentation Communication
Continual improvement
Knowledge library expands
PQS ManagementFeed Feed forward/back
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Slide 220 PharmOut 2013
What should regulators be looking for?
How does senior management demonstrate pharmaceutical quality system commitment?
Ensuring adequate resourcing
Pharmaceutical Quality System (PQS) importance is communicated
Strong interfaces and relationships with all externals
Management reviews process performance, product quality reviews and the PQS performance
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Slide 221 PharmOut 2013
Quality
Of particular importance
Quality must be built in and will not only improve by further testing and inspection
Better use of modern science through the lifecycle
Quality risk management is a key tool throughout the lifecycle
A strong quality system with appropriate knowledge management builds quality in throughout the lifecycle
An integrated approach to product development, manufacturing and quality
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Slide 222 PharmOut 2013
ICH tripartite integration
Q8 Q9 Q10
Processdevelopment
Characterisationof processDesign of Experiments (DoE)
Determine failure modes
Identify potential product parameters that impact quality
Batch records
Technical transfer
Supplier identification and selection
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Slide 223 PharmOut 2013
ICH tripartite integration
Q8 Q9 Q10
Commercial manufacture
Commercial process design
On line technology implementation
Analysis and trending of data
Develop control strategy
Manage risks
Standard Operating Procedures
ValidationProcess
Monitoring and establishing alert and action limits
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Slide 224 PharmOut 2013
Activity 4ICH Q8 Pharmaceutical development
Activity 4.5
Read and review Part II: Pharmaceutical development Annex Section 2.6
Summarise the main points in your workbook Work in pairs or individually Contribute to group discussion
WB 4.5/ 30 mins
-
ICH Q9 Quality Risk Management
Presented by John Montalto
13 May, 2013
-
Slide 226 PharmOut 2013
Quality Risk Management
If everything is critical, nothing is critical
-
Slide 227 PharmOut 2013
Quality Risk Management overview
-
Slide 228 PharmOut 2013
Initiating a QRM process
A policy and procedure must be in place before initiating QRM
Establish the QRM criteria and detail the scope of the process
This requires discipline and structure
-
Slide 229 PharmOut 2013
Initiating a QRM process
What is the problem, process or scenario being reviewed?
Be specific to define the problem and detail assumptions made
QRM is about communication, so if people are aware of assumptions they are better able to respond
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Slide 230 PharmOut 2013
ICH Q9 Initiating a QRM process
Be prepared with as much relevant information as possible and be conscious of time
Wherever possible have verifiable data available relevant to the process under review
-
Slide 231 PharmOut 2013
ICH Q9 Initiating a QRM process
Establish a multi disciplinary team Manage the process by establishing outcomes and
expectations and ensure predetermined acceptance criteria are established
-
Slide 232 PharmOut 2013
Risk assessment
1What might go wrong?
2What is the likelihood it will go wrong?
3What are the consequences?
-
Slide 233 PharmOut 2013
Risk assessment
Inputs to risk identification may be varied is your QMS able to support your data requirements?
Risk identification
-
Slide 234 PharmOut 2013
Risk assessment
Qualitative and quantitative process to comprehend the severity, likelihood and detectability of harm.
Risk analysis
-
Slide 235 PharmOut 2013
Risk assessment
Compare your quantitative outcome with the predetermined criteria to prioritise your efforts and identify what is not acceptable. The reliability of the data used is critical.
Risk evaluation
-
Slide 236 PharmOut 2013
Risk control
1Is the risk above your predetermined criteria/threshold?
2What can be done to reduce or eliminate risks?
3Are new risks introduced with risk controls?
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Slide 237 PharmOut 2013
Risk control
Ultimately, there is one decision to be made:
is the risk acceptable or does the risk require further control?
Performing a risk assessment with a pre-determined outcome in mind is non compliant and will not add value to your business
-
Slide 238 PharmOut 2013
Risk communication
Risk is all about facilitated communication - Have you identified all of the parties that need to be part of the communication process?
How do you communicate with internal stakeholders?
How do you communicate with patients?
Are your communication strategies formalised?
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Slide 239 PharmOut 2013
Risk communication
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Slide 240 PharmOut 2013
Risk review
QRM is a dynamic process that starts but does not necessarily end.
Outline what will trigger a review of your QRM processes Consider feedback and how you will handle information and
knowledge and ensure that as you acquire knowledge that the QRM system is maintained
-
Slide 241 PharmOut 2013
Informal and formal efforts
It is not appropriate to have a formal risk effort for all processes and questions that arise.
