A training session conducted for pharmaceutical professionals of a particular organization

1. Dispensing Operations
Keep them Safe, Compliant & Sustainable
Roohi B. Obaid
07 Dec 2019 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. Discussion
• Science & good
science
Sharing
• Current
Knowledge &
Experience
Navigation
• Towards mutual
goal & Future
directions
Knowledge Sharing Exercise
To Learn through Debate, Discussion & Experience of others

5. The first door from where
journey of contamination
begins

6. Dispensing Errors
Have anyone of you ever witnessed it?

7. Per day
dispensing and sampling
activity in a multiple drugs
& dosage form
Manufacturing Facility
How many years
you spent & have
experience in
Pharmaceutical Mfg
Facility

8. Dispensing Errors
Imagine the magnitude & quantum?

9. You have to supervise dispensing of
materials for Tablet Verapamil 40 mg.
What care you have to take in
completing this task?
1

10. What, How & Why harm
If material dispensed in common environment
with common tools

11. What, How & Why harm
If material dispensed in common environment
with common tools

12. What, How & Why harm
If material dispensed in common environment
with common tools

13. Traceability
What, How & Why harm
If material dispensed in common environment
with common tools

14. ContaminationTraceability
What, How & Why harm
If material dispensed in common environment
with common tools

15. Mix up ContaminationTraceability
What, How & Why harm
If material dispensed in common environment
with common tools

16. Mix up ContaminationConsistencyTraceability
What, How & Why harm
If material dispensed in common environment
with common tools

17. Mix up ContaminationConsistencyTraceability
What, How & Why harm
If material dispensed in common environment
with common tools

18. Traceability
in
Dispensing Operation
What …?
How…?
Why …?

19. Contamination
in
Dispensing Operation
What …?
How…?
Why …?

20. Mix up
in
Dispensing Operation
What …?
How…?
Why …?

21. Dispensing of materials
(formulation ingredients) is done in
designated and dedicated area.
Please write what harms can occur, if it is
done in the mixing room?
2

22. Lets keep thinking
continued …
Facility
Air quality, flow & pattern
Cleaning & Maintenance

23. Dispensing Booth
Velocity to control stability in working area

24. Dispensing Booth
Velocity to control stability in working area
Turbulence controlled

25. Dispensing Booth
Velocity to control stability in working area
Turbulence controlled
Uniform flow design of main working
area to protect operator & cross-
contamination with material

26. Dispensing Booth
Velocity to control stability in working area
Turbulence controlled
Diff. pressure gauge for monitoring
Uniform flow design of main working
area to protect operator & cross-
contamination with material

27. Dispensing Booth
Velocity to control stability in working area
Easy to maintain & clean
Turbulence controlled
Diff. pressure gauge for monitoring
Uniform flow design of main working
area to protect operator & cross-
contamination with material

28. Lets keep thinking
continued …
Tools
Inert, non-reactive
Easy to Clean

29. Lets keep thinking
continued …
Material Flow
Uni-flow
Resistant to Mix up

30. Lets keep thinking
continued …
Handling
Logical & Safe Handling
Real time recording

31. Lets keep thinking
continued …
Gowning & Gloves
Logical & Safe
Safe De-gowning

32. Lets keep thinking
continued …
Operations
Attentive & Coordinated
Batch wise

33. Simultaneous dispensing is a risk
Where is high, where is higher & where is highest

34. Product X
5 Batches of same
strength & dosage form
Product X
5 batches of different
strength & different
dosage forms
Excipient X
5 batches of different
products of different
strengths
Simultaneous dispensing is a risk
Where is high, where is higher & where is highest
1 2 3

35. Simultaneous dispensing is a risk
Where is high, where is higher and
where is highest
1. Product X - 5 Batches of same strength & dosage form
2. Excipient X - 5 batches of different products of different
strengths
3. Product X - 5 batches of different strength & different
dosage forms
3

36. Lets keep thinking
continued …
Station & Holding
Physically secure
Controlled & Recorded

37. Control Strategy

38. Sanitization
K ,A, S

39. Insufficient size Inadequate space
Rough floor Rough walls
Rough ceiling Poor air filtration
Poor drains Inadequate washing space

40. Inappropriate design & size Corrosion potential
Dirt, lubricant Accumulation of static material
Difficult cleaning Difficult Maintenance
Defective equipment Improper calibration

41. Improper Sampling Improper Testing
Improper Labeling Contaminated . MO/ Chem
Degradation from exposure to excessive conditions
Sunlight, heat, cold Moisture etc.

