Gathering of about 250 pharmaceutical professionals

1. Pharmaceutical Manufacturing
Return to Science
Obaid Ali
24th Oct 2018, PC Hotel Karachi

2. It reflects the views and understanding of presenter
& may not be construed to represent the views or
policies of organization or association to which
speaker has ties
Documents of US-FDA, Papers from
Pharmaceutical Technology & Review Scientific
Articles are used to construct presentation
Disclaimer
Reference

3. International guidance
documents and reference
materials there in

6. Certainty

7. Validation
4
Share “words”
please

8. Validation

9. Process
Lets narrate in
simple words

10. Process

11. Validation
To prove that something is
based on truth and is
acceptable

12. Process Validation

13. What can happen if we don’t
do validation
Imagine

14. The things for which you
cannot give guarantee
Imagine

15. You are coming here, let’s map
what can stop you to reach here
on time
What is not in your control?
What you can manage?
Imagine

16. Collection and evaluation of data
which establish scientific evidence
that a process is capable of
consistently delivering quality
product
Process Validation

17. Collection and evaluation of data
which establish scientific evidence
that a process is capable of
consistently delivering quality
product
Process Validation
From where will you
get the data?

18. Process Validation
Data
Process
Design
Process
Qualification
Process
Verification

19. Lets go back … what is the
deficiency in process validation
guidance continued since 1987
Imagine

20. 2011

21. 2011
Process Design
Process Qualification
Continuous Process Verification

22. Knowledge gained through
process development activities
for commercial process
Process Design

23. Confirmation of Process
Design for its capability to
reproduce in commercial
manufacturing
It includes qualification of
facility, utilities & equipment
Process
Qualification

24. Maintenance, continuous
verification & process
improvement
On going assurance that
routine production process
remains in a state of control
Assessed by collecting &
monitoring information during
commercialization
Continued
Process Verification

25. Available marketed product
represent greatest
2011
Patient Compliance
Risk

26. Process Design & Process
Qualification
It is not in market, it will
impact tomorrow
Continued Process VerificationStage 1 & 2
Stage 3 is for today

27. Product available in market
must comply the standards set
within regulatory science to
demonstrate consistency in
quality of each unit within
batch, batch after batch, time
after time and within shelf life
Obligations

28. … Collection and evaluation of
data, from the process design
stage through commercial
production which establishes
scientific evidence that a process
is capable of consistently
delivering a quality product.
Process validation involves a
series of activities taking place
over the lifecycle of product and
process.
FDA 2011

29. Manufacturers of legacy products
can take advantage of the
knowledge gained from the
original process development and
qualification work as well as
manufacturing experience to
continually improve their
processes. Implementation of the
recommendations in this guidance
for legacy products and processes
would likely begin with the
activities described in Stage 3
FDAAdvice

30. Legacy products / process
should be screened for
capability
Way to Move
Existing products

31. Acceptable products should
follow Stage 3 approaches
Way to Move
Existing products

32. Less capable products should
be re-developed and progressed
through Stage 1 & 2
Way to Move
Existing products

33. Those developed following the
guidance (Q8, QbD, Stage 1 & 2)
Way to Move
New products

34. Transition through Stage 2.5
Way to Move
New products

35. Followed by Stage 3
Way to Move
New products

36. My product is similar to the
reference products as far as
efficacy is concerned
My product is similar to the
reference product as far as
safety is concerned
Lets think 360

37. Impurity of my product is not
similar to reference product
and hence I don’t have yet any
indication that navigate its
impact on efficacy
Lets think 360

38. Impurity of my product is not
similar to reference product
and hence I don’t have yet any
indication that navigate its
impact on safety
Lets think 360

39. Does clinical relevance of
impurity has an impact on the
scale of similarity to establish
interchangeability
Lets think 360

40. Journey of CTD through eCTD
is about to hit KASA in next
generation review process
New Shift on way

41. Assess back mirror
performance to establish
whether the product is in state
of control or not
Stage 3 CpK

42. It should be more than 2,
otherwise please start from
Stage 1
Stage 3
CpK

43. Stage 1
Understand the Product
Understand the Process

44. Stage 1
Information & knowledge
Approach to control
process

45. Stage 1
Understand the sources of
variations
Detect the presence and
degree of variations

46. Stage 1
Understand the impact of
variations on the process &
ultimately on product attributes
Control the variations in a
manner commensurate with risk
it represent to the process &
product

48. Approach to validate
From lower to higher limit
1. Normal Operating Range
2. Proven Acceptable Range
3. Edge of Failures
Proven
Acceptable Range

49. 1 2
If the objective is to arrive on time, which road should you take

50. 1 2
Remember safety & speed is the matter of consideration

51. Risk Management Exercise
Its conventional to evaluate
risk and then implement
measures to mitigate it
Stage 1 …

52. In process development
Define risk mitigation
measures effective on
commercial scale prior to
having manufactured the
product on that scale
Stage 1 …

