This document discusses change management in pharmaceutical manufacturing, emphasizing regulatory compliance and real-world impacts of changes in processes, equipment, and materials on product quality. It highlights the need for effective quality management systems, proper risk assessment, and ongoing evaluation to ensure safety and regulatory adherence. Various case studies illustrate the severe consequences of inadequate change control, underscoring the importance of maintaining a state of control throughout the product lifecycle.

1. Change Management
in Pharmaceutical Manufacturing Operations
Roohi B. Obaid
04 Aug 2018 at Karachi

3. This presentation discusses Regulatory Science,
nothing more & nothing less
Reference: US-FDA Documents / Scientific Articles/
Real time hands on experience of Compliance & Enforcement
Personal point of view & nothing to disclose
Disclaimer

4. Lets align on
Common Regulatory Language

5. Source of API is changed …
Can it be caught through testing
If
?
A

6. Impact are possible that may not
caught in end product testing.
What
B
Can you make list please

7. A process of manufacturing (e.g.
from 25 to 30 min mixing to 30
to 35 min mixing) is little
changed.
Do you expect any impact
If
?
C

8. Manufacturing suite is changed for any
operation. E.g. primary packaging
done in area where this product was
not qualified but all including area and
packaging equipment was qualified for
GMP
Can you catch it in testing or any other
stage. Does it have any impact
IfD

9. You can do without any notification to RA
You have to notify RA but approval not required
Approval from RA is required
C
H
A
N
G
E
Make a list
E
F
G

10. If you want to remove assay
& dissolution from end
product testing that you
perform before blister
packaging
Can you do that ?
H

11. If you want to remove assay
of suspension from end
product testing that you
perform before filling
Can you do that ?
I

12. Background

13. Incidence
Deviation
Change
Disturb the balance
of control
Control
&
Manage

14. You can do without any notification to RA
You have to notify RA but approval not required
Approval from RA is required
C
H
A
N
G
E
Make a list

16. Regulations & Emerging Guidance

17. ICH Q Guidance Documents are the best
available agreed document used for
change management

18. Change in Specifications

19. Source of API is changed …
Can it be caught through testing
If
?
A

20. Impact are possible that may not
caught in end product testing.
What
B
Can you make list please

21. A process of manufacturing (e.g.
from 25 to 30 min mixing to 30
to 35 min mixing) is little
changed.
Do you expect any impact
If
?
C

22. Manufacturing suite is changed for any
operation. E.g. primary packaging
done in area where this product was
not qualified but all including area and
packaging equipment was qualified for
GMP
Can you catch it in testing or any other
stage. Does it have any impact
IfD

23. You can do without any notification to RA
You have to notify RA but approval not required
Approval from RA is required
C
H
A
N
G
E
Make a list
E
F
G

24. If you want to remove assay
& dissolution from end
product testing that you
perform before blister
packaging
Can you do that ?
H

25. If you want to remove assay
of suspension from end
product testing that you
perform before filling
Can you do that ?
I

26. Real Time Case Studies – ROOA

27. Paracetamol
Tablet A global company was manufacturing
Paracetamol Tablets since decades
Found out of specification for
dissolution
Hundreds of batches found OOS
Extensive recall & closure of facility
for 2 years

28. Paracetamol
Tablet

29. Paracetamol
Tablet
Over capacity

30. Paracetamol
Tablet
Use of gelatin as binder

31. Paracetamol
Tablet
Poor state of control

32. Paracetamol
Suspension A company was manufacturing
Paracetamol Suspension since years
Sedimented product, hard to suspend
Hundreds of batches found OOS in Govt.
supply
Closure of facility for a long period of
time

33. Paracetamol
suspension

34. Paracetamol
Suspension
Used compacted API
instead of micronized

35. Paracetamol
suspension

36. Paracetamol
Suspension
Xanthan gum soaking
time reduction

37. Soft Gelatin
Capsule A global company was manufacturing
different products in soft gelatin capsules
since decades
Disintegration failed n one product, drug
not released
Hundreds of batches of millions of
capsules recalled
Closure of facility for 2 years

