This document discusses managing change and deviations in pharmaceutical manufacturing according to Good Manufacturing Practices (GMP). It begins by defining a deviation as any departure from approved instructions or standards. It distinguishes between planned and unplanned deviations. It emphasizes the importance of fully investigating, documenting, and justifying all deviations in order to determine the root cause and implement corrective and preventive actions. The document also discusses change management procedures and the role of the quality unit in approving, implementing, and reviewing all changes to ensure they are properly controlled and the product quality is maintained. It stresses that any change to procedures, specifications or controls must be approved and reviewed by the quality unit.

1. Manage the Change for
Progress
Not for
Compliance
Roohi B. Obaid
24th Oct 2018, Hotel PC, 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. Deviation Permissibility in GMP
Change Management in GMP

4. Deviation

5. Deviation
It is a departure from
an approved
instruction or
established standards

6. Deviation
Divergence
Disobedience
Change
D
D
C

7. Handling of Deviations

8. Absolute Fact
The drug which is
tested is not used
The drug which is
used is not tested

9. Absolute Fact Product quality depends on each
step in manufacturing process that
must be controlled …
…. to maximize the probability and
enhance certainty ….
…. that the FPP will meet its quality,
design specifications, perform well &
uphold promise

10. Absolute Fact
Certainty
Probability
Control on Manufacturing Process

11. Quality System
OOS Investigations Deviations
Recall & Returns Complaints
Risk Management
Change Management

12. Obligation
ANY deviation from established procedure should be
documented and explained. Critical deviations should be
investigated, and the investigation and its conclusion should
be documented
[ICH]

13. Obligation
Document
Explain
Investigate
Document

14. Obligation
Written procedure should be established & followed for
investigating critical deviations or the failure of a batch … the
investigation should extend to other batches that may have
been associated with the specific failure or deviation
[ICH]

15. Obligation
Failure
Deviation
Written
SOP
Investigation

16. Deviation
GMP
Mistakes
or Error
Reprocessing or Rework
Unapproved changes
Performing an activity without proper training
Outside of operating parameter or in-process control limit
Failure to follow SOP or approved batch record instructions

17. Types ?
Activity performed
differently and or
modified than that
specified in an
approved document

18. Types ?
Activity performed
differently and or
modified than that
specified in an
approved document
Planned
Un-planned

19. Planned Deviation

20. Planned Deviation Pre-described, Pre-approved for specified
period for specific number of batches

21. Planned Deviation
Pre-described, Pre-approved for specified
period for specific number of batches
Feb 2016
Annual Maintenance
60 Batches .. One batch
per day
Jan 2016
Mfg ..
Schedule 5 to 10 Feb

22. Planned Deviation
Pre-described, Pre-approved for specified
period for specific number of batches
Approved well before execution
Handled through approved change control procedure
Changes should be evaluated for product impact significance

23. Planned Deviation
Unintentional
Pre-described, Pre-approved for specified
period for specific number of batches
Un-planned
Unexpected

24. Un-Planned Deviation
Uncontrolled event in
the form of non-
compliance at any stage
of manufacturing etc.
Incident

25. Quality
impacting
(purity, strength,
release, delivery etc.)
Non-quality
impacting
Sec. packaging, out of
trend, yield etc.)

26. Major
Critical Minor
Quality
impacting
(purity, strength,
release, delivery etc.)
Non-quality
impacting
Sec. packaging, out of
trend, yield etc.)

27. Typical examples Temperature,
humidity, air
pressure
Breakdown of
process
equipment
Equipment out
of calibration

28. Typical examples Alternative
equipment
used
Process done
but not
documented
In-process
control limit
went out

29. Investigating
Steps

30. Investigating
Steps
Discovery of
deviation
Documentation
of events
Immediate
corrective
action
Investigation of
root cause
Casual analysis
Corrective
action
Preventive
action
Effectiveness
evaluation
Review &
reshape the
policy

31. Investigation

32. Investigation
What was
discovered
Who was
involved
When did the
event occur
Where did the
deviation occur
How was the
deviation
discovered
How frequently
does the
process occur

33. Investigation
Remember, there is a big difference b/w
What happened & Why happened -OR- What happened & How happened
What was
discovered
Who was
involved
When did the
event occur
Where did the
deviation occur
How was the
deviation
discovered
How frequently
does the
process occur

34. Investigation
Fundamental questions

35. What Happened
Why How
Why
eg.
Dissolution failure

36. 1 mg 2 mg 4 mg
Same granules Different Strengths Different Thickness Same Surface Area

37. 1 mg 2 mg 4 mg
Same granules Different Strengths Different Thickness Same Surface Area
Degradation
+++
Degradation
++
Degradation
+

38. 4 mg 2 mg 1 mg

39. … A multiple injection manufacturing facility
Injection X 500 mg / 10 ml always found with yield 103 to 104%
Assay trend moves in between 101 to 103%
Process loss of 3 to 6% for other injection products
Lets think what is going on …
?