53. Use logic
Leverage prior knowledge of
similar products and
circumstances to the maximum
extent possible
Stage 1 …

54. Qualified Process Equipment
& Utilities
Validated Analytical Methods
Defined Sampling MethodsStage 2
Prerequisites

55. Establish Raw, In-process &
End Product Specifications
Written SOPs
(draft acceptable)
Written batch manufacturing
instructions
Stage 2
Prerequisites

56. Trained & Qualified Personnel
Approved Protocols
Stage 2
Prerequisites

57. As per defined manufacturing
instructions
Independent observer
throughout the process
Observer documents validation
activities
Approach

58. Independent monitoring may
be used
All process parameters set at
their defined set points
Remember worst case
conditions are inappropriate
Approach

59. Monitoring & Sampling must
be non-intrusive to the process
Utilize expanded sampling
throughout & all samples must
be tested concurrently &
considered in lot release
decisions
Can be accomplished in a step
wise manner
Approach

60. The optimal approach to
validation considers process
parameters, product attributes
& their relationship
Process & Product
Qualification

61. The optimal approach to
validation considers process
parameters, product attributes
& their relationship between
them
Drying time with moisture content
Mixing time with content uniformity
Operating conditions with degradation
Process & Product
Qualification
Don’t forget to establish link
during development

62. How much statistical
confidence is enough
How many batches are needed
to complete Stage 2
Interface
Stage 2 to 3
Manufacturer has to
answer

63. Risk based consideration &
will vary product to product as
well process to process & in
combinationInterface
Stage 2 to 3
Critical Decision

64. The amount of information
available to support the process
The robustness of the processInterface
Stage 2 to 3
Science behind

65. The availability of measureable in
process parameters linked to the
performance
The manufacturer experience with
similar processes
The manufacturer’s overall risk
tolerance
Interface
Stage 2 to 3
Science behind

66. It should be obvious that better
defined the process, the more
reproducible the results
Fundamentals

67. Forget statistically significant
because it relates to number of
batches
Very few products lend
themselves to this
The statistical minimum is at
least 15 batches & generally
higherFundamentals

68. Single answer is more likely
not going to be appropriate in
all scenarios
You have to decide case by
case
Fundamentals

69. Extensive sampling & testing
of every batch as in Stage 2
with release on an individual
basis (real time comparison to
prior results)
When variability is understood
& routine sampling plan is
established, this changes to …Stage 2.5

70. Sampling on a lower level of
intensity with release on
individual basis (real time
comparison to prior results in
Stage 3)
Stage 2.5

71. Continued monitoring & sampling of
process parameters & quality attributes
at the level established during the
process qualification stage until
sufficient data are available to generate
significant variability estimates.
These estimates can provide the basis
for establishing levels & frequency of
routine sampling & monitoring for the
particular product & process.
Monitoring can then be adjusted to a
statistically appropriate &
representative level
Stage 2.5
FDAAdvice

72. Validation Maintenance
To support continuation of
acceptance of process & its
products
Change Control is vital
Stage 3

73. Validation Maintenance
Real time evaluation of a
process against prior
performance for near
immediate detection of process
drift or unexpected change
Stage 3

74. Preventive maintenance
SOP
Change Control
Calibration Program
Reviews
Logbooks etc.
Stage 3

75. Real time Process Verification
Retroscopic vs. Real Time
Stage 3

76. Retroscopic vs. Real Time
Establishing documentary evidence
that a process does what it purports to
do based upon the periodical reviews
& analysis of historical data
Stage 3
Confirming the acceptability of
production materials using data
collected & evaluated as it is
developed

77. Retroscopic vs. Real Time
The results are essentially
known before the data is
gathered
Stage 3
Results are evaluated in
real time against prior
performance

78. Statistical Process Control
(SPC)
Review of original lot
results against the
historical data derived
from the same processProcess
Verification

79. Statistical Process Control
(SPC)
It provides a means for
near immediate
identification of
potentially adverse
variations in the product &
process
Process
Verification

80. Statistical Process Control
(SPC)
Operator is empowered to
make process adjustment
on the shop floor for
which he is authorizedProcess
Verification

81. Statistical Process Control
(SPC)
Comparison to prior lots is
considered to be
performed by QA
Process
Verification

82. Specification Limits
Compendial or Regulatory
Limit
Limits
What you want a process
to achieve?

83. Control Limits
Calculated from the
historical data
Boundary
What the process is
capable of achieving?

84. PROCESS
Reasonably centered within the
release specifications
Variability must fall within the
release limitBoundary &
Concern

85. For all Products
If product is not capable,
redevelop or discontinue are
the only options
Keep near real time is the best
approach to maintain quality &
regulatory expectationsImplementation

86. It is not new
It is a solid approach to design,
development & maintenance of
reliable process for making
quality drugs
Take Home
Thoughts

87. Continuous Process
Verification
Process Analytical
Technology
Difference

88. It is science and you know
science.
Deeper and logical look make
science strong.
Strong science is the guarantee
of human benefit … not
warranty as we learn everydayFinal Words

89. Keep thinking switch on,
always welcome knowledge
and be flexible to adapt change
required to accommodate
knowledge
Final Words