38. Soft Gelatin
Capsule

39. Changed the source of
gelatin and its adverse
effect with iron, impact not
carefully assessed before
change
Soft Gelatin
Capsule

40. Antibiotic
Cream
Genticyn HC Cream
Variations continued
Assay of one of the API found below
Company changed method …
Nether conclusive nor rational

41. Antibiotic
Cream

42. Zinc Sulphate
Solution
Did not meet specifications for
its pH as mentioned in USP
They developed their own
specification (ZSO4 syrup)
Govt. Supply batches failed

43. Zinc Sulphate
Solution

44. Benzyl Benzoate
Lotion
Phasing of emulsion
Millions of bottles rejected

45. Benzyl Benzoate
Lotion

46. Co-amoxiclav
Tablets
Dissolution failed
Several batches affected

47. Co-amoxiclav
Tablets

48. Injectable
Product
Solution color turned black
Huge recall .. Production stop
… ………..

49. Injectable
Product

50. Infusions
Product
Particles appear after some
times ..
Huge recall

51. Infusions
Product

52. Under weight tablets
compressed
Problem discovered after
compression of 23 batches of
one million tablets
Antimalarial
Tablet

53. Antimalarial
Tablet

54. Tragic
Incidence
Fexofenadine
During manufacturing a change
end up with blast
People died ….

55. Tragic
Incidence

56. Scenario
Addition of a new product in
the manufacturing facility (e.g.
Methyl Prednisolone Tablet)

57. Scenario

58. Scenario
Addition of a new line in the
manufacturing facility (e.g.
filling or packaging line)

59. Scenario

60. Scenario
Change in Equipment e.g.
change in punches

61. Scenario

62. Make your Change Control Effective
Rob Hughes, Astra Zeneca, 2011 Q10
Conference, Belgium, Virginia

63. SOP
for every step

64. Evaluation of change
SOP
for every step

65. Evaluation of change
Approval to proceed with the change
SOP
for every step

66. Evaluation of change
Approval to proceed with the change
Implementation of changeSOP
for every step

67. Evaluation of change
Approval to proceed with the change
Implementation of change
Review to ensure that change has been effective
SOP
for every step

68. Evaluation of change
Approval to proceed with the change
Implementation of change
Review to ensure that change has been effective
Review effectiveness of overall system
SOP
for every step

69. Clear accountability for each step
Keep simple

70. Clear accountability for each step
Consider upstream & downstream change impact
Keep simple

71. Clear accountability for each step
Consider upstream & downstream change impact
Prioritize urgent & important change
Keep simple

72. Probability, Severity & Detectability
Use Risk
Management
Tool in Change
Cycle

73. Probability, Severity & Detectability
Use of prior knowledge – development, other
manufacturing locations, similarities with other
products
Use Risk
Management
Tool in Change
Cycle

74. Probability, Severity & Detectability
Use of prior knowledge – development, other
manufacturing locations, similarities with other
products
Output should include understanding of adequacy
of control & additional ones as necessary
Use Risk
Management
Tool in Change
Cycle

75. Ensure change management system in place
Ensure IT system for change management validated
Approved change - lifecycle dependents
Audit impact of change & review effectiveness
Assure safety & quality of product
Quality Unit
Role

76. Scope of change management must
not cross the boundary of regulation
and must be within the space of
authorized company Quality System
Scope

77. Lets think
A company wish to change dissolution profile of its product
Can they do?

78. Lets think
A company wish to change dissolution profile of its product
Can they do?
No

79. Lets think
A company wish to remove manufacturing date from the label
Can they do?

80. Lets think
A company wish to remove manufacturing date from the label
Can they do?
No

81. Lets think
A company wish to change packaging machine
Can they do?

82. Lets think
A company wish to change packaging machine
Can they do?
Yes

83. Lets think
A company wish to change packaging from bottle to blister
Can they do?

84. Lets think
A company wish to change packaging from bottle to blister
Can they do?
No

85. Lets think
A company wish to change supplier of raw material (API)
Can they do?

86. Lets think
A company wish to change supplier of raw material (API)
Can they do?
Yes

87. Lets think
A company imports finished goods from site A of Country
Holland. They wish to change Manufacturing site from A to
B of the same country. A & B are the sites of the same
manufacturer.
Can they do?

