out of the box: application of quality risk management in ... · risk acceptance initiate quality...

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Annual RQA Conference

Brighton, 9 – 11 November 2016

“Your motivational partner for sustainable improvements in Quality & Compliance”

Out of the Box:

Application of Quality Risk Management

in

Pharmaceutical Product Lifecycle Processes

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Touch Points

Risk Management Uncertainties,

Medicinal Product Life Cycle Processes ICH Q8 /Q9 /Q10 /Q11 Q12

Risk Management and Quality Metrics within Product Lifecycle,

ICH Q9 Essentials and Risk Awareness in R&D,

Quality Risk Management Tool Selection in R&D Processes,

Install Continual Risk Management in R&D.

2

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3

Uncertainty and Quality Risk Management

Hazard

may

cause harm

Hazard

may not

cause harm

uncertainty

Hazard

less likely to cause harm

Mitigate Risks in relation to

probability, severity

& detectability

Lack of, or inadequate knowledge

Source: ICH Q9 Background presentation 2006

AWARENESS

INNOVATION

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4

“risk-based”

concepts and

principles

The ‘New’ Paradigm

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5

Risk Management across the Medicinal Product Lifecycle

Research

Preclinical

Phase Clinical

Phases

Launch

QualityICH Q9

Safety

Efficacy

Manufacturing

& Distribution

GLPGCP

GMP

GDP

Discontinuation:

End of life cycle

GPVP

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Risk Awareness and Metrics (I)

6

Juran:

’If not measured it cannot be managed’ is so true but…..

To some extend meaningless without questioning:

* Starting with WHY, WHAT, WHEN, WHO and HOW

do we measure?

* What types of Metrics /KPI’s are useful (for risk mitigation)

at what stage of the product life cycle?

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Risk Awareness and Metrics (II)

7

Baldrige Criteria

The goal of making measurements is to see operational performance more

clearly and hence make wiser long-term decisions (reduction of risk).

Kaplan and Norton

BSc (Customer /Stakeholder Satisfaction – Financial Stewardship –

Internal Business Processes – Organizational Capacity /Learning &

Growth):

Monitor organization performance against strategic goals to create future

value through investment in (managing risk in relation to) customers,

suppliers, employees, processes, technology, and innovation.

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Risk Awareness and Metrics (III)

8

John Moore Your measurements should expose your weaknesses (risk);

those are opportunities for improvement..

Hoshin Kanri Value your resources as experts in their field of activity, only by recognition

and acceptation of mistakes (risk awareness) we are able to learn and

improve.

Sharing success will drive forward encouraging maturity for changes and

improvements.

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9

Why Quality Metrics in Life Sciences?

Presentation Russell Wesdyk ( FDA /CDER)

Vision for 21st Century Manufacturing:

‘A maximally efficient, agile, flexible pharmaceutical manufacturing sector

that reliably produces high quality medicinal products without extensive

regulatory oversight’.

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Misuse of Metrics

10

• Lagging indicators easy way to satisfy the apparent demand but........

not to be used as a management fad.

• To conduct a post-mortem of recent performance.

• Lagging metrics are valuable tools for:

Deliver a business reflection of how it has been doing.

Background information for continual improvement.

Reveals hardly any information whether a strategy properly functions.

• Metrics measure past events do not provide information on future opportunities

or threats.

• Targets on lagging metrics contradictive with operational excellence.

Like a red traffic light while the accident already has occurred.

• Targeting lagging metrics lead to conflicts of interest and snitching behaviors.

LEADING indicators:

• Are less tangible.

• Important to show the direction of future results.

• Inform whether the LAGGING indicators will become better (or worse) in the future.

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LEADING AND LAGGING COMPLIANCE INDICATORS

Compliance is a lagging indicator or result of how much work is completed in the context of applied regulations.

Readiness of Compliance is a leading indicator for the pharmaceutical product reliability and Quality Culture.

The metric shall be part of the broader surveillance and business feedback system leading to future control and improvements (Management Review).

The use of lagging indicators for targeting improvement is like driving whilst constantly looking in the rear view mirror.

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12

The ICH Q9 document:

> Main body explains the “What?”

> Annex I give ideas on the “How?”

> Annex II give ideas on the “Where?”

> Pharmaceutical development (ICH Q8) and Quality Systems (ICH Q10)

will facilitate the “What?”, “How?” and “Where?”

How to use ICH Q9?