42. Inappropriate cleaning Multiple use
Open dispensing system exposing product
Poor line clearance between batches
Labeling Effective Labeling

43. Organic materials accumulation in/near HVAC
Ineffective filtration of air supply
Insufficient magnitude of pressure differential
Erroneous ratio of fresh & re-circulated air
Non-directional air flow, malfunctioning etc.

44. An Unfortunate
PIC Tragedy

45. Dispensing without recording
Simultaneous operations in one place
Unsafe & Poor Human Supervision
Out put driven strategy w/o reasonable control

46. Ciprofloxacin & Pesticide
Drum Mix up

47. Ciprofloxacin tablet kept in
contaminated drum
Drum was not clean & kept
mixed during supply chain
Tragic deaths
Unsafe practices of handling
used & clean drums

48. Remember

49. You are not allowed to take risk, no matter how it is safe
because it is a regulatory obligation
Each and every
material must be
opened & closed in
controlled booth to
avoid contamination

50. You are not allowed to take risk, no matter how it is safe
because it is a regulatory obligation
Only clean scoops will
be used in dispensing
operation
Careful & justified risk
may be taken

51. Mal functioning of Air
Supply System

52. Traces of
penicillin
contaminated
with other
materials
during
weighing

53. Traces of
penicillin
contaminated
with other
materials
during
weighing

54. Traces of
penicillin
contaminated
with other
materials
during
weighing
Worst recall of all
finished goods
converted from
materials suspected to
be contaminated during
unsafe use of balance in
dispensing operation

55. Be clear
Please

56. Foreign Matter in Materials
Poorly maintained equipment & environment
Human Factor during handling

57. Dispensing of Materials & Components

58. Dispensing of Materials & Components
Adequate
supervision by a
second person
Second person
must examine and
assure

59. Dispensing of Materials & Components
Release
of the components
by the Quality
Identification
of the containers
Correct
weight as per
Batch Production
Records

60. Dispensing of Materials & Components
Release
Correct
Identification

61. From GMP Regulations
Protection
• Of material & product
from potential
unreasonable
contamination
Protection
• Of personnel from
potential
unreasonable
exposure of materials

62. From GMP Regulations
Protection
• Of material & product
from potential
unreasonable
contamination
Protection
• Of personnel from
potential
unreasonable
exposure of materials

63. From GMP Regulations
Adequacy
• Orderly & logical
placement to avoid
cross-contamination
etc.
Washing
• Cleaning equipment
& washing should
not be source of
contamination

64. From GMP Regulations
Adequacy
• Orderly & logical
placement to avoid
cross-contamination
etc.
Washing
• Cleaning equipment
& washing should
not be source of
contamination

65. From GMP Regulations
Sampling
• Via authorized
person with
qualified,
specified and
clean tools
Sampling
• Method of
sampling
• Sampling plan
• Equipment to be
used
Sampling
• Precaution to
avoid
contamination &
deterioration
Sampling
• Amount to be
taken
• Type of sampling
container
• Etc.

66. From GMP Regulations
Sampling
• Via authorized
person with
qualified,
specified and
clean tools
Sampling
• Method of
sampling
• Sampling plan
• Equipment to be
used
Sampling
• Precaution to
avoid
contamination &
deterioration
Sampling
• Amount to be
taken
• Type of sampling
container
• Etc.

67. From GMP Regulations
Sampling
• Via authorized
person with
qualified,
specified and
clean tools
Sampling
• Method of
sampling
• Sampling plan
• Equipment to be
used
Sampling
• Precaution to
avoid
contamination &
deterioration
Sampling
• Amount to be
taken
• Type of sampling
container
• Etc.

