A view with a Case Study

1. C T D
Common Technical Document
On the line of Science
Applicant & Regulator Partnership
Case Study
Karachi 28 July 2019
Roohi B. Obaid
Obaid Ali

2. Manufacturing Process Attribute (Critical Parameters)
must not influence in
Batch Reproducibility, Product Performance & Product Quality

3. Bioequivalency does not always correspond to
therapeutic equivalency
Because of permitted range, evaluation method
and individual variation
Generic substitution had no impact on efficacy
of promised claim
Therapeutic Equivalency
Bio-equivalency

4. Enhanced Knowledge
Knowledge
End testing
End Testing
Knowledge
Towards Reduced Testing

5. Enhanced Knowledge
Knowledge
Commitment
(Controlled Process)
Commitment
Knowledge
Towards Flexible Process

6. Knowledge PredictabilityUncertainty

7. Knowledge PredictabilityUncertainty

8. Knowledge PredictabilityUncertainty

9. Knowledge PredictabilityUncertainty

10. Case Study
Ref: PDA (University of Pavia, Italian, Norwegian Medicine Agency, Pfizer)
Control Strategy

11. How Control Strategy can support
Process understanding
Risk - Change Management
Process Commitment
Relevant to all product types
(depth of understanding & complexity)
Sharing increase knowledge & gaining
value (industry & regulator)

12. Applicant believes
Showing a lot of process
understanding could lead to the
control strategy allowing for potential
operational flexibility and easier
subsequent optimization.
Design Space

13. Assessor Reflection
Risk assessment, criticality tables,
development, description of design of
experiments, not initially sufficient.
Information Presented

14. Effective Utilization
Enhanced development encourages a
focus on the most important aspects
of the manufacturing process,
commitment & controls
Control Strategy

15. Oncology Product
• Immediate Release Cap
• Two strengths
Drug Substance
• Genotoxic impurity,
• BCS Class IV
• PSD critical
• Non-hygroscopic
• Stable
• Single crystal form
Simple Product & Simple Process

16. Understand the patient need
Quality Target Product Profile
Understand CQAs & link the process
Typical Approach
Product Control Strategy

17. Analytical method
Input material specifications
Process description
In-process controls, GMP
Mfg operating commitments
DP Specifications &
Controls
Develop Optimal CS
Optimal to control CQAs

18. CQA is adequately controlled by IPC,
Do we need to describe process detail?
If

19. CQA is adequately controlled by the process,
Do we need to describe monitoring or testing?
If

20. Detail of process & detail of testing
Dependent on product & process understanding
So

21. CQA
PSD of DS
BCS Class IV, Oral solid dosage – critical
Applicant proposed PSD control with milled DS
No detail conditions for particle size reduction
How it will be done consistently? What will be the
processing conditions?

22. CQA
PSD of DS
Critical Manufacturing Steps
Milling is critical, that’s why appropriate detail is
required to be described

23. CQA
PSD of DS
PSD Control by Testing
Milling process, milling principle,
Manufacturing process description balanced to
controls applied
Increased sharing of knowledge of milling
Change to different milling type will be subject
to variation application

24. Balance Between input/output
Controls & Commitment
Link between Acceptance Criteria &
Operating Conditions
Controls linked to manufacturing
operating conditions (establish
boundary conditions for manufacturing)

25. Change
Any change to Acceptance
Criterion of an attribute can
change acceptable range of
manufacturing conditions

26. Impurity Palladium
Applicant had proposed an acceptance
criterion for impurity (Pd) that was
“safe” but was not close to batch data or
manufacturing experience
Tightening of limit was requested

27. Observation/Learning
Through testing or by process operating
conditions. Both approaches can be
used to make control strategy

28. Observation/Learning
What should acceptance criteria be
based upon?
Efficacy/Safety OR Process Capability?

29. Observation/Learning
The initially proposed limit
in DS specifications assured
patient safety
Acceptance criteria set the target for quality and
thus the establishment of manufacturing process
Boundaries of design space should not be
overly constrained as this could have a negative
impact on process capability

30. Enhanced Knowledge
Knowledge
End testing
End Testing
Knowledge
Towards Reduced Testing

31. Enhanced Knowledge
Knowledge
Commitment
(Controlled Process)
Commitment
Knowledge
Towards Flexible Process

32. Linking CS to RA
Development of Control Strategy should be
accompanied by conclusion from risk
assessment
Particularly when it is robust than
traditional approach (e.g.)
Reduced testing
Flexible manufacturing process
Particular parameter doesn’t need monitoring/ control
QA more reliant on process understanding

33. Linking CS to RA
The level of effort, formality
and documentation of
QRM should be
commensurate with the
level of risk
(ICH Q9)

