ICH Q8 and Q9 – A Review

T.G. Venkateshwaran, Ph.D.,

Associate Director,
Global Regulatory Affairs – CMC

September 10, 2007

ICH Q8 and Q9 – Discussion Topics

n Background
 Quality by Design

n ICH Q8 and Q9 and their relationship to

Pharmaceutical Stability
n Applications of Risk Management to understanding
Pharmaceutical Stability
Drug Substance
Drug Product
n Conclusions/Path Forward

ICH Q8, Q9 - A review - AAPS Stability Workshop,

September 2007
Pharmaceutical Quality Assessment Systems
– Elements of QbD

ICH Q8: ICH Q9:

+ + ICH Q10:
Pharmaceutical Quality Risk
Quality Systems
Development Management

Quality by Design : Systematic Approach

to Pharmaceutical Development and
Lifecycle Management

ICH Q8, Q9 - A review - AAPS Stability Workshop,

September 2007
ICH Q8- Pharmaceutical Development

n To design a quality product and manufacturing

process and deliver consistent performance (safety
and efficacy)
n Collation of knowledge establishing the rationale for

type of dosage form, formulation proposed is suitable

for the intended use, process and product
understanding
n Aspects of drug substance(s), excipients, container

closure systems and manufacturing processes that are

critical to product quality
Stability is a Critical Quality Attribute – Its understanding is
critical to the development of a quality product

ICH Q8, Q9 - A review - AAPS Stability Workshop,

September 2007
ICH Q9 – Quality Risk Management

Quality Risk Management is a systematic process for

the assessment, control, communication and review
of risks to the quality of the drug product across the
product lifecycle

QRM is a tool that enables focus on product/process

attributes that are critical to stability and is useful throughout
the lifecycle of the product

ICH Q8, Q9 - A review - AAPS Stability Workshop,

September 2007
ICH Q9 – Quality Risk Management*

System Definition
System Description
Risk Analysis
Risk Assessment

Risk Management
Hazard Identification
Risk Analysis Tools

Risk Estimation •PRA

•FMEA
Risk Evaluation •FMA
Acceptable?
•HAZOPS
Yes No
Monitoring and Control and •Etc
Re-evaluation Mitigation

Communication

*: Risk Assessment and Risk Management

ICH Q8,inQ9the Pharmaceutical
- A review Industry –
- AAPS Stability Workshop,
Clear and Simple – James L. Vesper,
September 2007 2006
Pharmaceutical Stability

API/Drug
Substance Drug
Formulation Finished
+ Product Packaging
Product
Excipients

n Stability of a pharmaceutical depends on

API – Physical and Chemical Stability
Compatability of the API with excipients
Compatability of the drug product with the packaging
systems
Environmental conditions – conditions for storage (light,
humidity and temperature) and time of exposure
ICH Q8, Q9 - A review - AAPS Stability Workshop,
September 2007
Pharmaceutical Stability – Use of Risk
Assessment During Development

n API Development –
Physical and Chemical Characteristics of API are investigated in
early stages – Understand characteristics of the API that are
important to the stability of the molecule and need to be controlled,
For eg: Crystallinity of an API
Understand and control manufacturing process so that there is a
control of organic and inorganic impurities, For eg: Formation of
enantiomers
Understand the impact of the environment and container closure
system on API stability and take measures to protect the API, For
eg: Use of a protective packaging in the case of API susceptible to
light

ICH Q8, Q9 - A review - AAPS Stability Workshop,

September 2007
Pharmaceutical Stability – Use of Risk
Assessment During Development
n Characteristics of the Drug Product Y
Intravenous drug product
API is manufactured using a semi-synthetic process
n Control of API quality ensures quality of drug product
produced
n Mechanism of degradation identified and QbD
principles used to control levels of degradant in API
and stability enhancement of API/DP

ICH Q8, Q9 - A review - AAPS Stability Workshop,

September 2007
Pharmaceutical Stability – Use of Risk
Assessment During Development
n Identified critical quality attributes of API by studying
parameters that affect drug product purity profile and drug
product stability
n Risk assessment (FMEA) performed on each unit operation of
the API manufacturing process
n Critical processing parameters identified as
 Control of raw materials/intermediates
 Control of synthetic parameters to prevent oxidative degradation
during the manufacturing process
 Control of crystallization (Large impact on API stability and little
effect on oxidative degradative content)
 Control of isolation conditions (handling/storage)

ICH Q8, Q9 - A review - AAPS Stability Workshop,

September 2007
 Pharmaceutical Stability – Effect of Scale-up on
Crystallization

Scale-up leads to
poor crystallinity

• Laboratory scale process • Upon scale-up crystal quality

produced high-quality and size changed, purity not
crystals impacted
– Bulk drug batches started
– Simple, anti-solvent failing long term stability
process for with minimal
– Process sent back to the
controls lab
– Crystal size consistent

ICH Q8, Q9 - A review - AAPS Stability Workshop,

September 2007
API Y – API Process Flow

Crude API

Antisolvent
Antisolvent
Dissolve in addition
addition
solvent
Hold
Hold for
for X
X hours
hours
Clarification

Filtration
Distill
Distill to
to
amorphous
amorphous foam
foam

Dissolve
Dissolve in
in Pre-parental
Solvent
Solvent B,
B,
nucleation
nucleation
API
Verify precipitation

ICH Q8, Q9 - A review - AAPS Stability Workshop,

September 2007
Crystallization Trajectory Established Early
Induction time = nucleation time + aging time

