Implementation of ICH Q8, Q9, Q10

Workshop A
Design Space (DS)

International Conference on Harmonisation of Technical

Requirements for Registration of Pharmaceuticals for Human Use
 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

Disclaimer

The information within this presentation is based

on the ICH Q-IWG
Q IWG members expertise and
experience, and represents the views of the ICH
Q-IWG members for the p purposes
p of a training
g
workshop.

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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

Introduction
• Structure of this session

- Key Steps in developing a Design Space

- Presentation of key messages on Design Space
- Discussion in one or more sub groups on
the key questions
- Wrap up
- Breakout report

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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Key StepsA:for
Workshop a product
Design Space under Quality by Design (QbD)
Pharmaceutical
Pharmace tical QTPP: Quality Target
Development QTPP : Definition of intended use & product
Product Profile

Prior Knowledge (science, GMP,

regulations, ..) CQA : Critical Potential CQA (Critical Quality Attribute) identified &
Q lit Att
Quality Attribute
ib t CPP (Critical
(C iti l Process
P Parameters)
P t ) determined
d t i d
Product/Process Development
CPP : Critical Design to meet CQA using Risk Management &
DOE : Design of Experiment Process Parameter experimental studies (e.g. DOE)

Link raw material attributes and process parameters

Q
QRM principle apply at any stage Ri k M
Risk Management to CQAs and perform Risk Assessment Methodology

Product/Process Understanding Opportunities Design Space (DS), RTR testing

Control Strategy Marketing Authorisation

Quality System PQS

Technology Transfer
f Commercial Manufacturing
PQS & GMP Batch Release
Quality Unit (QP,..) level support by PQS
Local Environment Strategy

Continual Manage product lifecycle, including

improvement continual improvement
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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

Key Messages (1)

• There are no regulatory
g y requirements
q to have a Design
g Space
p
• Quality Risk Management approaches need to be considered to
ensure the robustness of the Design Space
• Design
D i space can ill illustrate
t t understanding
d t di off parameter
t
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

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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

Key Messages (2) on prior Knowledge

• 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,
filings internal company
report or notebook, literature reference
- No citation necessaryy if well known and accepted
p by
y
scientific community

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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

Key Messages (3) on QRM / DS development

• 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
i f
information
ti becomes
b available
il bl
- Final iteration shows control of risks to an acceptable
level

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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

Key Messages (4) – 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

Kuala Lumpur, July 2010 slide 8

 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

Key Messages (5)– 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
C iti l parameter
t changes
h within
ithi ddesign
i space are
handled by the Quality System and changes outside
the design space need appropriate regulatory
notification
tifi ti
- Non-critical parameters would be managed by Quality
y
System

Kuala Lumpur, July 2010 slide 9

 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

Key Messages (6) - Presentation of Design

Space in regulatory submission
• Design Space need to be clearly presented and
justified in regulatory submission
- Design
D i S Space need
d to b
be d
described
ib d iin sufficient
ffi i
details in regulatory filing
- Description
p 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

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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

Training Topics review in Sub Group

• Design Space development
- Scope and applicability of DS
- Steps in Development of DS: illustration
- Prior knowledge
- QRM
- DOE & modeling
- Process Parameter and Quality Attribute as factors in
Design Space development
• Implementation of Design Space
• Presentation of Design
g Space
p in regulatory
g y submission

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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

Now Break out in sub group

g p

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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

Scope & Applicability of Design Space DS

• Can a DS be applicable to scale-up ?

• Can a DS space
p be applicable
pp to a site change
g ?
• Can a DS be developed for single and/or multiple unit
operations ?
• Is it possible to develop a DS for existing products ?
• Is there a regulatory expectation to develop a DS for
an existing
i ti product
d t?
• Can a DS be applicable to formulation ?

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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

DS development – Key Steps

• What are the key steps developing a DS ?