34. Linking CS to RA
Risk assessment
Process understanding
Control strategy
development

35. Linking CS to RA
Risk assessment conclusions
should be clearly associated to
individual process control
proposals
Individual process attributes are
the ones subject to Control
Strategy

36. Linking CS to RA
The output from RA & subsequent
experimental work is used to develop
and finalize the CS
Can be iterative – the more one
understands, the more one can continue
to refine commitment & controls

37. Linking CS to LCM • How can a well developed control
strategy support verification at
production scale, scale changes and
other lifecycle changes?
Post Approval Changes

38. Linking CS to LCM
• Well developed control strategy can
operate independently of scale
Post Approval Changes

39. Linking CS to LCM
• Can be independent of where in
Design Space one operates
For e.g. an impurity set by Design Space can be
assured by the same specification test
irrespective of scale or where in Design Space
one operates
Post Approval Changes

40. Linking CS to LCM • Following a change, a Design Space
complimented by (additional) control
is “less at risk” than a Design Space
operating by parametric controls
alone
Post Approval Changes

41. Linking CS to LCM • How can the complimentary value of
established controls be considered in
overall change management? (Along
with scale dependent process
knowledge)?
Post Approval Changes

42. Linking CS to LCM
• Enhanced knowledge focuses
necessary manufacturing
commitments and controls
More effective utilization of
Control Strategy

43. Linking CS to LCM • The understanding that supports
manufacturing process description /
Design Space can balance by
complimentary Control Strategy
More effective utilization of
Control Strategy

44. Linking CS to LCM
• A robust and well explained control
strategy can facilitate empowered
change management, the approval of
post approval change management
protocol or a Design Space
verification protocol
More effective utilization of
Control Strategy

45. Elaboration & Assessment
Manufacturing Operating Commitment
&
Control Tests
are indeed Control Strategy
Lets see how ad where Control
Strategy be presented in submission

46. Elaboration & Assessment
A clear presentation of control strategy and its
development in a submission is essential to
realize the added value of enhanced knowledge
in the market authorization
Lets see how ad where Control
Strategy be presented in submission

47. Elaboration & Assessment
• Control commitments are spread across the
dossier. CTD does not dedicate a section to
control strategy.
• Overall understanding is not easily provided
to assessor
Lets see how ad where Control
Strategy be presented in submission

48. Elaboration & Assessment
Control strategy summary in tabular format?
Development of control strategy
S.2.6 is probably suitable for a summary of the
various control strategy elements
• Development of synthesis including
quality of starting materials,
intermediates and reagents
Observation / Learning

49. Elaboration & Assessment
P.2 (between P.2 and P.2.1)
• Development of single control strategy
elements where appropriate
P.2.2
P.2.3
Observation / Learning

50. DS-CQA Acceptance
Criterion
CS CPP Reference
Attribute 1 Specification What aspects of
product/process
understanding
provides control?
What process
parameters are
committed to
linked to this
CQA?
Where in the
CTD can more
detail can be
found?
Attribute 2
Attribute 3
...
What did applicants provide in the dossier?

51. • Linkage between patient needs & process understanding
• Process understanding & its control
• Visible manufacturing commitments
• From QTPP to CQA to Controls (downward)
• From process to CQA (upward)
Value of such Summary Tables

52. Attribute QTPP
Target
CS Specifications Process
Control
Material
Attribute
CTD
(Ref.)
Method Criteria
Route Oral Product
design/develop
ment
NA NA NA NA P.2.2
Potency Complie
s with
FDA
Capsule fill
weight (CFW)
End testing
HPLC 95-105% CFW-IPC
DS Assay
NA P.5.1
Water
Content
Assure
quality
Controls on in
going
materials &
packaging
Not
proposed
Not
proposed
NA DS Moisture
excipient
controls
packaging
type selected
S.4.1
S.6
P.4.1
Control Strategy (Example)

53. Attribute QTPP
Target
CS Specifications Process
Control
Material
Attribute
CTD
(Ref.)
Method Criteria
Product
release
IR DP end test
Process controls
DS PSD
requirement
Dissolution Q 80%
30 min
Hardness -
IPC
Compressi
on force -
Parameter
DS - PSD S.4.1
P.3.3
P.3.4
P.5.1
P.5.2
Control Strategy (Example)

54. Specifications
Associated test methods
Mfg process description
Control of materials
Control of critical steps
S.4.1 -- S.4.5 ---- P.5.1 -- P.5.6
S.4.2 -- S.4.3 ---- P.5.2 -- P.5.3
S.2.2 ---- P.3.3
S.2.3 ---- P.3.4 -- P.4.1
S.2.4 ---- P.3.4
CS Elements should be provided & justified in CTD

