A workshop conducted with limited number of participants

1. Creating a Sustainable Culture of Quality
(Tutorial-3)
Roohi B. Obaid
05 May 2018, Karachi
[166 slides]

3. Knowledge Sharing Exercise
To Learn through Debate, Discussion &
Experience of others

4. This presentation discusses Regulatory Science,
nothing more & nothing less
Reference: US-FDA Documents / Scientific Articles
Thanks to Mary Oates, VP Global Quality Operations, Pfizer (Slide 103-140)
Personal point of view & nothing to disclose
Disclaimer

5. 1
2
3
6
5
4
7
8
9
12
11
10
13
14
15
18
17
16
Gp-A
Gp-B
Gp-C
Gp-F
Gp-E
Gp-D

6. 19 April 2018

7. Do not
confirm to
GMP
Methods, Facilities, Controls for
manufacturing, processing,
packing, or holding
Adulterated

8. Flow
1
Mix-up
3
Consistency
2
Contamination
Air Pressure
Maintenance of Machine
Cleaning
Labeling

9. Methods, Facilities, Controls for manufacturing, processing,
packing, or holding outside the GMP spirit
DS or DP is adulterated
Your

10. One password for multiple access

11. One password for multiple access
Out of Control

12. One password for multiple access
Out of Control Out of Track

13. One password for multiple access
Out of Control Out of Track

14. One password for multiple access
Out of Control Out of Track
Contributed to conclude DS is adulterated

15. Do not
confirm to
GMP
Methods, Facilities, Controls for
manufacturing, processing,
packing, or holding
Adulterated

16. What Harm
If one password for multiple use?
Take an example of HPLC

18. Developed
Who?

19. Developed
Manipulated
Who?

20. Developed
Manipulated
Deleted
Who?

21. Why independent password for each individual ?

22. Why independent password for each individual ?
Regulatory

23. Why independent password for each individual ?
Regulatory
Identification to track

24. Why independent password for each individual ?
Regulatory
Identification to track
Explore to Excel

25. 18 April 2018

26. Povidone Iodine preparation
10% solution

27. Testing of each batch for objectionable
microorganisms

28. Testing of each batch for objectionable
microorganisms
Testing of
Microbial
Attributes

29. Testing of each batch for objectionable
microorganisms
Testing of
Microbial
Attributes
Manufacturing
in suitable
environment

30. Testing of each batch for objectionable
microorganisms
Testing of
Microbial
Attributes
Manufacturing
in suitable
environment

31. Testing of each batch for objectionable
microorganisms
Testing of
Microbial
Attributes
Manufacturing
in suitable
environment
Inappropriate laboratory testing may lead to … adulterated

32. Laboratory record not in place

33. Laboratory record not in place
Raw data

34. Laboratory record not in place
Raw data
Weight of
samples, test
methods

35. Laboratory record not in place
Raw data
Record of
calculations
Weight of
samples, test
methods

36. Laboratory record not in place
Raw data
Record of
calculations
Deficiency may lead to …. adulterated
Weight of
samples, test
methods

37. Quality Unit
have to demonstrate ability
to fully exercise its
authority & responsibility
Authority
Resources
Staff
Remember

38. If a batch fails on 01 June 2016, draw the map & let us know how much
time is required to declare fail & to reach at destruction site?

39. Quality Unit
have to demonstrate ability
to fully exercise its
authority & responsibility
Authority
Resources
Staff
Remember

40. 18 April 2018

41. Absence in Repackaging of OTC
Transdermal Patches
Quality
Control Unit
Procedure for
repackaging
operation
Establishment of QC Unit is not an option, but obligation …. adulterated

42. Absence in Repackaging of OTC
Transdermal Patches
Mix up
potential
Record of
operations
Correct label, …. To prevent mix up & cross contamination by physical or
spatial separation is an obligation, not choice …. adulterated

43. Absence in Repackaging of OTC
Transdermal Patches
Distribution
record
Qualification
of recall
System by which the distribution of each lot can be readily determined to
facilitate its recall when necessary is an obligation, not option …. adulterated

