Presented to a small group of working professionals (Constructed from different documents of FDA, ISPE etc. available on public domain) - Personal point of view

1. Creating a Sustainable Culture of Quality
Roohi B. Obaid
07 Sep 2019
Fundamental
Module

3. (10 Min)
Pre - Assessment

5. Typically Consumer cannot
see Quality

6. History & Prior Knowledge
Case Studies & Discussion on
Phenomena
Future & Emerging Map

7. Tutorial
Critical Thinking & connecting
the dots
Group Discussion

8. What is GMP?
It is a set of
Regulatory
Methodology
to manufacture the
drugs

9. What GMP Does?
Protects
Integrity &
Quality
of manufactured
product intended
for human use

10. What GMP Does?
Ensures that products are
consistently produced &
controlled

11. What is the Intent of GMP?
Consistency
Contamination/cross-
contamination
Mix up

12. GMP Provides
Documentation
Traceability
Trust
Predictability

13. GMP Assures
Identity, quality &
strength of drugs
Correct procedures are
followed
Timely documented
Reviewed before release

14. If a drug qualifies all test, can it be released or
something else will be required?

15. Quality cannot be observed by every one
and/or by naked eye
Quality cannot be tested in a laboratory but has to be
built in to the product

16. If a drug is manufactured in GMP environment & qualifies all
tests, is it sufficient for quality or something remains?

17. Surveillance Complaints Recalls Vigilance

18. Pure
Consistent
Zero Mix
Up
Drug
1 2 3
Batch after Batch
Within Batch
Time after Time

19. GMP Elements
Premises Equipment Personnel Materials
Documentation
Qualification &
Validation
Etc.

20. GMP Systems
Quality
System
Production
System
Lab
Control
System
Facilities &
Equipment
System
Materials
System
Packaging
&
Labeling
System

21. GMP System Indicators & Attributes
Complaints Recall
Investigations
& CAPA
Internal
Audits
Reviews
Change
Management
Supplier
Qualification
Risk
Management
Deviations
Master
Maintenance
Plan
Master
Validation
Plan
Master
Training Plan
Calibration

22. Quality Safety Efficacy Identity Purity Strength

23. Background Concerns that
Develop Foundation for Culture of Quality

24. …. Lets have a deep breath and see ….
Who we are, What we do, What can go wrong &
Where we have to focus
It’s a matter of human life, it’s a matter of your
own progress & progress of company

25. …. Lets have a deep breath and see ….
Who we are, What we do, What can go wrong &
Where we have to focus
It’s a matter of human life, it’s a matter of your
own progress & progress of company

26. What will happen if we don’t have Penicillin?
What Penicillin did
Horrible death & Fear across

27. What will happen if we don’t have cardiovascular drugs?
E.g. What Captopril did
Life Crisis

28. What will happen if we don’t have drugs for Diabetes?
E.g. What sulfonylureas did?
Death Penalty

29. What will happen if we don’t have drugs for Psychiatry?
E.g. What haloperidol did?
Social Crisis

30. What will happen if we don’t have drugs for Asthma?
E.g. What salbutamol did?
Breath Crisis

31. …. Lets have a deep breath and see ….
Who we are, What we do, What can go wrong &
Where we have to focus
It’s a matter of human life, it’s a matter of your
own progress & progress of company

32. PIC Tragedy of Pakistan took about 125 lives ………

33. 149
deaths
Test was
passed
Signals not
responded
Finally
contamination
detected
Its not Pakistan & its 21 Century
Can you recall, what was the case & where it happened?

34. 2008
?

35. Over sulfated chondroitin sulfate (OSCS)

36. If it happened in Pakistan, were me & you able
to catch?
What do you think can it be caught in testing?
Do you think we are capable to catch such level
of contaminant or less?
No
Yes
Don’t
know

37. What happened in 1930? 107 people died

38. What happened in 1930? 107 people died
Diethylene glycol … repetition of tragedy
… even in 2017 … found lacking in
corporate companies too

39. What happened in 1941?
About 300
people died

40. What happened in 1941?
About 300
people died
When sulphatiazole tablets were
tainted with phenobarbital

41. What happened in 2015? Several deaths

42. What happened in 2015? Several deaths
When Ciprofloxacin tablets were
tainted with pesticide

43. Lets come on the same page
to walk & think together

44. Safety
Will you allow the use of a drug for yourself or your
loved one which is suspicious in terms of safety?

45. Safety
Can you catch presence of any toxic substance by testing

46. Efficacy
The drug is overheated in the dryer. What do you think?
Should it go to the market

47. Cleaning
An equipment is cleaned but not properly cleaned after
manufacturing of a male hormone. Time is not available
and you have to manufacture female hormone in the
same equipment.
What decision you think appropriate?