Encourage transparency

Create baseline for more science-based decisions

Facilitate communication

Matrix team approach

An aid to convince the stakeholders with trust

Encourage a preventive approach

Proactive control of risks and uncertainty

Benefit of knowledge transfer by team approach

Changes behavior

Better understanding of risk-based decisions

Acceptance of residual risks

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Organizations might have different meanings of risk

> Depending on the stage of the product life cycle.

> In R&D risk may become the innovation (creative benefit).

In general, "probability“, "severity“ and “detectability” must

be considered

> In a given stage definitions will fine-tune the concepts so that

a risk management program can be created and applied.

> Make the detail in the definition to fit the objective.

Accept the different "realities" among the stakeholders

> Harmonized guidance needs to focus concepts

into useful terms for the purpose (e.g. protection of patient [Q9])

Risk Awareness and Perception in R&D

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Failure Mode Effects Analysis (FMEA)

> Break down large complex processes into manageable steps

Failure Mode, Effects and Criticality Analysis (FMECA)

> FMEA & links severity, probability & detectability to criticality

Fault Tree Analysis (FTA)

> Tree of failure modes combinations with logical operators

Hazard Analysis and Critical Control Points (HACCP)

> Systematic, proactive, and preventive method on criticality

Hazard Operability Analysis (HAZOP)

> Brainstorming technique

Preliminary Hazard Analysis (PHA)

> Possibilities that the risk event happens

Risk ranking and filtering

> Compare and prioritize risks with factors for each risk

Quality Risk Management Tools (ICH Q9 Annex I)

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Contributing items to manage R&D quality risks

Process Risk

e.g. metrics, process performance and quality parameters

Product Risk (safety & efficacy)

e.g. quality attributes:

measured data according to specifications

System Risk (facility & people)

e.g. Strategy, establishment (components such as equipment,

IT), interfaces, operators risk, environment, design elements

System Risk (organisation)

e.g. Quality Planning, Quality systems, controls, measurements,

documentation, regulatory compliance

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Tool selection for the task

DETAIL GENERAL

Process Risk Product Risk

(safety & efficacy)

System Risk

(facility & people)

System Risk

(organization)

Flowcharts, Check Sheets, process

mapping, IshikawaX X X

Failure Mode Effect Analysis

(FMEA)X X X

Failure Mode Effect and Criticality

Analysis (FMECA)X X X X

Fault Tree Analysis (FTA) X X X

Hazard Analysis Critical Control

Points (HACCP)X X X X

Hazard Operability Analysis

(HAZOP)X X

Preliminary Hazard Analysis

(PHA)X X X

Risk Ranking and Filtering X X X

Supporting Statistical Tools X X

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Risk Review

Ris

kC

om

mu

nic

at i

on

Risk Assessment

Risk Evaluation

unacceptable

Risk Control

Risk Analysis

Risk Reduction

Risk Identification

Review Events

Risk Acceptance

Initiate

Quality Risk Management Process

Output / Result of the

Quality Risk Management Process

Ris

kM

an

ag

em

en

tto

ols

Step 1 Basic Data

Step 2 Process Conditions

Establish a

multidisciplinary team

Step 6 Risk Reduction

Measures

Requirement by a Quality

Management System

Summary

Step 3 Hazard Identification

Step 4 Hazard Assessment

Step 5 Risk Evaluation

Step 7 Residual Risk

© by Zurich insurance company

Zurich Hazard Analysis

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Potential Areas of Use(s)

Related but not the same! Critical Control Points are

expressed as Critical Quality Attributes (CQA’s).

To identify and manage process risks associated with

cultural, organizational, physical, chemical and biological

hazards (including microbiological contamination).

Useful when process understanding is key to support

identification of critical quality attributes (critical handovers

parameters / variables).

Facilitates performance by monitoring of critical attributes in

the process.

Hazard Analysis and Critical Control Points (I)

18

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Hazard Analysis and Critical Control Points (II)

How to perform in R&D?

1. Conduct hazard analysis: Map the process and

identify preventive measures for each step of the process

2. Determine critical quality attributes (CQA’s)

3. Establish target levels and critical limit(s)

4. Establish system to monitor the CQA’s

5. Establish corrective actions to be taken, if CQA is out

of control

6. Establish verification procedures, that HACCP works

effectively

7. Establish documentation of all procedures and keep

records

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Regularly evaluate lessons learned of processes

with recurring quality relevant problems.

Risk communication

Providing stakeholders with the update of the

overview of Risk control steps to include feedback.

Risk Review

Regularly the responsible process owner

updates the overview to become input to

management review supporting line/senior

management decisions .