68. From GMP Regulations
Sampling
• Via authorized
person with
qualified,
specified and
clean tools
Sampling
• Method of
sampling
• Sampling plan
• Equipment to be
used
Sampling
• Precaution to
avoid
contamination &
deterioration
Sampling
• Amount to be
taken
• Type of sampling
container
• Etc.

69. GMP
Intent
To maintain
Consistency
To diminish
Contamination
To diminish
Cross-contamination
To avoid
Mix-up/Integrity
To maintain
Traceability
Intent of GMP Regulations

70. Types of
Contamination
Particulates
Micro-
organisms
Cross-
contamination
Intent of GMP Regulations

71. Types of Cross-contamination
PARTICULATES
Dust
Dirt
Paper
Metal
Fiber
Etc.
MICROORGANISMS
Bacteria
Yeast
Moulds
CROSS-
CONTAMINATION
Drug
Materials

72. Source of
contamination
Air
Water
SurfacePeople
Pest
Types of Cross-contamination

73. Mode by which contamination produces harm
Physical
Contamination
Chemical
Contamination
Biological
Contamination
Particle, Fiber etc.
Moisture, Molecules etc.
Bacteria, Fungus etc.

74. Lets think
Reduce human intervention Control Air
Control Water Control use of equipment
Adequate filtration of water Air flow
Air Locks HEPA Filtration
How to reduce or
control
contamination/
cross-contamination

75. Lets prevent contamination

76. Lets prevent contamination
All containers must
be effectively cleaned
before they enter into
storage area
Follow suitable
equipment cleaning
procedure
Periodically
validate to confirm
effectiveness

77. Lets prevent contamination

78. Lets prevent contamination
Please avoid
simultaneous
handling
two or more …
Different Batches
Different Stages
Different Products

79. Lets prevent contamination
Please avoid
simultaneous
unloading
two or more …
Different Batches
Different Stages
Different Products

80. How contamination/
cross-contamination can be reduced or
controlled during dispensing operation?
4

81. Intent of GMP Regulations
Entrance of
Transition to
Manufacturing
Manufacturing
Dispensing
Room

82. Intent of GMP Regulations
Careful
attention
Design
Layout
Operation

83. Material
Personnel
Principle derives the
design of dispensing
room
(raw material staging,
dispensing weighing,
working process staging)

84. Material
Personnel
Unidirectional
Flow

85. Hazardous
Non Hazardous
Principle derives the
design of dispensing
room
(raw material staging,
dispensing weighing,
working process staging)

86. Segregate …
Hazardous
Non Hazardous

87. Manufacturing items
Designated space
Principle derives the
design of dispensing
room
(raw material staging,
dispensing weighing,
working process staging)
Storage … Materials

88. Remember;
in GMP… 1, 2, 3

89. Sufficient
Space
To provide for every operation Is mandatory
1

90. Physical
separation
To provide for every operation Is mandatory
2

91. Adequate
Lighting, Ventilation,
Utensils, Equipment
& Facilities
To provide for every operation Is mandatory
3

92. Mix ups (during working and handling of
different materials) are universal
phenomena, it happens all across the
world.
5
Write reasons of mix up based on
your own understanding.

93. Why are their
perforations in the
working bench?
Design of Dispensing Booth

94. Why are their
perforations in the
working bench?
Design of Dispensing Booth

95. Why are their
perforations in the
working bench?
To minimize the
rebound probability &
to enhance smooth flow
of air downwards
Design of Dispensing Booth

96. What is the
relationship of height
of working bench
from air supply
Design of Dispensing Booth

97. What is the
relationship of height
of working bench
from air supply
Design of Dispensing Booth

98. What is the
relationship of height
of working bench
from air supply
Working bench should
be at an optimum
height
Too close or too far
from air supply can
cause unreasonable
turbulence
Design of Dispensing Booth