48. Consistency
Can you catch the variation in consistency
by product testing?

49. HVAC
Can you list what is harm, if we do not supply HVAC in
a manufacturing facility?

50. Documentation
Why do we rely on document only and do not rely on a
trustworthy person?

51. Validation
Instrument is not a human being. Why do we require
exercise to develop trust on equipment performance?

52. …….. Dry at 15 to 20 minutes.
Why do not write dry up to 2% moisture level in batch
instructions?
Process Parameters

53. Quality Attributes
What would be the harm if a tablet is cracked?
Why it is not acceptable?

54. Use Reason
If you weigh and add correct
quantity of material
Do you think testing for
assay is required?

55. Use Reason
If you weigh and add correct
quantity of material
Do you think testing for
assay is required?
1
Tablet

57. Use Reason
If you weigh and add correct
quantity of material
Do you think testing for
assay is required?
2
IV Sol

58. Dextrose solution

59. Testing is an indicator of
quality insight

60. Group Discussion
Testing is sufficient
Testing is not sufficient
For
Quality

61. The drug which is tested, is not
given to patient
&
the drug which is given to patient
is not tested

62. Mistakes are not shared with bosses
Is it a Quality Culture?

63. Set the Tone of Quality Mode
beyond the Compliance

64. Regulations
EnforcementCompliance
Guarantee
?

65. Recalls

66. Aripiprazole
(1 mg/ml oral solution)
Potential small particles of API
may alter the efficacy
30 July 2019
MHRA
Oxycodone
(5 mg oral tablet)
Mix up of a strip of morphine
tablet 30 mg was reported
30 July 2019
TGA
Drospirenone
3 mg & Ethinyl
Estradiol 0.02 mg
OOS in dissolution
results at 3 mo
stability point
23 July 2019
FDA

69. Safe, efficacious & have correct identity
Assume …
…. Drugs are

70. Deliver the same performance as claimed
Assume …
…. Drugs will

71. Perform consistently over shelf life
Assume …
…. Drugs will

72. Made in a manner that ensure quality
Assume …
…. Drugs are

73. be available when needed
Assume …
…. Drugs will

74. Culture of Quality

75. Me, my kids &
parents use same
drug which I
manufacture

76. Me, my kids &
parents use same
drug which I
manufacture
No batch has ever
failed

77. Me, my kids &
parents use same
drug which I
manufacture
No batch has ever
failed

78. Sky scrapping
challenges ahead
Data Integrity
Integrated
Regulations
Quality
Metrics

79. Temperature Control lost for sometime
during supply chain?
Situation

80. Situation
Non-sterile Initially Fail
Pass after 2
weeks

81. Situation
Non-sterile Initially Fail
Pass after 2
weeks
Its not only fail but Quality System is now under
microscopic examination

82. Situation
Non-sterile Initially Fail
Pass after 2
weeks
Its not only fail but Quality System is now under
microscopic examination
Why?

83. No
It is not correct
Appropriate procedure to prevent objectionable
microorganisms in non-sterile products

84. No
It is not correct
Anti-microbial effectiveness test
Appropriate procedure to prevent objectionable
microorganisms in non-sterile products

85. No
It is not correct
Anti-microbial effectiveness test
Preservative must not be used as a substitute to GMP
Appropriate procedure to prevent objectionable
microorganisms in non-sterile products

86. No
It is not correct
Anti-microbial effectiveness test
Preservative must not be used as a substitute to GMP
Appropriate procedure to prevent objectionable
microorganisms in non-sterile products
Preservative is to reduce the viable microbial
population

87. Preservative is used to reduce bio-burden of a multi-
dose formulation
No
It is not correct

88. Preservative may not be used to reduce initial OOS
result
Preservative is used to reduce bio-burden of a multi-
dose formulation
No
It is not correct

89. Preservative may not be used to reduce initial OOS
result
Failure to meet established conditions must be
rejected
Preservative is used to reduce bio-burden of a multi-
dose formulation
No
It is not correct