44. If expiry of packet is
June 2020
What will be the expiry
of product taken out
from strip?

45. How much delay (in
days or months) can be
appropriate to put
product in a stability
chamber?

46. 09 April 2018

47. Inappropriate laboratory testing
for conformance to final specifications (OTC)
Identity &
Strength
Analytical data
to support
release
Drug product conformance with the final specifications for identity, strength of
each API prior to release is an obligation, cannot be ignored … adulterated
Testing
procedures &
specifications

48. Lets think
for CAPA

49. Lets think
for CAPA
Written Policy & SOPs for testing

50. Lets think
for CAPA
Testing requirements
Written Policy & SOPs for testing

51. Lets think
for CAPA
Testing requirements
Written Policy & SOPs for testing
Testing methods & its validation

52. Lets think
for CAPA
Testing requirements
Written Policy & SOPs for testing
Testing methods & its validation
Release Specifications, Acceptance
Criteria & justification

53. Scenario
Inspector wrote
You failed to test the incoming raw materials
(used to manufacture drug products) to
determine their identity, purity, strength and
other appropriate specifications

54. Scenario
Inspector wrote
You failed to test the incoming raw materials
(used to manufacture drug products) to
determine their identity, purity, strength and
other appropriate specifications
Inspector further wrote
Instead you used results from supplier’s COA without establishing the
reliability of supplier’s analysis through appropriate validation & without
conducting at least one specific identity test

55. Scenario
Company responded
We identified all incoming materials used in the
manufacture of our products against known
standards

56. Scenario
Company responded
We identified all incoming materials used in the
manufacture of our products against known
standards
Lets think
What will be next, how Regulatory Authority will respond

57. Scenario
You did not provide procedure for testing of
incoming materials

58. Scenario
You did not provide procedure for testing of
incoming materials
You did not provide results from any testing

59. Scenario
You did not provide procedure for testing of
incoming materials
You did not provide results from any testing
You did not provide any information on how you
will establish the reliability of your supplier’s
test results

60. Scenario
You did not provide procedure for testing of
incoming materials
You did not provide results from any testing
You did not provide any information on how you
will establish the reliability of your supplier’s
test results
Reliance on supplier’s COA to verify the identity of
components is not acceptable

61. Scenario
Provide plan to test each
component for
conformity with all
specifications for
identity, purity, strength
& quality
Explain how you intent
to perform at least one
identity test for each
component
If you accept supplier
COA for purity, strength
& quality, specify how
you plan to establish
reliability of your
supplier’s COA

62. Scenario
Inspector identified
Lacking in written procedure for QCU
operations

63. Scenario
Inspector indicated examples
GMP training, change control, annual product reviews, complaint
handling & oversight of various other basic drug manufacturing
& testing operations
Inspector identified
Lacking in written procedure for QCU
operations

64. Scenario
Company responded
Our firm is a small company & does not
have the resources for Quality Unit. We are
responsible for reviewing and approving all
quality related documents

65. Scenario
Company responded
Our firm is a small company & does not
have the resources for Quality Unit. We are
responsible for reviewing and approving all
quality related documents
Lets think
What will be next, how Regulatory Authority will respond

66. Scenario
Size of company does not matter at all
Quality Unit is a mandatory requirement
Authority & responsibility must be clear to carry
out the operation

67. Quality Unit
have to demonstrate ability
to fully exercise its
authority & responsibility
Authority
Resources
Staff
Remember

68. Tea Break

69. Lets try to respond in a way that observation
may be waived

70. Scenario
Batch record did
not include
information such
as

71. Scenario
Batch record did
not include
information such
as
Identity of the equipment
Actual time of process
Actual temperature
Filling operation steps
Packaging operation steps
Yield % age specifications

72. Lets discuss in group for three to five minutes & respond
how would you defend the case

73. Understand &
amend
accordingly
Implement
correctly in
true spirit
Submit factual
position with
evidence
1
2
3

74. Scenario
OTC drug product
released without
testing, identity &
strength

75. Scenario
OTC drug product
released without
testing, identity &
strength
Total aerobic microbial
count & objectionable
microorganisms were not
tested before release

76. Lets discuss in group for three to five minutes & respond
how would you defend the case

77. Understand &
amend
accordingly
Implement
correctly in
true spirit
Submit factual
position with
evidence
1
2
3

78. Submit detail
specification of
product
Demonstrate
capability &
validity of your
analytical methods
Submit plan for
conducting
Retrospective
testing of all
batches with valid
shelf life