103. Remember;
See what is what and how

104. Physically
Safe & Secure?
Resistance
Document
Lock

105. Bulk holding
studies?

106. Bulk holding
Control?
Humidity
Inventory
Temperature

107. Inventory &
Reviews?

108. Deviations in
Handling of
Bulk Holding?

109. Label Controls?

110. Environment
classification

111. Immediate contact material during dispensing
Paper sheets Plastic bags
Must be
inert and clean

112. Real Case of Unknown Peak found as Contamination
Unknown peak
identified in 13
lots of
Misoprostol tablet
After delayed &
lengthy
investigation, it
was identified as
toulene
Probable source
loose ink in
blister packaging
line

113. Why?
Penicillin cannot be dispensed
in a shared dispensing booth
used for
other non-penicillin materials

114. How?
Microbial count is important to monitor
throughout the storage of
in-process materials

115. How do you see it?
Material found contaminated with
some black particles but
disappeared upon conversion into
finished product

116. How do you see it?
Black particles were not observed during
sampling & initial tests, but were
visible in dispensing
It was filled & converted into finished
product, while finished product qualified
all the tests

117. API (Paracetamol) was sampled from 20
drums of same batch of same material with
same spatula/thief
The thief was not cleaned during sampling as
it was not in procedure
Drum No. 3 was found wrongly labeled as
Paracetamol & failed in identity test
Think
? Same

118. Possible Scenarios ….

119. Think
?
It was drum
of ibuprofen
API (Paracetamol) was sampled from 20
drums of same batch of same material with
SAME spatula/thief
The thief was not cleaned during sampling as
it was not in procedure
Drum No. 3 was found wrongly labeled as
Paracetamol & failed in identity test

120. Think
?
It was drum
of ethinyl
estradiol
API (Paracetamol) was sampled from 20
drums of same batch of same material with
SAME spatula/thief
The thief was not cleaned during sampling as
it was not in procedure
Drum No. 3 was found wrongly labeled as
Paracetamol & failed in identity test

121. Think
?
It was drum
of penicillin
API (Paracetamol) was sampled from 20
drums of same batch of same material with
SAME spatula/thief
The thief was not cleaned during sampling as
it was not in procedure
Drum No. 3 was found wrongly labeled as
Paracetamol & failed in identity test

122. Think
?
It was drum
of
paracetamol
but another
batch
API (Paracetamol) was sampled from 20
drums of same batch of same material with
SAME spatula/thief
The thief was not cleaned during sampling as
it was not in procedure
Drum No. 3 was found wrongly labeled as
Paracetamol & passed in identity test but
remain question on GMP

123. Boeringher Germany Nov 2012-13
Failed to thoroughly investigate the
source of foreign particles in an API
2008-09 Contaminated lots
Did not start formal project for CAPA

124. Boeringher Germany Nov 2012-13
Failed to
reject
capsules
contaminated
with foreign
particles
During weighing & visual inspection
200 micron to 5 mm, 0.4 ug to 9 mg
Final specifications were compliant
?

125. Boeringher Germany Nov 2012-13
?
Failure of Control Strategy
Failure of Standards and Specifications
Failure of Investigations, CAPA, Quality System

126. Boeringher Germany Nov 2012-13
?
Management
Decision to keep
adulterated drug in
market

127. RISK

128. RISK
S
E
V
E
R
I
T
Y

129. RISK
P
R
O
B
A
B
I
L
I
T
Y

130. RISK
D
E
T
E
C
T
A
B
I
L
I
T
Y

131. Detectable and controlled lion Less detectable & free small snack
Which is Dangerous

132. Fall less frequently (1 time in a month) Fall more frequently (10 times in a month)
Which is Dangerous

133. Combination of the probability of occurrence
of harm and the severity of that harm

134. The
investigation of
risks
is at once a
scientific activity
and an
expression of
culture
Managing Risk
is a Behavior

135. Parameters for “calculating” Risk
• PastProbability
• TodayDetectability
• FutureSeverity
T
I
M
E
Risk Priority Number

