Discussion Forum on ICH-Q8 & Q10 at Getz Auditorium on 24 Sep 2017

1. Discussion Forum on
ICH Q8 & Q10
Dr. Obaid Ali
Civil Service Officer / Deputy Director, DRAP
Member ISPE, PDA

2. Not the view of
DRAP
Current
judgment
No obligation
on DRAP
Regulatory
experience
References US-FDA ICH PDA ISPE
DISCLAIMER

3. Start small,
Learn, Evolve
Think big,
but Start

4. ICH-Q8 & ICH-Q10
Petition of the Day

5. 1- Phenomena &
Ideas
2- Tools and
approaches to move
forward
Cont’d

6. 3- Criticality, Risk &
Controls
4- Completing the
Sketch
(with an Example)

7. Phenomena & Ideas as a wake up call1

8. 05 Feb 2017
Bupripion HCl ER

9. 2.7 lakh bottle
Dissolution failure
At 18 month of
stability

10. Does anybody want to see such news early morning?

11. Does anybody want to see such news early morning?
Are you confident it will not happen with you?

12. Does anybody want to see such news early morning?
Are you confident it will not happen with you?
Don’t assume but
keep respecting
science

13. Does anybody want to see such news early morning?
Are you confident it will not happen with you?
Don’t assume but
keep respecting
science
Understand your
product &
process

14. Does anybody want to see such news early morning?
Are you confident it will not happen with you?
Don’t assume but
keep respecting
science
Understand your
product &
process
Before it
happens

15. Drug quantity is
correct

16. Drug quantity is
correct
Drug is not available
for absorption

17. Drug quantity is
correct
Drug is not available
for absorption
Do you expect
effect?

18. Therapeutic
effect under
question

19. Therapeutic
effect under
question
Disease may progress

20. Therapeutic
effect under
question
Disease may progress
A series of
consequences
may emerge

21. Therapeutic
effect under
question
Disease may progress
A series of
consequences
may emerge

22. Therapeutic
effect under
question
Disease may progress
A series of
consequences
may emerge
Pain killers

23. Therapeutic
effect under
question
Disease may progress
A series of
consequences
may emerge
Pain killers Cardiac drug

24. Therapeutic
effect under
question
Disease may progress
A series of
consequences
may emerge
Pain killers Cardiac drug Anti epileptic drug

26. Tools & Approaches to move forward2

27. Product Designing and Development
Integration Collaboration
Meet the Patient Needs

28. Pharmaceutical
Development
Technology
Transfer
Commercial
Manufacturing
Product
Discontinuation

29. Drug substance development
Formulation development
Delivery system development
Mfg process development
Scale up
Analytical method validation
P
H
A
R
M
A
C
E
U
T
I
C
A
L
D
E
V
E
L
O
P
M
E
N
T

30. Development to
Commercial Mfg
Change
Contract
Manufacturing
T
E
C
H
N
O
L
O
G
Y
T
R
A
N
S
F
E
R

31. Acquisition & Control of materials
Facilities, utilities, equipment
Production
Quality
Testing & Release
Storage & Distribution
C
O
M
M
E
R
C
I
A
L
M
A
N
U
F
A
C
T
U
R
I
N
G

32. Documentation Retention
Sample Retention
Continuous Product
Assessment
Reporting
P
R
O
D
U
C
T
D
I
S
C
O
N
T
I
N
U
A
T
I
O
N

33. Why How

34. Traditional
Enhanced
Approaches

35. Identify
potential
CQAs
1 Define Mfg
Process
2 Define
Control
Strategy
3

36. SystematicEvaluation&
Understanding
1
Functionalrelationshipthat
linkMA&PPtoCQAs
2
QRMtoestablish
appropriateControlStrategy
forDesignSpace
3

37. Systematic Evaluation &
Understanding
1/3

38. Functional relationship that
link MA & PP to CQAs
2/3

39. QRM to establish
appropriate Control
Strategy for Design Space
3/3

40. A systematic approach to acquiring, analyzing,
storing and disseminating information related to
product, manufacturing process and components
A Systematic process for the assessment, control,
communication and review of risk to the quality
of the drug product across the product lifecycle
Knowledge
Management
Quality Risk
Management

41. Traditional
Approach
Information Flow
Development
Quality Unit
Development
Scientist
Manufacturing
Operations
Manufacturing
Quality Unit

42. Integrated
Approach
Information Flow
Dev. Quality
Unit
Dev. Scientist Mfg Scientist Mfg Operations
Mfg Quality
Unit

43. Regulatory
Traditional Approach
Reviewers Recommendations
GMP Recommendations
Compliance Recommendations

44. Regulatory
Integrated Approach
Reviewer
ComplianceGMP
Information Flow

45. No Silos No gate Keepers Openness Sharing Teamwork
Applies to both Industry and Regulators

46. CAPA
Traditional Approach
Performance & Quality Monitoring
System
Change
Management
System
Performance &
Quality
Monitoring
System
CAPA
Change
Management
System
Reactive Approach
Integrated Approach Proactive Approach

47. Criticality, Risk & Controls3

48. Criticality, Risk & Controls
Assess Production Process for
CPP Controls are
additional to
Standard Level of
Control
5 Step
Approach
What is
critical &
how to
control it

49. 1/5
Layout the process parameters in each step

50. 1/5
Layout the process parameters in each step
1, 2, 3, 4, 5, 6, …
List down all operations, parameters, units

51. 2/5
Compile experimental conditions
(target, proven, operating ranges) &
establish design space

52. 2/5
Purpose proven
Range 20-160
Design Space
30-150
Expected Control
Range40-140
Operating
Range
60-120
Target
80-100

53. 3/5
Understand the consequences of high
and low points of a range overlay the
likely production control capabilities

