Presented by John Montalto 13 May, 2013 - PharmOut Q9 10 QRM overview ... • The International...

ICH Q8 & Q9

Presented by John Montalto

13 May, 2013

PharmOut 2013

Guidelines

Please contribute

Please stop me to ask a question

Please relax and enjoy yourself

Phone on silent

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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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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Assessment

Open book assessment

30 minutes

Hand in Assessment and Feedback form.

Thank-you!

Introduction to Pharmaceutical Development and Quality Risk Management


13 May, 2013

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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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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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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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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


- 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


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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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

The quality paradigm


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


Science and knowledge

Quality risk management

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Quality paradigm


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 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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|1835 | 1960s 1990|1998 | 2000 | 2006 | 2008 2010 | 2011 |2012


was created

ISO 14971 Medical



devices published

ICH Q9



equipment from a


ICH Q8

ASTM E2500-

07

ASTM E2500-

07

ICH Q10

ICH Q11

ISO 31000 Risk


and guidelines

ICH established



13 May, 2013

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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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The aims of pharmaceutical development include:

The design of a quality product and its manufacturing process

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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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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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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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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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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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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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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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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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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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Considerations should include:

Drug substances

ExcipientsContainer closure

Manufacturing processes

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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 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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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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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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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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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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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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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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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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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

Quality by Design


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 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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Holistic Approach

Continued Process Verification

Process Qualification

Process Design



Process Design



Process Design

Extensive product and process design efforts can lead to streamlined efforts in later stages of product lifecycle

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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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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


13 May, 2013

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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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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

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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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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?

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What controls would you put in place in order to reduce the risk?

(Establish a control strategy)

WB 5.3/ 5 mins

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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

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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

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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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Identifying variables


Appearance Temperature Aroma Texture Taste

Sweetness

Bitterness

Aftertaste

Critical Quality Attributes(CQA)

Taste Temperature (Safety)

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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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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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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


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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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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

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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.

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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.

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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?

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Control strategy

ICH diagramatic example of real time feed back loop

NEEDS A DIAGRAM FROM JOHN

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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

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Control strategy

Control strategy is a continuum of controls, as opposed to one discrete control for one parameter

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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

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Control strategy

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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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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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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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How would you use control strategies to verify your validation efforts?

An ongoing process

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An ongoing process

While design space is optional, Control Strategy is never optional

Jacques Morenas, PIC/S Chair, April 2011

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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

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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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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Product knowledge drives Process development

Develop Control Strategy


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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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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

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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

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Implement Control Strategy

Every process and product has an associated control strategy:

Overall strategy for a product

Discrete control strategy for an

operation

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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

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Batch release

Control Strategy and batch release decisions are separate

Control Strategy is not the only consideration when batch release decisions are determined

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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

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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.

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Traditional approach

Emphasis on end-product testing

Operating ranges set on observed process data

Generally narrow target range

Process capability (or lack of capability)

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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)

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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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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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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



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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

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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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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

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QTPP

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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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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


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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

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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

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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

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Raw material variability may have an impact on DoE.

The handover of information from process development to commercial manufacture may include raw material suppliers

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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

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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

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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

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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

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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


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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.

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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


Continued Process

Verification

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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.

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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

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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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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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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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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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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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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

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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)

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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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Process in control & capable?

Need to evaluate overall process variation over time

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A more realistic process

Intra and inter batch variation over time

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Special Cause Variation

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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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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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Process Capability Analysis-Minitab

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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

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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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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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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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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

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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

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Activity 4.4

Read and review Part II: Pharmaceutical development Annex Section 2.4 to 2.4.6


WB 4.4/ 45 mins

The outcomes of Pharmaceutical Development


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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


Knowledge library expands

Control strategyFeed forward/back

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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


Knowledge library expands

PQS ManagementFeed Feed forward/back

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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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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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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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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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Activity 4.5

Read and review Part II: Pharmaceutical development Annex Section 2.6


WB 4.5/ 30 mins

ICH Q9 Quality Risk Management


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If everything is critical, nothing is critical

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Quality Risk Management overview

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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

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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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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

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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

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Risk assessment

1What might go wrong?

2What is the likelihood it will go wrong?

3What are the consequences?

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Risk assessment

Inputs to risk identification may be varied is your QMS able to support your data requirements?

Risk identification

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Risk assessment

Qualitative and quantitative process to comprehend the severity, likelihood and detectability of harm.

Risk analysis

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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

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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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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

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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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Risk communication

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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

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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

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Risk management tools

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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


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|1835 | 1960s 1990|1998 | 2000 | 2006 | 2008 2010 | 2011 |2012


was created

ISO 14971 Medical



devices published

ICH Q9



equipment from a


ICH Q8

ASTM E2500-

07

ASTM E2500-

07

ICH Q10

ICH Q11

ISO 31000 Risk


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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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

Quality Risk Management Relevant resources


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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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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

PharmOut 2013

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

PharmOut 2013

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

Regulators and Quality Risk Management


13 May, 2013

PharmOut 2013

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?

PharmOut 2013

Regulat

Presented by John Montalto 13 May, 2013 - PharmOut Q9 10 QRM overview ... • The International...

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Transcript of Presented by John Montalto 13 May, 2013 - PharmOut Q9 10 QRM overview ... • The International...