Annex II: Potential Applications

ICH Q9 QUALITY RISK MANAGEMENT

II. 3 Quality risk management as part of…

Development
Industry

Competent
Authorities
See also next chapters
using the intention to be applicable for development
II.4: Facilities, Equipment and Utilities
II.5: Materials Management
II.6: Production
II.7: Laboratory Control and Stability Studies
II.8: Packaging and Labelling
Note: Process understanding and criticality may be applied only to new products
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Annex II: Potential Applications
ICH Q9 QUALITY RISK MANAGEMENT CONSIDERATIONS

About development

Critical
Parameters
that contribute
to variation in customer
requirements

Parameters that impact

customer requirements

All parameters and dimensions

that define a product
T. Matsumura, Eisai Co.
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Annex II: Potential Applications
ICH Q9 QUALITY RISK MANAGEMENT

II.3: QRM as part of development

 To design a quality product and its manufacturing process

> to consistently deliver the intended performance
of the product (see ICH Q8)

 To enhance knowledge of product performance

over a wide range of
> material attributes
(e.g. particle size distribution, moisture content, flow properties)
> processing options
> process parameters

ICH Q9
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Annex II: Potential Applications
ICH Q9 QUALITY RISK MANAGEMENT EXAMPLE

Quality by design: “Special Cause” or “Common Cause”

Note: Non detected OoS
could result in a patient risk
Production

Validation

 Consequence: Frequent, major OOS

 Corrective actions eliminate “Special Cause”
Result: Unstable process Based on A. Hussain, FDA, September 2004
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Annex II: Potential Applications
ICH Q9 QUALITY RISK MANAGEMENT EXAMPLE

Quality by design : “Special Cause” or “Common Cause”

Production

Validation

 Reduce “Common Cause” Variability

 Consequence: On the continuous improvement path
Result: Stable & Capable A. Hussain, FDA, September 2004
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Annex II: Potential Applications
ICH Q9 QUALITY RISK MANAGEMENT EXAMPLE

Quality by design : “Special Cause” or “Common Cause”

Production

Validation

 Consequence: Minor, occasional OoS

 Reduce “Common Cause” Variability
Result: Stable- Yes; Capable? A. Hussain, FDA, September 2004
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Annex II: Potential Applications
ICH Q9 QUALITY RISK MANAGEMENT

II.3: QRM as part of development

 To assess the critical attributes of
> Raw materials
> Solvents
> Active Pharmaceutical Ingredient (API)
> Starting materials
> Excipients
> Packaging materials

 To establish appropriate specifications, identify critical

process parameters and establish manufacturing controls
ICH Q9
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Annex II: Potential Applications
ICH Q9 QUALITY RISK MANAGEMENT

II.3: QRM as part of development

 To decrease variability of quality attributes:
> reduce product and material defects
> reduce manufacturing defects

 To assess the need for additional studies

(e.g., bioequivalence, stability)
relating to scale up and technology transfer

 To make use of the “design space” concept

(see ICH Q8)

ICH Q9
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Annex II: Potential Applications
ICH Q9 QUALITY RISK MANAGEMENT EXAMPLE

P2 of CTD as part of a regulatory submission

In line with Quality Risk Management ?

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Annex II: Potential Applications
ICH Q9 QUALITY RISK MANAGEMENT EXAMPLE

P2 of CTD as Quality Risk Management process ?

Initiate
Quality Risk Management Process

Formulation & Process design Risk Assessment

Risk Identification

Risk Analysis
Process understanding
Risk Evaluation
unacceptable
Manufacturing Concept

Risk Management tools

Risk Communication
Risk Control

Process control Concept Risk Reduction

Risk Acceptance
Product release Concept
Output / Result of the
Quality Risk Management Process
Regulatory strategy
Risk Review

Review the submission Review Events

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 Annex II: Potential Applications
ICH Q9 QUALITY RISK MANAGEMENT EXAMPLE
Target Product Profile
Developm.