88. Lets think
A company imports finished goods from site A of Country
Holland. They wish to change Manufacturing site from A to
B of the same country. A & B are the sites of the same
manufacturer.
Can they do? No

89. Particulars Inspection Review
API FG Manufacturer FG Manufacturer
FG Regulatory Authority Regulatory Authority
Container Closure ??? ???
Bioavailability Site ??? ???
Machine ??? ???
Primary Responsibility
RA can extend …

90. Change for Quality Improvement
Bernadette Doyle, GSK, 2012, USA

91. Why
Change?
It is not the strongest of
the species that survive,
nor the most intelligent,
but the one most
responsive to change

92. ICH Q10 & Change
Management
A systematic approach to
proposing, evaluating,
approving, implementing and
reviewing the change

93. ICH Q10 & Change
Management
Change management is a
much boarder scope than
change control

94. ICH Q10 & Change
Management
CM includes the oversight &
management of the entire
portfolio of change & the
change process including all
components of change control

95. ICH Q10 & Change
Management
CM applies across the entire
product lifecycle

96. Change Management
System (CMS)
A company must have an
effective CMS in order to
evaluate, approve &
implement change

97. CMS
The level of efforts & formality of the
evaluation should be commensurate with
the level of risk
QRM should be utilized to
evaluate the proposed changes

98. CMS
Current product & process understanding
… design space well established
Proposed change should be
evaluated

99. CMS
Appropriate expertise & knowledge to
evaluate proposed changes
Expert Team

100. CMS
Evaluation of change after
implementation to confirm the change
objective.
Post Changes

101. Continual
Improvement
It facilitates innovation &
strengthen the link between
pharmaceutical development
& manufacturing activities

102. Continual
Improvement Product quality improvement

103. Continual
Improvement Product quality improvement
Process improvement

104. Continual
Improvement Product quality improvement
Process improvement
Variability reduction

105. Continual
Improvement Product quality improvement
Process improvement
Variability reduction
Adaptation of innovation

106. Continual
Improvement Product quality improvement
Process improvement
Variability reduction
Adaptation of innovation
Quality system enhancement

107. Continual
Improvement Product quality improvement
Process improvement
Variability reduction
Adaptation of innovation
Quality system enhancement
Fulfill quality needs consistently

108. Continual
Improvement
Quality Risk Management
Knowledge Management

109. Opportunities
Optimize science & risk based
post approval change process
to maximize benefits from
innovation & continual
improvement

110. Expectations from your
Pharmaceutical Quality System
Richard. L. Friedman, FDA, 2012,
Baltimore, USA

111. Producer
Risk
Consumer
Risk

112. Probability

113. ProbabilityAlpha

114. ProbabilityAlpha Beta

115. Producer Risk
Alpha Adequate product is rejectedIf

116. Producer Risk
Alpha
Consumer Risk
Beta
Adequate product is rejected
Defective product is accepted
If
If

117. This probability depends upon
inspecting and rejecting good product or the
cost of supplying that product

118. Risk Reduction Opportunities
Facilities
& Process
Ingredient
Variability

119. Deficient Facilities & Processes
Old Mfg
Platform

120. Deficient Facilities & Processes
Old Mfg
Platform
Unpredictable
Mfg

121. Deficient Facilities & Processes
Old Mfg
Platform
Unpredictable
Mfg
Manual Intensive
Operations

122. Deficient Facilities & Processes
Old Mfg
Platform
Unpredictable
Mfg
Manual Intensive
Operations
Open Process

123. Deficient Facilities & Processes
Old Mfg
Platform
Unpredictable
Mfg
Manual Intensive
Operations
Open Process Human error

