Implementation of ICH Q8, Q9, Q10
Breakout A
Design Space
International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use
ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Disclaimer
The information within this presentation is based
on the ICH Q-IWG members expertise and
experience, and represents the views of the ICH
Q-IWG members for the purposes of a training
workshop.
© ICH, Washington D.C., October 2010
© ICH, October 2010, Breakout A: Design Space
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Introduction
• Structure of this session
- Discussion of key messages on Design Space
- Examples from the Case Study
- Wrap up
-
- Feedback on barriers to implementation
- Feedback on issues where further clarification is required
Breakout report
© ICH, Washington D.C., October 2010
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Introduction
• There are no regulatory requirements to have a Design Space
• Quality Risk Management approaches need to be considered to
ensure the robustness of the Design Space
• Design space can illustrate understanding of parameter
interactions and provides manufacturing flexibility
-
Proven acceptable range alone is not a design space
• Design space can include critical and non-critical parameters
• Design space should be verified and opperational at full scale
-
No requirement to develop a design space at the full manufacturing
scale
Many options exist for how (and where) to present a design space
© ICH, Washington D.C., October 2010
© ICH, October 2010, Breakout A: Design Space
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Training Objectives
• Design Space development
- Steps in Development of Design Space
- Prior knowledge
- QRM
- DOE & modeling
- Process Parameter and Quality Attribute as factors in
Design Space development
• Implementation of Design Space
• Presentation of Design Space in regulatory submission
© ICH, Washington D.C., October 2010
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Steps in Development of Design Space
• Consider QTPP in establishing the Design Space
• Initial determination of CQAs
• Assess prior knowledge to understand variables and their
impact
-
Scientific principles & historical experience
• Perform initial risk assessment of manufacturing process
•
•
•
relative to CQAs to identify the high risk manufacturing steps
(->CPPs)
Conduct Design of Experiments (DoE)
Evaluate experimental data
Conduct additional experiments/analyses as needed
© ICH, Washington D.C., October 2010
© ICH, October 2010, Breakout A: Design Space
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
QbD Story per Unit Operation
QTPP
& CQAs
Quality
Risk Management
Process
Variables
Design of
Experiments
Design
Space
Control
Strategy
Batch
Release
Illustrative Examples of Unit Operations:
API
Crystallization
Blending
Compression
Real Time
Release testing
(Assay, CU, Dissolution)
© ICH, Washington D.C., October 2010
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
DS development - Prior knowledge
• Key messages
- Prior knowledge may include :
- internal knowledge from development and
-
manufacturing
- External knowledge: scientific and technical
publications (including literature and peer-reviewed
publications)
Citation in filing: regulatory filings, internal company report
or notebook, literature reference
No citation necessary if well known and accepted by
scientific community
© ICH, Washington D.C., October 2010
© ICH, October 2010, Breakout A: Design Space
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
DS development - Prior knowledge
• What might be applicable sources of Prior Knowledge ?
• Identify other type of prior knowledge that can be used
in DS development
Example from Case Study : Crystallization of the drug substance
-
Particle size control needed during crystallization
Prior knowledge/1st principles shows that other unit operations
(Coupling reaction, aqueous workup, filtration and drying) have low risk
of affecting purity or PSD.
> Knowledge from prior filings
> Knowledge from lab / piloting data, including data from other
compounds using similar “platform” technologies
> First principles knowledge from texts/papers/other respected
sources
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© ICH, Washington D.C., October 2010
ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
DS development - QRM
• Risk assessment is based on prior knowledge and
relevant experience for the product and manufacturing
process
- Gaps in knowledge could be addressed by further
-
experimentation
Assignments of risk level must be appropriately justified
• Risk assessments/control will iterate as relevant new
information becomes available
- Final iteration shows control of risks to an acceptable
level
© ICH, Washington D.C., October 2010
© ICH, October 2010, Breakout A: Design Space
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
DS development - QRM
• Training questions
- If the risk acceptance criteria (conclusions) are different
than scientific theory/prior knowledge would indicate, then
is further explanation provided to justify unexpected
conclusions?
- If there are gaps in the information then what would the
plan be to make adjustments to further reduce risk?