Process Improvement and Management Review

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Compare and prioritize risks

How to perform?

Requires evaluation of multiple diverse quantitative and

qualitative actors and factors for process risk.

Involves breaking down a basic risk question into as many

components as needed to capture the actors and factors

involved in the risk.

These actors and factors are combined into a single Critical

Quality Attribute with relative risk score that can then be

compared, prioritized and ranked.

Ranking Process Risk

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Leading Tactics for Business Quality: Organization, Asset management, performance & improvement.

What do we establish to effectively achieve goals and objectives?

How can objectives be enabled?

Objectives for ICH Q12: Product Lifecycle Management

22

ASSETS

ESTABLISHMENT

ENABLERS

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Operational Processes for Product Lifecycle Management

PRODUCT REALIZATION

How to develop and establish safe and effective products of consistent quality?

MAIN STREAM PROCESSES

PR 01:

Target Discovery

Early Stage Dev.

PR 03:

Pharmaceutical

Development

PR 05:

Commercial

Manufacturing

PR 02:

Clinical

Research

PR 06:

Surveillance and

Discontinuation

ENABLING PROCESSES

PR 12:

Quality Assurance

PR 11:

Quality Control

PR 09:

Analytical

Development

PR 08:

Design Space

QbD

PR 07:

Logistics

Management

PR 10:

Maintenance

Monitoring

PR 04:

Technology

Transfer

CLINICAL RESEARCH REALIZATION

How to develop and establish consistent clinical trial quality?


CO 01:

Protocol

Development

CO 03:

Trial

Preparation

CO 05:

Safety Information

Processing

CO 02:

Statistical Programming

and Analysis

CO 06:

Report

Development

ENABLING PROCESSES

CO 11:

Surveillance and

Discontinuation

CO 09:

Regulatory Communication

and Reporting

CO 08:

Trial Processing &

Monitoring

CO 07:

Logistic & Supplies

Management

CO 10:

Clinical QA

CO 04:

Data Validation

& Management

NEW ENTITY REALIZATION

How to develop and establish quality in target and lead discovery?


LD 01:

Target

Identification

LD 03:

Drug

Design

LD 05:

Bio-Degradation

Profiling

LD 02:

Lead

Discovery

LD 07:

Phase 1 Safety

& Early Efficacy

ENABLING PROCESSES

LD 12:

Surveillance

LD 10:

Regulatory &

Patenting

LD 09:

Monitoring & Scientific

Evaluation Reporting

LD 08:

Computer Aided

Drug Design

LD 11:

Quality by Design

Method Development

LD 04:

Biological Efficacy

& Early Safety

LD 06:

Pre Clinical

Evaluation

CAPA GENERATING (COMPLIANCE) CONTROL SYSTEMS

Complaint

Handling

Vigilance,

Product Surveillance

Investigations

Deviation

HandlingChange

Control

Audits and

AssessmentsInspections

COMPLIANCE MANAGEMENT

QRM in Research & Development:• High Level of Uncertainty, express doubts and

weakness.

• Standardization vs Normalization.

• Define Critical Quality Attributes.

• Identify Quality Target Product Profile (ICH Q8)

- Intended use (administartion route,

dosage form) in clinical setting.

- Dosage strength(s).

- Exp. Date IMP vs primary packaging.

- Therapeutic moiety release or delivery

affect pharmacokinetics.

- Drug substance quality and potency.

• QbD continuous risk monitoring.

• Mitigation of risk at all stages of drug design.

• Awareness and reference of risk to quality.

• Communicate also acceptance of risk.

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Take Home Apply Quality Risk Management at the initiation of a process.

Quality Risk Management must become routinely applied within the product life cycle (ICH Q8, Q10 and Q11).

Define Critical Quality Attributes (related but not identical to Critical Control Points /Metrics) during process mapping by reviewing all actors and factors relevant for that process.

Handovers within processes and inter-action between processes are always a Critical Quality Attribute.

Recognize and consider risk being difficult to detect.

Risk management is important as part of continual improvement (CAPA handling).

Apply continual risk monitoring and feedback during R&D.

Log and document within a Risk Mitigation File.

A basic start for Product Lifecycle Management (ICH Q12).

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Integration of QRM into existing systems

and regulatory processes

will take

Time, Trust, Commitment and

Communication

Massaaki Imai on Gemba Kaizen:

Do not rush nor re-engineer, strive for incremental improvements!

Source: ICH Q9 Background presentation 2006

Creating a Quality Culture

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