124. Old Mfg
Platform
Antiquated facilities,
inefficient /unstable
processes

125. Unpredictable
Mfg
If you do not take advantage
of contemporary technology
Frequent start & stop to
correct problems & to pull
samples (e.g. tablet, sterile
Mfg. lines)

126. Open vs. closed
Unit vs. integrated operations
Manual Intensive
Operations

127. Human Error still
very prominent
root cause
Open Process

128. Human Error Analysis
Deep insight into the
underline cause
Human error

129. Ingredients Variability's
Excipients as root cause

130. Ingredients Variability's
Excipients as root cause
Naturally derived excipients

131. Ingredients Variability's
Excipients as root cause
QRM for supplier selection,
monitoring & management
Naturally derived excipients

132. Rest assure
A Quality Culture will
always lead to
sustainable compliance

134. Imagine
How many decisions
you take daily?
How much directions
you receive verbal/
phone/ face

135. Imagine
How many decisions
you take daily?
How much directions
you receive verbal/
phone/ face

136. It is your choice to go for quality
or manage undocumented
Your decision influence
your direction & ultimate
destiny
Imagine
How many decisions
you take daily?
How much directions
you receive verbal/
phone/ face

137. It is your choice to go for quality
or manage undocumented
Your decision influence
your direction & ultimate
destiny
Imagine
How many decisions
you take daily?
How much directions
you receive verbal/
phone/ face

138. Strong Quality Culture & Manufacturing Consistency
Unreliable Systems & Manufacturing Problems

139. Quality
Culture
Support for the Quality Organization
Action speaks louder than words
Quality of work you accept becomes your
standard
QA is independent & not subordinate to
other organizational units

140. Memorandum
… EU
The manufacturer shall establish &
implement an effective
Pharmaceutical Quality Assurance
System involving the active
participation of the management &
personnel of the different
departments

141. Memorandum
… FDA
when it employs conditions &
practice that assure compliance ..
with the intent of … cGMP
regulations that pertain to
their system
A manufacturer is
considered to be operating in
a state of control ..

142. Memorandum
… FDA cGMP includes the implementation
of oversight & control over the
manufacture of drugs to ensure
quality, including managing the risk
of and establishing the safety of raw
materials, the materials used in
manufacturing of drugs & finished
drug products

143. Memorandum
… FDA The system which assures overall
compliance with cGMP and internal
procedures & specifications is
certainly the Quality System
Remember, Quality System is not
only undertaken by QA/QC, it
involves many other responsible
departments

144. Be Aware
Please If the management of the firm is
unwilling or unable to provide
adequate corrective actions in an
appropriate time frame …
Formal regulatory actions designed
to meet emerging situations
encountered are taken

145. Be Aware
Please
Always be prepared to
demonstrate that you are
operating in a state of control

146. A condition in which the set of
controls provide assurance of
continued process performance &
product quality
(ICH Q10)
What is
State of Control

147. After establishing & confirming the
process, manufacturer must
maintain the process in a state of
control over the lifecycle of process,
even as material, equipment,
production environment, personnel
& manufacturing procedure changes
(FDA, PV Guidance 2011)
Don’t Forget

148. Technology transfer is insufficient to support
desired commercial operation
Is it GMP Compliant
?

149. The manufacturing process is weak in operating
in a state of control
Is it GMP Compliant
?

150. The manufacturing facility has inadequate system
for managing changes
Is it GMP Compliant
?

151. Excessive variation due to outdated
production technology ….
Major manufacturing & quality
problems
Never consider innovations
Manufacturing going on
Is it GMP Compliant
?
Take a
Scenario