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© ICH, Washington D.C., October 2010
Case Study
ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Example
Breakout A: Design Space
Illustration from the Case Study - Risk Assessment for PSD Control
Unit Operation
Parameter
IM
PA
C
PR T
OB
De .
tec
t
What is the Impact that ------------- will have on purity? 1) minimal 5) moderate 9) significant
What is the Probability that variations in ------------ will occur? 1) unlikely 5) moderately likely 9) highly likely
What is our Ability to Detect a meaningful variation in --------------- at a meaningful control point? 1) certain 5) moderate 9) unlikely
Comments
RPN
Crystallization
Crystallization
Feed Temperature
Water content of Feed
1 5 1
1 5 5
5
25
To be investigated
in DOE
405
9 5 9
Crystallization
Addition Time (Feed Rate)
Crystallization
Seed wt percentage
9 5 5
1 1 1
Crystallization
Antisolvent percentage
Crystallization
Temperature
Crystallization
Agitation (tip speed)
Crystallization
Seed particle size distribution
Crystallization
Feed Concentration
9 5 9
9 5 5
9 1 1
1 1 1
Change in addition time is easy to detect, but rated
high since there is no possible corrective action
225
1 Yield loss to crystallization already low (< 5%), so
reasonable variations in antisolvent percentage (+/10%) will not affect the percent of batch crystallized,
and will not affect PSD
405 Change in crystallization temperature is easily
detected, but rated high since no possible
corrective action (such as, if seed has been
dissolved)
225 Prior knowledge indicates that final PSD highly
sensitive to Agitation, thus requiring further study.
9 Seed PSD controlled by release assay performed
after pin milling.
1
Same logic as for antisolvent percentage
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© ICH, Washington D.C., October
2010 working documents like this would likely not be included in the submission
Detailed
© ICH, October 2010, Breakout A: Design Space
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
DS development – DOE & Modeling
• Target the desired quality attribute range from QTPP
• Determination of edge of failure is not required
• Modeling is not required to develop a Design Space
• Models need to be verified, updated and maintained
© ICH, Washington D.C., October 2010
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
DS development – DOE & Modeling
- Does
the DOE results, as presented in the case study,
provide sufficient information to define a design space?
- Describe which parameters are addressed by univariate vs.
multivariate DOEs and how these are factored into the
design space
- Model implementation: Describe how variability due to the
process operations and/or analytical method is considered
in use of the model
- Describe the process for maintenance & updating of the
model
© ICH, Washington D.C., October 2010
© ICH, October 2010, Breakout A: Design Space
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
DS development – Process parameter &
quality attributes
- Design space presentation in the submission could
-
include critical and non-critical parameters
- Critical parameter ranges/model are considered a
regulatory commitment and non-critical parameter
ranges support the review of the filing
- Critical parameter changes within design space are
handled by the Quality System and changes outside
the design space need appropriate regulatory
notification
Non-critical parameters would be managed by Quality
System
© ICH, Washington D.C., October 2010
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
DS development – Process parameter &
quality attributes
• Illustration & training questions
- Has the model for PSD Control (next slide) been
-
demonstrated to be scale and equipment independent?
Is a mathematical model always needed to have a design
space?
How to evaluate the impact of changing non-critical
process parameters when included in the design space ?
- Technical evaluation of a change of non-critical is the
same scientific principle as for critical
© ICH, Washington D.C., October 2010
© ICH, October 2010, Breakout A: Design Space
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Illustration from case study : QTPP and CQAs
QTPP
Dosage form and strength
Immediate release tablet
containing 30 mg of active ingredient.
Specifications to assure safety
and efficacy during shelf-life
Assay,
Uniformity of Dosage Unit (content uniformity) and
dissolution.
Description and hardness
Robust tablet able to withstand transport and handling.
Appearance
Film-coated tablet with a suitable size to aid patient
acceptability and compliance.
Total tablet weight containing 30 mg of active ingredient
is 100 mg with a diameter of 6 mm.
Drug Product CQAs
•Assay
•Content Uniformity
CQAs derived using Prior Knowledge
(e.g. previous experience of developing tablets)
•Dissolution
CQAs may be ranked using quality risk assessment.