136. T
O
T
A
L
S D P

137. T
O
T
A
L
S D P
Identify Assess Manage Mitigate

138. T
O
T
A
L
S D P
Identify Assess Manage Mitigate

139. T
O
T
A
L
S D P
Identify Assess Manage Mitigate

140. T
O
T
A
L
S D P
Identify Assess Manage Mitigate

141. Lets see how it works
Road Traffic Pedestrian

142. Lets see how it works
Without
Stop Board
With
Stop Board

143. Lets see how it works Stop Sign
2 Multiply by 3 Multiply by 10 = 60
D P S T

144. Lets see how it works Stop Sign
Light
2 Multiply by 2 Multiply by 10 = 40
D P S T

145. Lets see how it works Stop Sign
Light
Pedestrian
sign
2 Multiply by 1 Multiply by 10 = 20
D P S T

146. Lets see how it works Stop Sign
Light
Pedestrian
sign
Back
Counting
1 Multiply by 1 Multiply by 10 = 10
D P S T

147. Probability
SeverityDetectability
Risk Management Example
R I S K
H M L

148. Reference
Quality Risk Management in Pharmaceutical Dispensing Center
M. Chitmetha, S. Prombanpong, and T. Somboonwiwat
International Journal of Chemical Engineering and Applications,
Vol. 4, No. 4, August 2013
Risk Management Example

149. ProbabilitySeverity
Calculate Risk

150. Risk Assessment Matrix
Severity
Probability
Frequent Likely Occasional Not often Unlikely
Catastrophic E E H H M
Critical E H H M L
Marginal H M M L L
Negligible M L L L L

151. 1. Description
• Scale &
Weight
2. Failure
Mode
• Incorrect
reading
3. Possible
causes
• Scale not in
the correct
position
Equipment Analysis 1

152. 4. Local Effect
• Wrong weight
of starting
materials
5. Final Effect
• Sub-standard
drug
6. Compensating
Action
• Daily check
and self-check
before use
Equipment Analysis

153. 1.DESCRIPTION
• Scale and
weight
2. FAILURE
MODE
• Incorrect
reading
3. POSSIBLE
CAUSES
• Load cell error
Equipment Analysis 2

154. 4. LOCAL
EFFECT
• Incorrect
weight of
starting
materials
5. FINAL
EFFECT
• Sub-standard
drug
6.
COMPENSATI
NG ACTION
• Calibration
every 3
month &
Daily check
Equipment Analysis

155. 1. DESCRIPTION
• HVAC System
2. FAILURE
MODE
• Humidity
uncontrolled
3. POSSIBLE
CAUSES
• Dehumidifier
malfunction
Equipment Analysis 3

156. 4. LOCAL EFFECT
• Too much
moisture in
materials
5. FINAL EFFECT
• Quality of
Product
6.COMPENSATING
ACTION
• Calibration,
Control
Equipment Analysis

157. 1.
DESCRIPTION
• HVAC
System
2. FAILURE
MODE
• Temperature
uncontrolled
3. POSSIBLE
CAUSES
• Compressor/
electronics
breakdown
Equipment Analysis 4

158. 4. LOCAL EFFECT
• Materials
spoiled
5. FINAL EFFECT
• Quality of
Product
6. COMPENSATING
ACTION
• Periodic
preventive
maintenance
Equipment Analysis

159. 1. DESCRIPTION
• HVAC
System
2. FAILURE
MODE
• Pressure
uncontrolled
3. POSSIBLE
CAUSES
• AHU
breakdown
or door
problem
Equipment Analysis 5

160. 4. LOCAL EFFECT
• Unclean room
5. FINAL EFFECT
• Contamination
6. COMPENSATING
ACTION
• Annual
calibration
Equipment Analysis

161. 1. DESCRIPTION
• Transfer starting
material from
unclassified area
to classified/
dispensing area
2. FAILURE
MODE
• Wrong delivery
starting material
to classified
/dispensing area
3. POSSIBLE
CAUSES
• Human error
Operations Analysis 1

162. 4. LOCAL
EFFECT
• Delay the
schedule
5.FINAL EFFECT
• Rework
6.COMPENSATING
ACTION
• Double check
by operator in
dispensing
area
Operations Analysis