79. In case of failure,
customer
notification to
facilitate recall
may be attached
Lesson
learned
Same approach is
extended to other
products too if
required

80. 29 March 2018

81. OTC
Drug Product
Raw data not available to verify?
Credibility of microbiological testing?

82. OTC
Drug Product
Raw data not available to verify?
Credibility of microbiological testing?
Subject to
regulatory
action

83. Scenario
OTC
Drug Product

84. Scenario
OTC
Drug Product
Accelerated studies for
6 weeks
Did not perform long term
study

85. Lets discuss in group for three to five minutes & respond
how would you defend the case

86. 15 March 2018

87. Failure to adequately investigate OOS results and to implement
appropriate corrective actions

88. Failure to adequately investigate OOS results and to implement
appropriate corrective actions
What
happened
Retest result were recorded & original fail results were
disregarded
Phase 2 investigation failed to evaluate manufacturing
operations for potential root cause
Phase 1 laboratory investigation did not support invalidation of
results

89. Failure to adequately investigate OOS results and to implement
appropriate corrective actions
Retroscopic review of OOS result
A pattern of recurring similar OOS result with
insufficient investigation & CAPA exist

90. Firm responded that it was impossible to

91. Firm responded that it was impossible to
Make reliable Retroscopic root cause determination for the
failing results

92. Firm responded that it was impossible to
Make reliable Retroscopic root cause determination for the
failing results
Provide scientific rational for decision because considerable
time has elapsed since the original OOS occurrence

93. Lets see how Regulatory Authority will respond

94. 26 March 2018

95. Failure to thoroughly investigate any unexplained discrepancy
What
happened
5 lots failed in dissolution (May – Nov 2016)
Methyl Phenidate HCl ER suspension
Dissolution test method declared as cause of failure, not
manufacturing
Failed 3 lots in release testing & 2 when tested for stability

96. Failure to thoroughly investigate any unexplained discrepancy
What
happened
Firm modified dissolution test method several times
1 lot upon retest also failed even by new method
Deviated from the original one that was used for approval

97. Please discuss & list down the questions & concerns

98. Lets see
how Regulatory Authority will move & respond
Retrospective
review of
dissolution for all
lots with valid
shelf life
Risk assessment
that evaluate
quality of
distributed
batches
Investigation & CAPA
plans for Mfg process
variability & dissolution
method

99. Your response to regulatory authority must provide sufficient
evidence of corrective actions to bring operations into compliance
with GMP
Moreover, interim measures during implementation of CAPA must
be in black & white
Take Home Message

100. Testing is essential to ensuring that the drug product manufactured
meets established specifications for the chemical & microbial
attributes they purport to possess
Take Home Message

101. Remember, process performance qualification alone no longer
protects from regulatory observations, unless an approach for
monitoring batch to batch variation on an on-going basis is in place
Take Home Message

102. Lunch & Prayer Break

103. Strength and Elasticity in Sustaining the Quality

104. 1 Quality of Product & Safety of Consumer
2Birth of Quality Culture
5 Quality Culture Indicators
6Closing Words
3 Criticality of Quality Culture
4Maintaining Quality Culture

105. Quality Drugs: A Continuous Concern
Quality Culture is the keystone

106. Product
Quality
Product
Efficacy
Patient
Safety
Claim
Promise
D
E
L
I
V
E
R
Y
S
U
P
P
L
Y

107. SYSTEM
CONTROLS
Ensures every product meets quality standards
Is it enough ???

108. Your decision impacts product quality Uncounted decisions taken daily
Every decision is not supported by SOPs
Complex
manufacturing
environment
Potential
risks

109. Does compliance not guarantee?
Is compliance not enough?
Are System & Controls meaningless?
Is Experience not bullet proof?