40. Remember
Deviation is a
beauty
It evolves
knowledge and
science, but …

41. Remember
Deviation is a
beauty
It evolves
knowledge and
science, but …
Don’t let it affect your product
quality, performance & promise

42. Obligations & Emerging Expectations

43. Significant
deviations are fully
investigated

44. Every deviation is
fully recorded

45. Assessment of
deviations from
specified procedures

46. Incorporate risk
assessment

47. Focus deviations on
Periodical Quality
Reviews

48. … for deviations
from manufacturing
formula, process,
packaging & testing
instructions
Authorization ..

49. Policies, procedures,
records of actions
that took part in
construction of
decision for
deviation

50. Policies, procedures,
records of actions
that took part in
construction of
decision for
deviation
DOCUMENT

51. What have been
done to avoid it?
Why it was
unavoidable

52. What have been
done to avoid it?
Why it was
unavoidable
REASON?

53. Any signal deviating
from trend will be
investigated

54. Deviations in
stability programs,
no matter it is
authorized

55. Quality System staff are
effectively integrated into
manufacturing & involved in
non-conformance
investigation

56. Investigation,
conclusion & follow up
must be documented

57. Justify deviations
from the written
procedures

58. Don’t leave any failure
uninvestigated, no
matter, batch is
destroyed or already
been consumed

59. Investigation will
always be extended
to other batches &
reason of limit will
justify

60. Let’s unfold …

61. Deviations

62. Deviations
1
2
3
4

63. Deviations
1
2
3
4
Use of Tray Dryer instead of FBD

64. Deviations
1
2
3
4
Exceeded the time specified for
boiling a liquid e.g. > 10 min

65. Deviations
1
2
3
4
Used the wrong sieve no. for sieving

66. Deviations
1
2
3
4 Changed the mixing order of
ingredients during batch processing

67. Non-
Conformance

68. 1
2
3
4
Non-
Conformance

69. 1
2
3
4
Work done but not recorded
Non-
Conformance

70. 1
2
3
4
Line clearance not done,
another batch started
Non-
Conformance

71. 1
2
3
4
Change in size of packaging
by supplier
Non-
Conformance

72. 1
2
3
4 Testing by a person who is not
qualified for the purpose
Non-
Conformance

73. Incident

74. 1
2
3
4
Incident

75. 1
2
3
4
Sieve break during operation
Incident

76. 1
2
3
4
Material dropped on the floor while
shifting to hopper
Incident

77. 1
2
3
4
Mix up of 40 mg & 240 mg label
Incident

78. 1
2
3
4 Blister machine suddenly
malfunctioned
Incident

79. Discrepancy

80. 1
2
3
4
Discrepancy

81. 1
2
3
4
Yield / Inventory
Discrepancy

82. 1
2
3
4
Temperature / Humidity
Discrepancy

83. 1
2
3
4
Monitoring devices
Discrepancy

84. 1
2
3
4 Measuring equipment
Discrepancy

85. Take Home Message
Your corrective
action must not be
Biased
&
must Match with
potential root cause

86. Take Home Message
The purpose of
conducting
investigation
must not be to
release the batch

87. Take Home Message
…
It is to determine the
root cause for the
deviation

88. Take Home Message
…
It is to implement
appropriate &
meaningful CA

89. Take Home Message
…
It is to evaluate the
implicated system

90. Take Home Message
Make sure that policy,
procedures, forms, process
flow are well understood &
aligned to walk and talk
together

91. Take Home Message
Appropriate training &
trained staff for investigations
is inevitable to reach logical
decisions that satisfy
regulatory expectations

92. Take Home Message
Be simple
Don’t make the process
unreasonably complicated or
over complicated

93. Take Home Message
Don’t expect that everyone
can be a good investigator

94. Change Management in GMP

95. Background

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

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

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

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

101. Producer
Risk
Consumer
Risk

102. Probability

103. ProbabilityAlpha

104. ProbabilityAlpha Beta

105. Producer Risk
Alpha Adequate product is rejectedIf

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

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

108. Risk Reduction Opportunities
Facilities
& Process
Ingredient
Variability

109. Deficient Facilities & Processes
Old Mfg
Platform

110. Deficient Facilities & Processes
Old Mfg
Platform
Unpredictable
Mfg

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

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

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

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

115. 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)

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

117. Human Error still
very prominent
root cause
Open Process

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

119. Ingredients Variability's
Excipients as root cause

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

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

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

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

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

126. 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

127. 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

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

129. 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

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

131. SOP
for every step

132. Evaluation of change
SOP
for every step

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

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

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

136. 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

137. Clear accountability for each step
Keep simple

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

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

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

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

142. 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

143. Ensure change management system in place
Quality Unit
Role

144. Ensure change management system in place
Ensure IT system for change management validated
Quality Unit
Role

145. Ensure change management system in place
Ensure IT system for change management validated
Approved change - lifecycle dependentsQuality Unit
Role

146. Ensure change management system in place
Ensure IT system for change management validated
Approved change - lifecycle dependents
Audit impact of change & review effectiveness
Quality Unit
Role

147. 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

148. Change Management & GMP Obligations

149. 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

150. 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 Unit, not the laboratory
Laboratory

151. 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

152. 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

153. Thank You