Irrespective of the mechanism used, all outcomes should be formalised and justified
-
Slide 242 PharmOut 2013
Risk management tools
-
Slide 243 PharmOut 2013
Risk management tools
The risk management tool is of secondary importance:
Select a method that your people are comfortable with.
Use the most appropriate model for the process under review.
Consider the QRM exposure within your organisation and use an appropriate model.
-
The history of Quality Risk Management
Presented by John Montalto
13 May, 2013
-
Slide 245 PharmOut 2013
Influences on pharmaceutical development and risk management
|1835 | 1960s 1990|1998 | 2000 | 2006 | 2008 2010 | 2011 |2012
first factory mutual insurer
was created
ISO 14971 Medical
devices Application of
risk management to medical
devices published
ICH Q9
Failure Modes Effects
Analyses were used to improve efficiency and run time of
equipment from a
reliability perspective
ICH Q8
ASTM E2500-
07
ASTM E2500-
07
ICH Q10
ICH Q11
ISO 31000 Risk
management principles
and guidelines
ICH established
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We all have different risk tolerances
Personal perceptions Personal perceptions need to be
managed, if data available did not
support your perception would you be able to
adjust?
Personal tolerances should be put aside
rely on the acceptance criteria
established by management
Embrace the reality that we
all think in different ways
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Why are we here?
The establishment and maintenance of a satisfactory system of quality assurance and the correct manufacture of medicinal products relies upon people.
PIC/S Guide to Good Manufacturing Practice for Medicinal Products Part I - January, 2013
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A risk management history
1940s and 1950s
Military and Aerospace (MIL
STDs)
1960s reliability,
engineering approaches;
FMECA, HACCP
1980s ISO 14971 Risk
Management for Medical
Devices
Other industry standards.
2005 ICH Q9 Quality Risk Management
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PIC/S GMP
The term risk is mentioned 370 times in the PIC/S GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS PART I, II and the annexes
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Risk Management
QRM has evolved over an extended period of time:
Initially risk management was focussed on asset protection
Now risk management is used to profile and estimate an organisations exposure to various failure modes
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Quality Risk Management
QRM has revolutionised GMP compliance:
Some organisations have not realised this revolution
All decisions in a GMP regulated environment should be based on QRM criteria
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Definitions
Harm
physical injury or damage to the health of people, or damage to property or the environment
Hazard
potential source of harm
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Definitions
Risk
combination of the probability of occurrence of harm and the severity of that harm
Risk Management
systematic application of management policies, procedures and practices to analyse, evaluate and control risk across the product lifecycle
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Definitions
Risk
combination of the probability of occurrence of harm, the severity of that harm and the detectability of that harm
Risk Management
systematic application of management policies, procedures and practices to analyse, evaluate and control risk across the product lifecycle
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Definitions
Risk can be categorised as SOD
Severity Opportunity Detection
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Quality Risk Management Relevant resources
Presented by John Montalto
13 May, 2013
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ISO 31000 Risk Management
The risk culture of an organisation
External and internal External and internal risk that
organisations need to manage
ISO 31000 considers two themes that risk management in the regulated industries does not consider.
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ISO 31000
The risk management framework within ISO 31000.
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Risk management creates value
Risk management
Critical organisational process Is the basis for making decisions Directly addresses uncertainty Systematic and structured system Tailored People and cultures are considered Transparent and dynamic Enables Continual improvement
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Risk management
Management commitment:
The internal and external context of the organisation
How is an organisation perceived?
Management must commit to risk management
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Risk management
A policy must be established Internal communication and reporting processes
People must be accountable for their decisions Establishing a common risk criteria allows for transparency in
decision making
Adequate resources must be available
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Risk management
The risk management process and system must be monitored and reviewed
Communication and consultation is fundamental to risk management
Risk criteria must be considered and established
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NAB
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NAB
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Risk Magazine, September 2010
David Lewis, who headed the Australian Prudential Regulation Authoritys (APRAs) probe, said as the investigation unfolded it became clear that the problems were not confined to the trading desk. During our investigation, we interviewed a lot of people involved including the four traders, he said. The traders were young; highly motivated; and very gung-ho as traders tend to be. One thing became clear immediately: they didnt think that they had done anything wrong.
They didnt think that they were stealing anything; they thought it was their job to make money for the bank and in their minds this is what they were doing. Yes, they knew that they were breaking the banks rules. But, to them, these were just bureaucracy that got in the way of what the bank really expected them to do.
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Risk Magazine, September 2010
Lewis added that the investigation revealed widespread issues within NAB, despite sophisticated controls system, and most were connected with cultural and human elements, as opposed to system breakdowns. Despite several probes, NABs internal audit department was warned off when it queried what was happening on the FX options desk. Internal auditors were told the traders were untouchable.