110. An environment where every person understands Product
Quality & Patient Safety
Without quality culture, product & public safety cannot be
assured
Single most important indicator to determine the ability of
delivering the quality drugs
Q
U
A
L
I
T
Y
C
U
L
T
U
R
E

111. Quality is built in from the beginning
Risk to providing quality medicines are
understood & mitigated
Performance is monitored in real time &
course corrections are made as needed
CoQ

112. An eagerness to solve problem
Share learning and drive to RFT
Issues are escalated and resolved
collaboratively
CoQ

113. No pointing of finger or laying blame
Difficult decisions are made to do the
right things
Don’t care about obstacles for right
things
CoQ

114. Report mistakes fearlessly
Learn from mistakes
Quality is everyone’s responsibility
CoQ

115. Birth of Quality Culture
Does not happen by accident
It has to be created
Relevant process &
control must be in place Understood & Followed

116. Numerous
workarounds
Numerous
waivers
Lack of Control
Please close your eyes
& try to visualize the
operation floor

117. Kindly remember
Quality Culture
builds on the expertise & processes in the organization
and results in behaviors & decision making that will
result in quality outcome

118. Doing the right things and
doing things right
is valued above ….
Continuous improvement is the
priority resulting in eagerness
to ….
Must create an environment in which
Culture driven by leadership … Must provide the fundamentals to product quality
Cost Speed Identify Address Issues

119. Strong management oversight
Adequate resources
Training of colleagues
Maintenance of plant & equipment
Focus on continual improvement
An organization capable of
making right decisions to
protect product quality
Provide
Fundamentals

120. Is Quality Culture Measurable?
The concept is not new
• What’s your inner (gut) feeling whether it exists or not?
Challenges of current environment urged to quantitatively evaluate
• A semi-quantitative tool was developed that uses data gathered mainly from
interviews of employees across all levels in the firm together with
observations of operations and review of supporting documentation
The tool can be used both internally & externally

121. A relationship with a third party was under evaluation
Due diligence identified the acceptability of all relevant systems,
controls and processes at a potential partner
The quality culture assessment identified significant weaknesses
Cont’d
Hypothetical External Example 1

122. Particularly, on this basis the business agreement was not
pursued
The potential partner later experienced significant
quality failures
Hypothetical External Example 1

123. Open, eager to learn, committed to continuous improvement, management
focused on delivery of quality product
Systems & controls were inadequate but culture was strong
Third party partnership under evaluation
Cont’d
Hypothetical External Example 2

124. When combined with existing culture, product quality was assured
The firm worked diligently to improve systems, resulting in
acceptable controls
Hypothetical External Example 2

125. Management must
proclaim the value of
escalating issues &
opening deviation
investigations
Management must help
employees recognize
deviations &
implement a process
for effectively raising
them
Management must
establish a monitoring
mechanism and track
and publish metrics
What if Lack of Culture: Symptoms & Actions

126. Management must celebrate an increase in deviations and hold
accountable those who do not bring them forward
Management must ensure that deviation investigations get to true root
cause and define full scope of the issue
What if Lack of Culture: Symptoms & Actions

127. Management must ensure that holistic corrective actions are implemented
to prevent recurrence
Management must reinforce the criticality of continuous improvement
What if Lack of Culture: Symptoms & Actions

128. Its about behaviors, not SOPs
• Without a strong quality culture, risks
to product quality cannot be fully
mitigated
Criticality of Quality Culture

129. Quality culture cannot be externally imposed
and is not introduced only through changes to
GMP systems
• Quality culture cannot be changed in the
near-term but can be lost very quickly if
focus on it is lost
Criticality of Quality Culture

130. Management must be vigilant in keeping the organization
focused on the right behaviors and decisions
Pressures exist and culture can change quickly if not
protected
• Supply demands
• Supply chain complexity
• Cost reduction
Maintaining Quality Culture

131. May result in organizational & procedural changes
The risk of such changes must be understood and
mitigated
• Risk assessment tools can be utilized
• Assessment may indicate the risk is too great to take
• Can be utilized retrospectively
Cost Pressures

132. May erode quality culture by driving decisions that can
adversely affect product quality
Early indicators should be in place
• Quantitative (e.g. over-due items)
• Decision-making at the operational level
If early signals indicate potential impact, corrective actions
should be implemented immediately
Cost Pressures

133. Quality Pyramid based on safety
Regulatory
body action
Notification to
Management/
Market Action
Recordable event
Near miss
At risk behavior
Quality Culture/leadership