152. Change Management & GMP Obligations

153. Any CHANGE in procedure for production &
process control designed to assure identity, strength,
quality & purity shall be approved by the appropriate
organizational unit & reviewed & approved by the
Quality Control Unit
Manufacture

154. Any change in such specifications, standards,
sampling plan, test procedures or other laboratory
control mechanisms shall be drafted by the
appropriate organizational unit & reviewed &
approved by the Quality Control Unit
Laboratory

155. Manufacturer must review at least annually the
quality standards of each drug product to determine
the need for change in drug product specifications, or
manufacturing or control procedures
Improvement

156. Manufacturer must review at least annually the
quality standards of each drug product to determine
the need for change in drug product specifications, or
manufacturing or control procedures
Improvement
The best way is to document why it is required
or why it is not required

157. Innovation, continual
improvement, outputs of process
performance & product quality
monitoring, CAPA drive change.
To evaluate, approve & implement
these changes properly, a company
should have an effective change
management system
Change
Management

158. Design
OOS results may indicate a flaw in
product or process design, for e.g.
A lack of robustness in
product formulation

159. Design
OOS results may indicate a flaw in
product or process design, for e.g.
Inadequate raw material
characterization or control

160. Design
OOS results may indicate a flaw in
product or process design, for e.g.
Substantial variation introduced
by one or more unit operations of
the manufacturing process

161. Design
OOS results may indicate a flaw in
product or process design, for e.g.
A combination of these
factors can be the cause of
inconsistent product quality

162. Design
Product & Process re-design
need to be undertaken to ensure
reproducible product quality
Re

163. The process is not monitored for
process performance
Is it GMP Compliant
?

164. The process is not monitored for
product quality
Is it GMP Compliant
?

165. The process is not monitored to see &
maintain the State of Control
Is it GMP Compliant
?

166. Manufacturer routinely reacts to problems
(Rejections, Returns, Complaints etc.)
Is it GMP Compliant
?

167. Building
Knowledge
To develop & use effective
monitoring & control system for
process performance & product
quality, thereby, providing assurance
of continued suitability & capability
of process
ICH Q10

168. Do engage in real time
for continued process
verification by scrutiny
of inter-batch & intra-
batch variations
Inter-Batch Intra-Batch

169. Qualified person or Responsible Person is not
aware of major product quality problem (e.g.
Complaints, Returns etc.)
Is it GMP Compliant
?

170. Remember
Please
Procedure must be established to
assure that responsible officials of
the firm, if they are not personally
involved in or immediately aware
of such actions are notified in
writing of any investigation
conducted under obligations

171. Remember
Please
Ensure a timely and effective
communication & escalation
process exist to raise quality issues
to the appropriate level of
management

172. The manufacturer routinely reacts to the
production failures by making corrective actions
but does not take any preventive actions
Is it GMP Compliant
?

173. Prevention
Prevention from contamination,
loss of process control, error, defect,
deviation, uncertainty, inconsistency,
mix up potential
It is basic theme and purpose of
cGMP regulations

174. CAPA
An effective program will decrease
process variation & product quality

175. You are the owner & applicant for a
multi-use ophthalmic product
You learned that your contract
manufacturer has received a
complaint that 2 batches contained
leaking containers
Cont’d
Take a
Scenario

176. This contract manufacturing site
produces batches for you when you
cannot meet the demand at your site
The 2 lots have already been
distributed
The investigation of the complaints
include testing of retaining sample
Cont’d
Take a
Scenario

177. You learned from testing that 3 other
lots produced over the last 2 years
have a significant number of leakers
You had qualified the facility solely
by testing the first 3 lots it produced
Is it GMP Compliant
?
Take a
Scenario

178. Management does not provide adequate &
appropriate resources (human, financial, material,
facilities & equipment) to sustainably meet
cGMP in order to maintain robust operation
Is it GMP Compliant
?

179. Thank You