90. Preservative may not be used to reduce initial OOS
result
Failure to meet established conditions must be
rejected
Preservative is used to reduce bio-burden of a multi-
dose formulation
Rejection is not an option but obligation
No
It is not correct

91. Holding for 2 weeks is a great question that provides
opportunity …
No
It is not correct

92. … to reduce microorganisms introduced during
manufacturing by addition of preservative
Holding for 2 weeks is a great question that provides
opportunity …
No
It is not correct

93. … to reduce microorganisms introduced during
manufacturing by addition of preservative
It is an opportunity to see & review manufacturing
process & identify the weakest area
Holding for 2 weeks is a great question that provides
opportunity …
No
It is not correct

94. … to reduce microorganisms introduced during
manufacturing by addition of preservative
It is an opportunity to see & review manufacturing
process & identify the weakest area
Holding for 2 weeks is a great question that provides
opportunity …
Look back & see desensitization of Quality
Management System
No
It is not correct

95. Lets see another case

96. 2X mg X mg
1/2X
mg

97. Lets discuss what is culture & how it
influences on quality

98. Defined as the
shared beliefs, values,
attitudes, and behavior
patterns that characterize
the members of an
organization.
CULTURE

99. Quality Culture
It starts with leadership that
understands that human behavior and
motivations are critical to meeting
ongoing quality requirements, and
naturally emphasizes continuous
improvement of processes

100. 1
2 3
4
Let’s identify attribute of culture

101. Let’s identify correct relationship
Girl and Mehndi
Boys and Mehndi
Girl and Tattos

102. Let’s identify correct relationship
Mehndi &
Bangles
Boys and Bangles
Girl and Bangles

103. Let’s identify correct relationship
Eid
Exam day
Fun

104. Quality
Metrics
Indicator of
operational reliability Quality Culture

105. What is Metrics?
Objective or quantitative
measurement of any parameter
Provides a meaningful
interpretation

106. Quality Metrics in Pharmaceuticals
Objective measure of state of quality at the
Additional tool in
surveillance tool box
Product Site System

107. Quality
Metrics
Lot
Acceptanc
e Rate
Product
Quality
Complaint
Rate
Right first
time Rate
Invalidate
d OOS
Rate
APR or
PQR on
time Rate
CAPA
Rate
Ability to
initiate
voluntary
CAPA

108. Lots rejected/total lots in a year
Lot Acceptance Rate

109. Lot Acceptance Rate
4/355=

110. Deviated lots/ total lots
in a year
Right First Time Rate

111. 38/355=
Right First Time Rate

112. APR triggered CAPA/ total
number of APRs
Corrective & Preventive Action (CAPA) Rate

113. Corrective & Preventive Action (CAPA) Rate
3/30=

114. Process capability or
performance index for each
critical quality attribute that
triggers a CAPA
Ability to initiate voluntary CAPA

115. Ability to initiate voluntary CAPA
Cp value

116. The number of batches for which
complaint received/ total number of
batches (very specific to the product)
Product Quality Complaint Rate

117. Product Quality Complaint Rate
6/30=

118. Invalidated initial OOS tests /
total number of tests in a year
Invalidated OOS Rate

119. Invalidated OOS Rate
200/9900=

120. The number of APRs within
30 days of annual due date /
the total number of products
produced during the year
APR or PQR on time Rate

121. APR or PQR on time Rate
05/40=

122. Expectation of Regulatory Agency from Manufacturer
Extensive
knowledge of
Critical products
Process parameters
Quality attributes

123. Be clear about ….. Role of Regulatory Agency
Verification & audit to
Keep
manufacturing
supplements /
variations
minimum

124. Recap: Why Quality Metrics?
Improves process performance
Continuous improvement in PQS
Improves product quality
Increased operational excellence
Important element of oversight

125. Quality Metrics ultimately leads to
QM
leads to
Patient access to
reliable therapies
Fewer drug shortageFewer recalls

126. Key Focus of Regulatory Agency
Robustness of
Manufacturing
process
Lot
Acceptance
Rate Robustness of
Lab
Operations
Invalidated
OOS Rate
Voice of
customer/
patient
Product
Quality
Complaint
Rate

127. Further Emphasis of Regulatory Agency
Process capability
& performance
Quality culture
CAPA
effectiveness
Meeting PQS
timeframes
Senior
management
commitment to
quality

128. Cultural Scores & Site Performance Key Quality Metrics
Pharmaceutical OnlineKen Congdon, 26 May 2015
Stronger culture is correlated with
fewer action limit excursions in steriles
1/4 ISPE