134. Resource & System Maturity
1 • An expedited complaint becomes overdue
2 • ↑ in number of operator errors/ batch
3 • ↑ in Doc. Errors corrected before lot release
4 • ↑ in # of unplanned quarantine shipments
5 • ↑ in % employee turnover
6 • Relative degree of experience with staff
Quality indicators from the Pyramid characterized by key focus area

135. Leadership Quality
1
• Leadership drives programs that enhance
quality culture, RFT. etc.
2
• % of reported near misses addressed, this
means action defined & communicated &
colleague rewarded for reporting
Quality indicators from the Pyramid characterized by key focus area

136. Change Impact
1 • ↑ in number of rejected lots
2 • ↑ in % complaints per units produced
3
• # of capital projects linked to GMP or compliance being
delayed
4
• ↓ in process robustness/ capability (% products that have
defined capabilities that are tracked
Quality indicators from the Pyramid characterized by key focus area

137. Regulatory Impact
1
• Self-identified risk areas (Internal Audits)-step
back from tactical findings from audits & look
more across the board
Quality indicators from the Pyramid characterized by key focus area

138. Cultural Aspects
1 • ↓ in compliance to training curriculum
2 • ↓ in investigation effectiveness ratio
3 • Feedback loop
Quality indicators from the Pyramid characterized by key focus area

139. Resource Availability
1 • ↑ in average disposition cycle time
2 • ↓ in % PM completed on time
3 • Minimum staffing requirements met
4 • Staffing per workload unit
Quality indicators from the Pyramid characterized by key focus area

140. Keep walking & talking on…
Respect values
Come out from fear to report
Celebrate mistakes
Be knowledgeable
Understand your product & process
Closing words
Thank you of your attention

141. Concluding Talk

142. Why Pharmaceutical Manufacturers face Compliance Issues
Fire fighting
1

143. Why Pharmaceutical Manufacturers face Compliance Issues
Fire fighting
Right first time
1
2

144. Why Pharmaceutical Manufacturers face Compliance Issues
Fire fighting
Right first time
Maintaining a reliable state of quality
& compliance
1
2
3

145. Right first time from top to bottom

146. The management must identify

147. The management must identify
Complaint handling
Change
Management
Review Strategies

148. The management must identify
Monitored
Reviewed
Effective

149. Global Radar & Navigation
Data Integrity Culture of Quality

150. Trustworthiness / Integrity of Data
Data that is reliable
Data that is authentic
Data that is useable
Complete & Accurate
Proven to be what it say, it is
Can be located, retrieved, presented & interpreted

151. Culture of Quality Quality Metrics
Lagging Metrics & Leading Metrics

152. Lagging Metrics
Batch Failure
Right First Time
OOS Investigation
Leading Metrics
Quality System
Effectiveness
Process Capability
Quality Culture Index

153. Lets move beyond regulatory compliance & explain opportunity to capture
unexpected event before it happens
Respect & use knowledge, experience, data, pattern, trend & good science to
improve efficiency & maintaining culture of quality

154. 1/5
Tie with Quality is
a Core Value
Simple, loud & clear

155. No matter what the situation is, quality will
always be placed above all

156. Think beyond
compliance
Gather knowledge
& learn from others
Be proactive
Utilize the best of
capacity to identify
signals

157. 2/5
Setting ethical
standards & Training

158. Policy
Procedures
Training
Implementation
Quality
Mission
Data
IntegrityWHO, ICH Q10
To ensure
S E Q
Reconstruction of activities

159. 3/5
Openness &
transparent Reporting

160. Blocks in Reporting
Fear to report
1
I don’t think there
is an impact
Impact exists, but
nobody bother to
response
2 3

161. Blocks in Reporting Howto
Overcome
Direct / cross functional reporting
(seniors, leadership)
Reward for reporting
Give recognition through training
that it has impact
Feedback on reporting,
update with progress
Report Collection Unit
1
2
3

162. 4/5
Recognition of
Consequences

163. Recognition of
Consequences
Patient OrganizationYourself

164. 5/5
Hear the gut &
ground sound

165. Check engagement of people on the floor
Are they fearlessly reporting?
Are they celebrating mistakes?
Are they learning or not?
Report to
Senior
Management

166. Thank you