Meanwhile, risk managers failed to properly challenge the traders and the executive risk Committees managed to miss the early warning signs of the coming scandal, despite regular breaches of daily excess limits being reported.
Most seriously, Lewis said, the organisational culture at the bank was a far cry from its stated Policy and procedure.
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NAB
Billions of dollars traded annually Massive, lucrative bonuses were awarded Young, highly educated professionals
What does this say about the culture of the organisation?
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NAB Activity
List 3 mechanisms you would implement to reduce risks for currency traders
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GMP says...
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ISO Quality Standards
ISO 13485 Medical devices --Quality management systems --Requirements for regulatory purposes
ISO 14971 Medical devices --Application of risk management to medical devices
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ISO 13485 says...
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ISO 14971 says...
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ISO 14971 components
1. Scope
2. Terms and definitions
3. General requirements for risk management
4. Risk analysis
5. Risk evaluation
6. Risk control
7. Evaluation of overall residual risk acceptability
8. Risk management report
9. Production and post-production information
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Risk Management Process
The manufacturer shall establish and
maintain risk management
policies
Hazard identification
Estimate and evaluate associated
risks
Monitor the effectiveness of risk
controls
Integrate and review as part of
the Quality Management
System
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(ISO) Risk management overview
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Intended use
The intended use/intended purpose and any reasonably foreseeable misuse of the medical device must be considered
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Risk Management Process
The risk management process must be documented.
One challenge for manufacturers is how to establish the risk reports and risk management files: what rationale will be used to set up the system?
Where a documented design and development process exists, appropriate parts of the risk management processes must be included
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Compliance
Compliance is verified by inspection of the risk management file.
The risk management file is a set of records and other documents, that are produced by a risk management process
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Management Responsibilities
Define a risk management policy
Ensure the provision of adequate resources and the assignment of trained personnel
Review risk management activities regularly to ensure continuing suitability and the effectiveness of the process
Document the process
Maintain the risk management file
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Qualification of Personnel
The manufacturers risk management personnel must have the knowledge and experience appropriate to the tasks assigned to them
This shall include, where appropriate: knowledge and experience of the medical
device
knowledge and experience with risk management techniques
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Risk Management Plan
The plan scope, identifying and describing the medical device and the life cycle phases for which the plan applies
A verification plan
Assignment of responsibilities
Requirements for review of risk management activities
Criteria for risk acceptability (guidelines in Annex E)
Change management
The risk management plan shall be part of the risk management file and needs to include:
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Justification
Quality risk management is not exclusively a quantitative process.
Risk justifications are critical and must be adequately structured and supported by evidence
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Intended use of the medical device
For the particular medical device being considered, the manufacturer shall describe the intended use/intended purpose and any reasonably foreseeable misuse
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Intended use of the medical device
The manufacturer shall list all those qualitative and quantitative characteristics that could affect the safety of the medical device and, where appropriate, their defined limits
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Post production
Risk management is an ongoing process and requires the ongoing capture and analysis of knowledge
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Competition and regulation
Need to focus skilled resources where risks to patient safety are highest
Do more with less Maximise resource effectiveness
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Competition and regulation
A thorough understanding of business processes and Critical Quality Attributes (CQAs) is essential
Risk management methodologies Different methodologies may be more applicable throughout
the product lifecycle
The result should be the ability to better prioritise your work
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How do we practically use this risk based approach?
Dr. H. Gregg ClaycampDirector, Division of Compliance Risk Management and Surveillance, FDA, CDER Office of Compliance.
There is no magic bullet!
It is a multi disciplinary team applying an agreed methodology, making an educated and experienced judgement and then seeking ways to mitigate the risk.
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Risk management process
Management establish and maintain risk management
policies
Hazard identification
Estimate and evaluate
associated risks
Monitor the effectiveness
of risk controls
Ongoing part of the Quality Management
System
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Risk management process
Analyse
Evaluate
Control
Production and Post
Production information
Ongoing part of the Quality Management
System
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Activity 6ICH Q9 Quality risk management
Read and review ICH Q9 Quality risk management
Sections 3-6
Summarise the main points in your workbook
Work in pairs or individually
Contribute to group discussion
WB 6/ 60 mins
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Regulators and Quality Risk Management
Presented by John Montalto
13 May, 2013
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Regulators and risk management
Identify and clarify the events considered undesirable
What can go wrong?
Qualify or quantify the likelihood and consequence of the risk
Why?
Evaluate each risk and decide if they are acceptable or require action
What can be done?
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Regulat