129. Cultural Scores & Site Performance Key Quality Metrics
Pharmaceutical OnlineKen Congdon, 26 May 2015
Stronger culture scores are associated
with higher lot acceptance
2/4 ISPE

130. Cultural Scores & Site Performance Key Quality Metrics
Pharmaceutical OnlineKen Congdon, 26 May 2015
Sites with higher quality culture scores
have lower deviations recurrence
3/4 ISPE

131. Cultural Scores & Site Performance Key Quality Metrics
Pharmaceutical OnlineKen Congdon, 26 May 2015
Sites with higher quality culture scores
have higher CAPA effectiveness
4/4 ISPE

132. Identified Essential Attributes for Culture of Quality
Harvard Business ReviewSurvey April 2014
Leadership Emphasis
Message Credibility
Peer Involvement
Employee Ownership

133. Identified Essential Attributes for Culture of Quality
Harvard Business ReviewSurvey April 2014
Maintaining a leadership emphasis on quality
What they say & What they do
1/4

134. Even when executives have the best intentions, there are
often gaps b/w
What they say & What they do
As a result, employees get mixed messages about whether
quality is truly important. Company leaders must first buy
into quality improvement initiatives and clearly
demonstrate their own personal commitment to this effort
to employees

135. Identified Essential Attributes for Culture of Quality
Harvard Business ReviewSurvey April 2014
Ensuring Message Credibility
One Message
2/4

136. Quality messaging should be tailored in such a
way that it resonates with every employee.
Different messages may need to be developed to
resonate appropriately with employees at
different sites.
The key is to regularly test these messages with
employees, solicit their feedback, and refresh
these messages over time if necessary

137. Identified Essential Attributes for Culture of Quality
Harvard Business ReviewSurvey April 2014
Encouraging Peer Involvement
Participation
3/4

138. A variety of different tactics can be used to
create positive social pressure that encourages
employees to participate in (& even generate)
quality initiatives. These can include friendly
“quality competitions”.
The key is to test these tactics and solicit
feedback to see which are most effective with
employees.

139. Identified Essential Attributes for Culture of Quality
Harvard Business ReviewSurvey April 2014
Increasing Ownership & Empowerment
Engage in Decisions
4/4

140. Employees should be free to apply their own
judgment to situations that fall outside the
common directive but within frame of approved
procedure & authority. Providing the right level of
guidance & training is crucial to this effort
Remember, they must know how to act when they
encounter specific quality issues.

141. Visible Signals of Quality Culture
Consistently
walks the
talk

142. Visible Signals of Quality Culture
Constant display
of putting patient
above everything
Consistently
walks the
talk

143. Visible Signals of Quality Culture
Constant display
of putting patient
above everything
Consistently
walks the
talk

144. Visible Signals of Quality Culture
Constant display
of putting patient
above everything
Consistently
walks the
talk
With great
people skill
& strong
value

145. Visible Signals of Quality Culture
Right tone at the
top
Constant display
of putting patient
above everything
Consistently
walks the
talk
With great
people skill
& strong
value

146. Visible Signals of Quality Culture
Right tone at the
top
Constant display
of putting patient
above everything
Consistently
walks the
talk
With great
people skill
& strong
value
More than
financial
rewards

147. Visible Signals of Quality Culture
Right tone at the
top
Focus on the
right value
Constant display
of putting patient
above everything
Consistently
walks the
talk
With great
people skill
& strong
value
More than
financial
rewards

148. Visible Signals of Quality Culture
Right tone at the
top
Focus on the
right value
Constant display
of putting patient
above everything
Constant display of
concern for quality
Consistently
walks the
talk
With great
people skill
& strong
value
More than
financial
rewards

149. Visible Signals of Quality Culture
Right tone at the
top
Focus on the
right value
Constant display
of putting patient
above everything
Constant display of
concern for quality
Consistently
walks the
talk
With great
people skill
& strong
value
More than
financial
rewards

150. Roots of Strong Quality Culture
Introduction of Improvement & Innovation for quality
driven productivity
Adaptation & Investment in Technology to ensure state
of control over system
Promotion of change & continuous improvement in
Quality System

151. Roots of Strong Quality Culture
Prompt adaptation of best practice, low staff rotation
Proactive & transparent behavior
Strong relationship based on dialogue, science & mutual
respect