•Tablet Mechanical Strength
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© ICH, Washington D.C., October 2010
ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
API Crystallization:
Design Space & Control Strategy
20 to 30ºC
Particle Size
Crystallization
Temperature
Particle Size
Crystallization
Feed Time
Particle Size
Crystallization
Agitation
Particle Size
Crystallization
Seed Wt%
1 to 2 wt%
Hydrolysis
Degradate
Distillation /
Crystallization
Water Content
< 1 wt%
Control between 23 and 27ºC
5 to 15 hours Control via flow rate settings
Quality system should ensure
1.1 to 2.5 m/s changes in agitator size result in
change to speed setting
© ICH, Washington D.C., October 2010
© ICH, October 2010, Breakout A: Design Space
Controlled through weigh scales
and overcheck
Control via in process assay
(e.g. < 0.5%)
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Implementation of Design Space
• What PQS element need to be considered ?
• How DS is captured in batch documentation and batch
release ?
• How DS knowledge used in managing changes in the
manufacturing process?
• What information would be transmitted to the
manufacturing site?
© ICH, Washington D.C., October 2010
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Presentation of Design Space in regulatory
submission
• Design Space need to be clearly presented and
justified in regulatory submission
- Design Space need to be described in sufficient
details in regulatory filing
- Description could include critical and non critical
parameters to assure complete understanding
- Designation of criticality need to be justified in
regulatory submission based on QRM and/or
experimental results
© ICH, Washington D.C., October 2010
© ICH, October 2010, Breakout A: Design Space
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Presentation of design space in regulatory
submission
• What is needed in the manufacturing process
description in the filing to demonstrate the
implementation of the Design Space?
• What is the appropriate level of detail to present DOE
and it’s conclusions in regulatory submissions ?
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© ICH, Washington D.C., October 2010
ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Illustration from the case study :
Options for Depicting a Design Space
• In the idealized example at left, the
Seed
wt%
Pressure
•
oval represents the full design
space. It would need to be
represented by an equation.
Alternatively, the design space can
be represented as the green
rectangle by using ranges
-
Temperature
a portion of the design space is not
utilized, but the benefit is in the
simplicity of the representation
Large square shows the ranges tested in the DOE
Red area shows points of failure
Green area shows points of success.
© ICH, Washington D.C., October 2010
© ICH, October 2010, Breakout A: Design Space
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Acknowledgement
This presentation has been developed by members of the
ICH Quality Implementation Working Group (Q-IWG)
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Jean-Louis Robert (rapporteur)
Diana Amador-Toro
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Robert G. Baum
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Nicholas Cappuccino
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David Cockburn
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Georges France
•
Richard L. Friedman
•
Nigel Hamilton
•
Hirotada Nagai
•
Yukio Hiyama
•
Fusashi Ishikawa
•
Takao Kiyohara
•
Urs Kopp
Akira Kusai
Yoshihiro Matsuda
Motoaki Mitsuki
Elaine Morefield
Jacques Morénas
Masatoshi Morisue
Markus-Peter Müller
Tamiji Nakanishi
Moheb Nasr
Kazuhiro Okochi
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Anthony Ridgway
Rachael Roehrig
Stephan Rönninger
Swroop Sahota
Hideki Sasaki
Tetsuhito Takarada
Shigeki Tamura
Krishnan Tirunellai
Mats Welin
Jean M. Wyvratt
A J van Zyl
© ICH, Washington D.C., October 2010
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Implementation of ICH Q8, Q9, Q10
Breakout: A
Design Space
Discussions
Moheb Nasr
Georges France
International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use
© ICH, October 2010, Breakout A: Design Space
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Acknowledgement
Facilitators
• Regulator:
-
Krishnan Tirunellai
Sharmista Chatterjee
Eric Duffy
Erin McCaffrey
• Industry:
-
John Lepore
Tim Watson
Kevin Seibert
John Berridge
© ICH, Washington D.C., October 2010
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Disclaimer
• This represents a high level summary of
workshop discussion without judgement or
endorsement
© ICH, Washington
Washington,D.C.,
D.C.,October
October2010
2010
© ICH, October 2010, Breakout A: Design Space
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Are we clear with the key messages?
Mainly YES
• Different level of understanding of the key messages and the main
concepts, resulting in questioning of interpretation
-
For example: what is the definition of knowledge space
• Lack of clarity about Change Management of non-critical parameters
when included in the Design Space
• Lack of clarity about Change Management of non-critical parameters
when not included in the Design Space
• Regulatory expectation of process description: inclusion or not of
non-critical parameters
© ICH, Washington D.C., October 2010
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Are there practical concerns on implementation?