8000

6000

4000
A/S added
A/S added immediately after
before nucleation
nucleation

2000
A/S added
Aging after aging

0
0 20 40 60 80 100 120 140
Time (min)
ICH Q8, Q9 - A review - AAPS Stability Workshop,
September 2007
Response Surface Curves: Solvent Content

Antisolvent Add’n Time

Antisolvent Add’n Time

Operating Operating
area area

(min)
(min)

0% solvent content 5% solvent content

Induction Time (h) Induction Time (h)

• Response surface model for

crystallinity as a function of antisolvent
Antisolvent Add’n Time

add’n rate & induction time at constant

mixing speed
(min)

• Acetone content shows a significant

impact on crystal quality
– Antisolvent add’n time and
induction time also important
10% solvent content *Degree of crystallinity determined by DSC
and particle size measurement
Induction Time (h)

ICH Q8, Q9 - A review - AAPS Stability Workshop,

September 2007
Solvent Level Optimization

Model prediction of solvent level for optimum crystallinity and yield

c Yield/ crystallinity
‹ +10% confidence limit
z -10% confidence limit
1. 0 0
90

88 0. 9 0

86 0. 8 0

84
0. 7 0

Crystallinity
82
0. 6 0
Yield

80
0. 5 0
78

76 0. 4 0

74
Higher
0. 3 0
In-process control crystallinity
72
limit set for solvent 0. 2 0 Ease of solvent
70
concentration of removal
0. 1 0
68
NMT “x” v%
0. 0 0
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10

Solvent content (V%) Solvent content (V%)

ICH Q8, Q9 - A review - AAPS Stability Workshop,

September 2007
 Modified Process with Controls
Dissolve
Dissolve API
API in
in Age
Age crystals
crystals
solvent
solvent NLT
NLT “y”h
“y”h
Verify precipitation
Design Space for
Stepwise
Stepwise OD control
Clarification
Clarification antisolvent
antisolvent
add’n
add’n
• Solvent content in
amorphous foam
Distill
Distill to
to NMT x %
amorphous
amorphous foam
foam Hold
Hold “z”
“z” hh
• Minimum induction
time of “y” hours
• Antisolvent added
Crystallize
Crystallize Filtration stepwise at defined
Filtration
rate of addition
• Minimum hold time
of “z” hours
Solvent NMT
Pre-parental
Criteria x% v/v API
not met

ICH Q8, Q9 - A review - AAPS Stability Workshop,

September 2007
Pharmaceutical Stability – Use of Risk
Assessment During Development - Summary

n Experiments demonstrated that API crystallinity

impacts API and drug product stability
n DOE (small scale) to investigate factors affecting
crystal quality performed
Factors investigated include Induction time, mixing speed and
solvent content
Design space for controlling crystal quality developed based on
results of the DOE
Manufacturing performed at small scale and stability confirmed

ICH Q8, Q9 - A review - AAPS Stability Workshop,

September 2007
Pharmaceutical Stability - Drug Product

n Factors considered during formulation/process

development
Interaction of API with excipients
- Preformulation studies performed to understand interactions (physical or
chemical)
- Stress degradation studies are performed to identify any impurities formed as a
result of API with excipients and also identify potential degradation products of
the API
API stability during the drug product manufacturing process. For eg:
degradation product formation and enantiomer formation
- Monitored using assays (physical and chemical) as necessary
Understand the impact of the environment and container closure
system on drug product stability and take measures to protect the
drug product, For eg: Use of a protective packaging in the case of
drug product susceptible to moisture

ICH Q8, Q9 - A review - AAPS Stability Workshop,

September 2007
Optimization of Container Closure System
During Development
Identify the attributes
Identify the risks
of the drug product
associated with the failure
that could be potentially affected
to meet attributes
during storage in the package

Mitigate risks by
developing appropriate
controls
e.g. alternate packaging

ICH Q8, Q9 - A review - AAPS Stability Workshop,

September 2007
Example of Drug Product Container Closure
System Design Space
n Immediate release dosage form – sensitive to hydrolysis
n Drug product critical quality attributes are not influenced by
environmental factors
n Level of moisture in drug product controlled during manufacturing
n A number of packaging materials were investigated during development
n Based on data during development, understanding of the
product/process, permeability of packaging material (MVTR data) and
stability data on a packaging material (for eg . PVC/ACLAR), propose to
use packaging material of as good or better permeability in application –
would this be acceptable?

ICH Q8, Q9 - A review - AAPS Stability Workshop,

September 2007
Impact of QbD in Understanding Stability -
Conclusions
¾ Pharmaceutical Development (Q8) enables us to understand
the impact of various API/drug product properties on stability

¾ Risk management helps to understand the factors and mitigate

the risk of stability failure – This can be by design change or by
establishing controls upstream in the process

¾ In combination principles of ICH Q8 and Q9 help develop

stability programs that are based on sound scientific principles
and help achieve the intended goals – mitigate the risk of stability
as a potential cause for product recalls/failures

ICH Q8, Q9 - A review - AAPS Stability Workshop,

September 2007
Acknowledgements

Michael O’Brien
Subodh Deshmukh
Michael Kolb
Parimal Desai
Richard Saunders
Patricia F. Mann
T.G. Venkateshwaran
Steve Simmons
Donald Esherick
Ferdinando Aspesi
Richard Saunders
Shailesh Singh

ICH Q8, Q9 - A review - AAPS Stability Workshop,

September 2007