152. Principle of Quality Culture
Product & Process Understanding Sensible Business Management
Sufficient depth of science to
explain why deviations have
not impacted on quality of
product
Too fast growth & operating at
limit of capacity triggers often
issues & non-compliance

153. How mature is your quality system
1 2 3 4
Level
Richard L. Friedman, FDLI Workshop Washington DC, July 2014US-FDA
Small problems ultimately snowball into larger ones, and
management becomes aware only when there is a crisis

154. How mature is your quality system
1 2 3 4
Level
Richard L. Friedman, FDLI Workshop Washington DC, July 2014US-FDA
Nearly always reactive, but there is willingness to change.
Patchwork corrections are the norm

155. How mature is your quality system
1 2 3 4
Level
Richard L. Friedman, FDLI Workshop Washington DC, July 2014US-FDA
More proactive. Increasingly detects emerging adverse trends,
surfaces major issues, and makes lasting manufacturing and
system improvements

156. How mature is your quality system
1 2 3 4
Level
Richard L. Friedman, FDLI Workshop Washington DC, July 2014US-FDA
Routinely acts preventively as described in level 3. Fully
institutionalizes and reinforces (rewards) a vigilant culture that
makes meaningful manufacturing and systemic improvements

157. Systems Thinking
System is the product of
interacting parts
Improving the parts taken
separately will not improve
the system

158. Strong Quality Culture Efficient Quality System
Consistent
manufacturing
It’s the culture that decides the path
Poor Quality Culture Unreliable Quality System Defects and Recall

159. Lets make it simple, clear & loud

160. Me, my kids &
parents use same
drug which I
manufacture
No batch has ever
failed

161. Drug manufactured in non-cGMP
environment
It does not mean that there is necessarily
something wrong with the drug
But “intention in question”

162. Please remember
Lack of adverse event reports cannot be
taken as evidence of no harm….
“Something is wrong” does NOT mean
as evidence of harm or no harm….

163. Innocence
• Quality
mainly
outsourced
to regulators
Awareness
• Quality unit
will identify
the issue
Understanding
• Quality
system &
Metrics
reveals
reality &
drives action
Competence
• Quality
mind set in
all functions.
Design
quality in &
anticipate
issues
Excellence
• Competitive
advantage
through
prevention
of quality
issues
Journey of uncertainty to certainty … it matters

164. Linkage
Science &
compliance
Challenge
Traditional
validation &
continuous
verification
Maintain
Process
robustness &
drives reliability
Product & Process
Criticality
CoQ
beyond compliance
New technology

165. Even a great quality system will fail, if the
Quality Culture
is not equal standard

166. The question isn’t whether we are honest or not…
The question is how strong your culture of quality is…

167. Post - Assessment

168. Testing costs the company
You added API & witnessed throughout the tablet manufacturing.
1

169. Testing costs the company
You added API & witnessed throughout the tablet manufacturing.
Do you think to conduct assay of this
batch is necessary?
1

170. You have received dispensed materials that are
already weighed & witnessed as per available record sheet
2

171. Do you think verification of weight is
necessary before starting a batch?
You have received dispensed materials that are
already weighed & witnessed as per available record sheet
2

172. Dispensed 100 days earlier. Supply of cartons was missing … left
unattended in controlled room
3

173. Dispensed 100 days earlier. Supply of cartons was missing … left
unattended in controlled room
Can materials be used after 100 days or
does it need some working?
3

174. During manufacturing of aseptic product, a powerful explosion was
heard in a nearby building
4

175. During manufacturing of aseptic product, a powerful explosion was
heard in a nearby building
Do you think it should be reported to boss
and documented?
4

176. Smell or taste was felt in your throat of other product that is being
manufactured in other suites of your company
5

177. Smell or taste was felt in your throat of other product that is being
manufactured in other suites of your company
Should it be recorded or reported?
5

178. Some blisters of any other batch … a human error because blisters
brought for supervisor from next room and left unattended
6

179. Some blisters of any other batch … a human error because blisters
brought for supervisor from next room and left unattended
Does it require to be recorded?
6

180. Mix ups are a universal matter, it happens all across the world.
7

181. Mix ups are a universal matter, it happens all across the world.
Write reasons of mix up based on your
own understanding.
7

182. Unintentionally intelligence about quality
8

183. Unintentionally intelligence about quality
Should it be reported to your boss?
8

184. Thank You