(e.g. on harmonisation among regions needed, by region/local issue)
• Design Space and scale up
- Verification at full scale
- Expectation of Design Space verification
- Use of SUPAC 10x approach to scale up Design
Space
- Can we use Design Space development to replace
SUPAC recommendations
- Define which parameters are scale independent
© ICH, Washington D.C., October 2010
© ICH, October 2010, Breakout A: Design Space
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Are there practical concerns on implementation?
(e.g. on harmonisation among regions needed, by region/local issue)
• Need a new approach for process validation for
QbD type product with a Design Space
- What is the value of conducting traditional validation
studies with a single point within Design Space?
- Is it an acceptable approach to conduct PQ Batches
at different points within design space?
- Continuous Process verification to replace
traditional 3 batches process validation?
© ICH, Washington D.C., October 2010
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Are there practical concerns on implementation?
(e.g. on harmonisation among regions needed, by region/local issue)
• Linkage between QTTP to CQA to Design Space
-
Clinical relevance of Design Space
- Potential tightening of specification based on batch history
- Consider the impact of changes to Design Space on clinical
safety and efficacy
- Utility of in vivo data to link Design Space to QTPP
• Should we consider all CQAs when developing a Design
Space?
© ICH, Washington D.C., October 2010
© ICH, October 2010, Breakout A: Design Space
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Are there practical concerns on implementation?
(e.g. on harmonisation among regions needed, by region/local issue)
• Implementation of Design Space in commercial
manufacturing facilities
-
PQS issues, batch record, …
Plan for knowledge retention
• Tech transfer of Design Space
-
From development to manufacturing plant
From site to site
Outsourcing
• Prior knowledge
-
Documentation and presentation of the prior knowledge in the
regulatory submission
How to utilize prior knowledge from other product development?
© ICH, Washington D.C., October 2010
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Are there practical concerns on implementation?
(e.g. on harmonisation among regions needed, by region/local issue)
• Verification, updating and maintenance of models
-
Consider developing an ICH guidance/Q&A on best practices for
modelling
Regulatory implications of model update
• How to facilitate the Life Cycle management of a QbD type
application, including a Design Space
-
Introduction and/or updating of Design Space after initial
approval
Development of a Design Space for legacy products
© ICH, Washington D.C., October 2010
© ICH, October 2010, Breakout A: Design Space
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Are there practical concerns on implementation?
(e.g. on harmonisation among regions needed, by region/local issue)
• Concern about regulatory expectation/harmonization in
the review of Design Space in different region inside and
outside ICH?
-
Lack of global harmonization (outside ICH region) could reverse
progress with the implementation of Q8,9 & 10
Impact of different change management regulatory processes
over the life cycle of the product
• Level of detail and location in regulatory submission
-
Consider revising CTD to adapt QbD type information (Design
Space, Control Strategy, Quality Risk Management, etc.)
• There is a training need for regulators and industry
© ICH, Washington D.C., October 2010
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Are there practical concerns on implementation?
(e.g. on harmonisation among regions needed, by region/local issue)
• Lack of clarity of regulatory commitment versus
information intended for assessment purpose
• Need for appropriate scientific dialogue between
industry and regulators (inspectors & assessors)
before, during & after assessment
• Concern about the cost and the impact on time to
market
• Relationship between incoming raw material
attributes (API, Excipients,…) and Design Space?
© ICH, Washington D.C., October 2010
© ICH, October 2010, Breakout A: Design Space
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Where is more clarification required for practical
harmonised implementation?
• There is a need for more discussion on
determination and the use of criticality in
development of Design Space, Control Strategy
and regulatory processes
- There is a need for criticality justification regardless of
inclusion into Design Space?
- Should we consider an additional medium risk
Process Parameter?
- Should we reduce the emphasis of “Criticality”?
© ICH, Washington D.C., October 2010
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ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout A: Design Space
Where is more clarification required for practical
harmonised implementation?
• There is a need for more practical examples of
Design Space development and presentation
(e.g. complex Design Space and Models)
- Is there a need for determination of uncertainty and
robustness of Design Space?
• The level of GMP relevance during DS
development
- For example: Need for clarity about analytical
methods used in the development of Design Space
(GMP validated versus Development methods)?
© ICH, Washington D.C., October 2010
© ICH, October 2010, Breakout A: Design Space
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