54. 3/5
Understand the consequences of high and
low points of a range overlay the likely
production control capabilities
Consequences
Going out

55. 4/5
Assess the risk of the process parameters on
quality (CQA) to determine if it is a likely CPP
and consider needed control

56. 4/5
Assess the risk of the process parameters on
quality (CQA) to determine if it is a likely CPP
and consider needed control
Severity
Probability

57. 5/5
Assess what additional work is needed to
determine if parameter is characterized as CPP

58. 5/5
Assess what additional work is needed to
determine if parameter is characterized as CPP
Impact on CQA
Risk of Failure
outside proven
Range

59. Completing the Sketch4

60. Why How
e.g. Saxagliptin

61. Saxagliptin
Case Study
Chirstine M.V. Moore, FDA
Stephen Liebowtiz, BMS
Lets see how Knowledge Management &
Quality Risk Management is used

62. A systematic approach to acquiring, analyzing,
storing and disseminating information related to
product, manufacturing process and components
A Systematic process for the assessment, control,
communication and review of risk to the quality
of the drug product across the product lifecycle
KM
QRM
Saxagliptin

63. Pharmaceutical
Development
Formulation
Development
Scale up
Mfg Process
Development
Saxagliptin

64. Lifecycle
Pharmaceutical
Development
Commercial
Manufacturing
Technology
Transfer
Pharmaceutical
Development
Formulation
Development
Scale up
Mfg Process
Development
Saxagliptin

65. Saxagliptin
Dipeptidyl peptidase IV Inhibitor
C18H25N3O2 H2O, pKa 7.2
Molecular Weight 333.43
BCS Class III, chemically instable

66. Controlling Intramolecular Cyclization

67. Occurs in solid & solution state
Accelerate with commonly used excipients
Accelerate when processed under wet and dry granulation
Acidic environment stabilizes
S
A
X
A
G
L
I
P
T
I
N
Cyclization by attack of amino group on the
nitryl group to form cyclic amidine that converts into
DKP in presence of water

68. The enhanced pharmaceutical development used risk
assessment and DOE to evaluate criticality
of Process Parameters and Support Development of the
Control Strategy and Design Space
S
A
X
A
G
L
I
P
T
I
N

69. Expanded data leveraged to develop the mechanistic
model of the coating operation used to predict Process
Performance
The enhanced pharmaceutical development used risk
assessment and DOE to evaluate criticality
of Process Parameters and Support Development of the
Control Strategy and Design Space
S
A
X
A
G
L
I
P
T
I
N

70. Expanded data leveraged to develop the mechanistic
model of the coating operation used to predict Process
Performance
Product quality is assured through
Manufacturing Process Control combined with
Conventional End Product Testing
The enhanced pharmaceutical development used risk
assessment and DOE to evaluate criticality
of Process Parameters and Support Development of the
Control Strategy and Design Space
S
A
X
A
G
L
I
P
T
I
N

71. Controlling Intramolecular Cyclization

72. Cyclization
Occurs in solid & solution state
Accelerate with commonly used excipients
Accelerate when processed under wet and dry granulation
Acidic environment stabilizes
S
A
X
A
G
L
I
P
T
I
N

73. Coating
contains Drug
Placebo
Tablet
Drug product
strategy
Critical
manufacturing
step ?
COATING
S
A
X
A
G
L
I
P
T
I
N

74. What may go wrong … Analysis of Variables
Steps
• Coater
Design
• Accessories
Movement
• Pan Load
• Pan Rotation
speed
• Baffle design
Spraying
• Rate
• Nozzle
design
• Air to liquid
ratio
• Nozzle tablet
distance
• Suspension
homogeneity
Drying
• Inlet
temperature
• Air volume
• Air humidity
S
A
X
A
G
L
I
P
T
I
N

75. Comparison of different Spray Nozzles & Spray Patterns

76. Online Monitoring of Coating Process

77. Process Optimization on Commercial Scale Equipment

78. Acquired knowledge ….
Quality
Attributes
identified after
assessment are
CU & Potency
Design space
established using
fundamental
process
understanding,
modeling & DOE
Predictive model
of CU & Potency
created for the
coating steps

79. Drug Product
Critical Quality
Attributes
Potential Critical
Process Parameters
Critical Process
Parameters
Critical steps
Additional control
points beyond standard
unit operation controls
Data Analysis to define a Control Strategy

80. Performance
Critical to assure that Drug
Product is manufactured to
meet the attributes of
Desired
Quality

81. Please Remember
QRM in Manufacturing-Going Beyond
Product Development
QRM begins in Product
Development & continues
in Manufacturing as part of
Lifecycle Management
Knowledge gained during
Development is fundamental to a
Process & Manufacturing History
builds on that Knowledge Base

82. Recap
1
2
3
KM & QRM begin in Product Development & continue
throughout the Product Lifecycle
Understanding the Product & its Manufacturing Process are
needed to create an Effective Control Strategy
QRM is integral to executing an effective Control Strategy &
maintaining the Product

83. Quality
Capable & trustable
to fulfill
Label Claim, Promise
&
Regulatory Expectations

84. Closing Words
Audit
communicate &
monitor your
suppliers
Understand CQA
of your product
Understand CPP
of your process
Validate your
process

85. Closing Words
Develop a
Control
Strategy
Maintain
your
equipments
& facility
Trend and
monitor all
the
components
Modify the
Control
Strategy if
required
Maintain the
state of
control

86. Safe,
efficacious
& have
correct
identity
Deliver the
same
performance
as claimed
Perform
consistently
over shelf
life
Made in a
manner that
ensure
quality
Will be
available
when
needed

87. Have a very good day and learning
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Thank You