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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

Steps in Development of Design Space

• Consider QTPP in establishing the Design Space (Back up slide1)
• 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)
( CPPs)
• Conduct Design of Experiments (DoE)
• Evaluate experimental data
• C d t additional
Conduct dditi l experiments/analyses
i t / l as needed
d d

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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

QTPP :Quality
Q lit T Targett P
Product
d tP Profile
fil
defines the objectives for development

Dosage form and strength Immediate release tablet taken orally

containing 30 mg of active ingredient
Specifications to assure safety Assay, Uniformity of Dosage Unit (content
Assay
and efficacy during shelf-life 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

• QTPP: A prospective summary of the quality characteristics of a drug

p
product that ideally
y will be achieved to ensure the desired q
quality,
y taking
g
into account safety and efficacy of the drug product. (ICH Q8 (R2))
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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

DS development - Prior knowledge

• What might be applicable sources of Prior Knowledge ?

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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

DS development - Prior knowledge

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,
data including data from other
compounds using similar “platform” technologies
> First principles knowledge from texts/papers/other respected
sources

Back up Slide 2 & 3

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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

DS development - QRM
• 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 Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

Illustration from the Case Study - Risk Assessment for PSD Control
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

PR T
De .
t
C
OB
tec
Unit Operation Parameter Comments

PA
IM
RPN
5
1 5 1
Crystallization Feed Temperature To be investigated
Water content of Feed 1 5 5 25
Crystallization in DOE
405
9 5 9 Change in addition time is easy to detect, but rated
Crystallization Addition Time (Feed Rate) high since there is no possible corrective action
225
9 5 5
Crystallization Seed wt percentage
1 Yield loss to crystallization already low (< 5%), so
reasonable variations in antisolvent percentage (+/-
1 1 1
10%) will not affect the percent of batch crystallized,
Crystallization Antisolvent percentage and will not affect PSD
405 Change in crystallization temperature is easily
detected, but rated high since no possible
9 5 9
corrective action (such as, if seed has been
Crystallization Temperature dissolved)
225 Prior knowledge indicates that final PSD highly
9 5 5
Crystallization Agitation (tip speed) sensitive to Agitation, thus requiring further study.
9 Seed PSD controlled by release assay performed
9 1 1
Crystallization Seed particle size distribution after pin milling.
1
1 1 1
Crystallization Feed Concentration Same logic as for antisolvent percentage

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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

DS development – QTPP and CQAs

- How are CQAs determine ?

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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

Ill t ti from
Illustration f case study
t d : QTPP and
d CQAs
CQA
QTPP
Immediate release tablet
Dosage form and strength containing 30 mg of active ingredient.

Specifications to assure safety Assay,

and efficacy during shelf-life 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.
compliance
Total tablet weight containing 30 mg of active ingredient
is 100 mg with a diameter of 6 mm.

Drug Product CQAs

•Assay
CQAs derived using Prior Knowledge •Content Uniformity
(e.g. previous experience of developing tablets)
•Dissolution
CQAs may be ranked using quality risk assessment.
•Tablet Mechanical Strength

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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

API Crystallization:
Design Space & Control Strategy
Particle Size Crystallization Temperature 20 to 30ºC Control between 23 and 27ºC

Particle Size Crystallization Feed Time 5 to 15 hours Control via flow rate settings

Quality system should ensure

Particle Size Crystallization Agitation 1.1 to 2.5 m/s changes in agitator size result in
change to speed setting

Controlled through weigh scales

Particle Size Crystallization Seed Wt% 1 to 2 wt%
and overcheck
Hydrolysis Distillation / Control via in process assay
Water Content < 1 wt%
Degradate Crystallization (e.g. < 0.5%)

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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

Implementation
p of Design
g Space
p

• What PQS element need to be considered ?

• How DS S is captured in batch documentation and batch
release ?
• How DS knowledge g used in managing
g g changes
g in the
manufacturing process?
• What information would be transmitted to the
manufacturing site?

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 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

Presentation of design space in regulatory

submission

• What
Wh t is
i needed
d d iin th
the manufacturing
f t i 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 Quality Implementation Working Group - Integrated Implementation Training Workshop

Workshop A: Design Space

Illustration
Ill t ti ffrom the
th case study
t d :
Options for Depicting a Design Space
• In
I the
th idealized
id li d example
l att lleft,
ft th
the
oval represents the full design
space. It would need to be
represented
ep ese ted by a an equat
equation.
o
• Alternatively, the design space can
wt%
Pressure

be represented as the green

Seed

rectangle by using ranges

- a portion of the design space is not
SP

utilized, but the benefit is in the

Temperature 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.

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