55. Improved communication during the
procedure can often avoid
disagreementmisunderstanding &

56. How to make submission content clear and compelling
Applicant need to think
hard about
Assessor has to be able to reach
same conclusion as applicant

57. Why information is being requested by the regulator
Be clear
Keep
reading
regulator
’s mind
Science Rational

58. Are CQAs sufficiently assured by the
control strategy proposed?
If not
What additional controls/commitment or
justification should be considered?
Regulator or Applicant
Ask yourself

59. Does risk assessment conducted need to be
shared in more detail to justify “enhanced”
reduced element of commitments &
controls
If these do not seem to sufficiently assure
quality?
Regulator or Applicant
Ask yourself

60. Does the experimentation conducted allow
the applicant to conclude to substitute end
product testing and or establish flexible
processing/ Design Space?
Regulator or Applicant
Ask yourself

61. Does the control strategy assures the
quality across the lifecycle?
If not
What additional controls or change
management commitment should be
considered? (DS verification: non-routine
test)
Regulator or Applicant
Ask yourself

62. Variation
between batches of originator may themselves
threaten patient safety
Patient experience unexplained toxicity when
taken Lamotrigine (GSK) in 2010
Upon investigation, GSK accepted responsibility for
an altered formulation due to changes made to
the manufacturing process
Ref: Patel V, 2012

63. The highest strength is soluble
in 250 ml or less of aqueous
media within the pH range of 1
to 6.8 at temperature 37 + 1C.
Highly Soluble
Less Permeable
Rapid Dissolving
BCS Class III
1

64. 85% or more of labeled amount
of API dissolved within 15
minutes using USP apparatus 1
at 100 RPM or apparatus 2 at
50 RPM in
500 ml or less in 0.1 N HCl or
simulated gastric fluid USP
without enzyme.
and ...
Highly Soluble
Less Permeable
Rapid Dissolving
BCS Class III
2

65. 85% or more of labeled amount
of API dissolved within 15
minutes using USP apparatus 1
at 100 RPM or apparatus 2 at
50 RPM in
A pH 4.5 buffer
as well as...Highly Soluble
Less Permeable
Rapid Dissolving
BCS Class III
2

66. 85% or more of labeled amount
of API dissolved within 15
minutes using USP apparatus 1
at 100 RPM or apparatus 2 at
50 RPM in
A pH 6.8 buffer or simulated
intestinal fluid USP without
enzyme
Highly Soluble
Less Permeable
Rapid Dissolving
BCS Class III
2

67. The test product formulation is
qualitatively the same and
quantitatively very similar to
Reference
Highly Soluble
Less Permeable
Rapid Dissolving
BCS Class III
3

68. Change in excipients expressed
as % (w/w) o total formulation
less than or equal to the:
Filler (+ 10%)
Disintegrant, starch (+ 6%)
Disintegrant, other (+ 2%)
Binder (+ 1%)
Lubricant, Ca or Mg Stearate
(+ 0.5%)
Very
Similar

69. Change in excipients expressed
as % (w/w) o total formulation
less than or equal to the:
Lubricant, other (+ 2%)
Glidant, talc (+ 2%)
Glidant, other (+ 0.2%)
Binder (+ 1%)
Film coat (+ 2%)
Very
Similar

70. Change is acceptable within
limit but the total additive
effect of all excipients changes
should not be more than 10%
Very
Similar

71. If excipients in the formulation are
not suspected to affect on drug
absorption &
Excipients qualitatively the same and
quantitatively similar, then
Bio-waiver may be possible upon
demonstration of similarity in
comparative dissolution with
reference productRecap

72. If excipients and formulations are
suspected to have an effect on drug
absorption but excipients may affect
absorption within +10% comparative
to reference drug and
Excipients qualitatively the same and
quantitatively similar, then
Bio-waiver may be possible upon
demonstration of similarity in
comparative dissolution with
reference product
Recap

73. If not in any case whether it is
similarity of excipient or
suspect to have an effect on drug
absorption of any excipient or
More than 10% potential to change
absorption of drug ….
It is not for Biowaiver
Recap

74. New drug is also subject to bioequivalence of clinical formulations
Waiver is granted on the basis of sound argument

75. Enhanced transparency within an organization
and within Regulatory Authorities
C T D
Common Technical Document

76. More focused on mitigation of
high risk element
C T D
Common Technical Document

77. Support continual improvement and ensure
technical advancement
C T D
Common Technical Document

78. Can Module 3 be simplified to reduce
burden by waiving some detail
C T D
Common Technical Document