Development
Drug substance properties; prior knowledge

Proposed formulation and manufacturing process Research

Re-evaluation and confirmation

Re-evaluation and confirmation

Determination of
Formulation understanding Operation

Cause – Effect relationships

Process understanding
(Risk Identification with subsequent Risk Analysis) Phase 1

Risk-based classification
(Risk Evaluation)

Parameters to investigate (e.g. by DOE)

(Risk Reduction 1. proposal; 2. verified)

Product and process

FORMULATION characteristics on the PROCESS
DESIGN SPACE final drug product DESIGN SPACE
Phase 2 BY UNIT OPERATION
CONTROL
Review events Phase 3
STRATEGY
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EFPIA PAT TG, 2006
 Annex II: Potential Applications
ICH Q9 QUALITY RISK MANAGEMENT EXAMPLE
Risk Management approach to focus on critical attributes
Unit operation

Dispensing Granulation Drying Blending Tableting

Quality Attributes

Dissolution Significant
influence
Disintegration
Initial
Hardness
assessment
Assay
Prior
Content knowledge
Uniformity
First & Second
Degradation
review cycle
Stability Formulation
and Process
Appearance understanding

Identification Third
review cycle
Water
Control
Strategy
Microbiology

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EFPIA PAT TG, 2006
 Annex II: Potential Applications
ICH Q9 QUALITY RISK MANAGEMENT EXAMPLE
low
Risk to patient Process understanding
Control Strategy
Unit operation
1
Unit operations Blending
Dispensing (Raw
/ Granulation Drying (Magnesium Tableting Packaging
Material Properties)
Quality attributes Stearate)
Power Not critical to Not critical to
Dissolution Particle size API
consumption
Prior knowledge
quality quality
Prior knowledge
water amount and Not critical to Not critical to
Disintegration Particle size API
feed rate
Prior knowledge
quality quality
Prior knowledge
Quality Attributes

Not critical to Not critical to

Hardness Prior knowledge Prior knowledge Prior knowledge
quality quality
Prior knowledge

Assay Prior knowledge Prior knowledge Prior knowledge Prior knowledge NIR measurement Prior knowledge
Power Not critical to Not critical to
Content uniformity Prior knowledge
consumption quality quality
NIR measurement Prior knowledge
Water amount and Not critical to
Degradation Prior knowledge
feed rate quality
Prior knowledge Prior knowledge Prior knowledge
Control water
Stability Prior knowledge Prior knowledge
content
Prior knowledge Prior knowledge Prior knowledge
Not critical to Not critical to
Appearance Prior knowledge Prior knowledge
quality
Prior knowledge
quality
Prior knowledge

Identification NIR of raw material Prior knowledge Prior knowledge Prior knowledge Prior knowledge Prior knowledge
Control water
Water Prior knowledge Prior knowledge
content
Prior knowledge Prior knowledge Prior knowledge
Specification of Purified water
Microbiology starting material used
Prior knowledge Prior knowledge Prior knowledge Prior knowledge

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EFPIA PAT TG, 2006
Annex II: Potential Applications
ICH Q9 QUALITY RISK MANAGEMENT EXAMPLE

Responsibilities in regulatory operations

Initiate
Industry Quality Risk Management Process

Risk Assessment

Risk Identification
Team focused

Risk Analysis

Risk Evaluation
unacceptable

Risk Management tools

Risk Communication

Risk Control
Internal consultation

Risk Reduction B) Inspectorates

Risk Acceptance
Stakeholder involvement

Output / Result of the

Quality Risk Management Process A) Reviewers
Risk Review

Review Events

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Annex II: Potential Applications
ICH Q9 QUALITY RISK MANAGEMENT EXAMPLE

QRM as part of development

provide risk-based knowledge to manufacturer
Past Future
Parameters and range We have additional dimensions

 Open question:
How to challenge information for submission?

Answer the questions in ICH Q9 Chapter 4:

> What might go wrong?
> What is the likelihood (probability)
it will go wrong?
> What are the consequences (severity)?
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 Development and Manufacturing EXAMPLE

Conventional approach: Testing after each step to minimize the

risk prior to the next step

Raw
Materials
Blending Tabletting Packaging

Validation
Raw
Materials
Blending Tabletting Packaging

PAT: Continuous or more frequent testing and control during each

step to minimize/control the risk prior to the next step

PAT: Process Analytical Technology Takayoshi Matsumura, Eisai