163. 1. DESCRIPTION
• Transfer starting
material from
classified area to
dispensing booth
2. FAILURE MODE
• Wrong delivery of
starting material to
dispensing booth /
Receive wrong Lot
No. of starting
materials
3. POSSIBLE
CAUSES
• Human error
Operations Analysis 2

164. 4. LOCAL EFFECT
• Weigh wrong
starting
materials/starting
materials mixing
Lot No.
5. FINAL EFFECT
• Sub-standard
Drug/Impact to
FIFO and
Traceability
system
6. COMPENSATING
ACTION
• Review and
remove the cause
that influence in
decision of
material
movement
Operations Analysis

165. 1.
DESCRIPTION
• Data logging
2. FAILURE
MODE
• Entry
incorrect data
3. POSSIBLE
CAUSES
• Human error
Operations Analysis 3

166. 4. LOCAL EFFECT
• Non
traceability
problem &
incorrect data
being use
5. FINAL EFFECT
• Sub-standard
Drug
6. COMPENSATING
ACTION
• Double check
by second
person
Operations Analysis

167. 1.
DESCRIPTION
• Dispense bulk
pack of
starting
materials
2. FAILURE
MODE
• Dispense
incorrect type,
quantity, Lot
No. of starting
materials
3. POSSIBLE
CAUSES
• Human error
Operations Analysis 4

168. 4. LOCAL EFFECT
• Wrong
ingredients/
starting materials
mixing Lot No.
5. FINAL EFFECT
• Impact to FIFO
and Traceability
system
6. COMPENSATING
ACTION
• ????
Operations Analysis

169. 1. DESCRIPTION
• Labeling
2. FAILURE
MODE
• Wrong label
on weighed
starting
materials pack
3. POSSIBLE
CAUSES
• Human error
Operations Analysis 5

170. 4. LOCAL
EFFECT
• Wrong
ingredients
5. FINAL EFFECT
• Sub-standard
drug
6.
COMPENSATING
ACTION
• ????
Operations Analysis

171. 1.
DESCRIPTION
• Sortation
2. FAILURE
MODE
• Mix up of
weighed
materials
3. POSSIBLE
CAUSES
• Human error
Operations Analysis 6

172. 4. LOCAL
EFFECT
• Wrong
ingredients
5. FINAL EFFECT
• Mix up
6.
COMPENSATING
ACTION
• Double check
before execute
to bundle
Operations Analysis

173. 1.
DESCRIPTION
• Placing of
bundle
2. FAILURE
MODE
• Mix up of
bundle with
bulk pack
3. POSSIBLE
CAUSES
• Human error
Operations Analysis 7

174. 4. LOCAL
EFFECT
• Wrong
ingredients
5. FINAL EFFECT
• Mix up
6.
COMPENSATING
ACTION
• ????
Operations Analysis

175. 1.
DESCRIPTION
• Cleaning
return grill
2. FAILURE
MODE
• Strain
remaining at
return grill
3. POSSIBLE
CAUSES
• Improper
cleaning
Operations Analysis 8

176. 4. LOCAL
EFFECT
• Poor quality
5. FINAL EFFECT
• Cross-
contamination
6.
COMPENSATING
ACTION
• SOP and
Training
Operations Analysis

177. 1. DESCRIPTION
HVAC System
2. FINAL EFFECT
Contamination
3. COMPENSATING
ACTION
Annual Calibration
Summary of High Risk Failure Modes

178. 1. DESCRIPTION
Materials Transfer
2. FINAL EFFECT
Sub-standard drug
3. COMPENSATING
ACTION
????
Summary of High Risk Failure Modes

179. 1. DESCRIPTION
Data logging
2. FINAL EFFECT
Sub-standard drug
3. COMPENSATING
ACTION
Double check
Summary of High Risk Failure Modes

180. 1. DESCRIPTION
Labeling
2. FINAL EFFECT
Sub-standard drug
3. COMPENSATING
ACTION
???
Summary of High Risk Failure Modes

181. Actions to Mitigate Risks

182. Description HVAC System
Final Effect Pressure Uncontrolled
Proposed
mitigation action
Door redesign ... Preventive maintenance for
AHU with warning system ….
Pressure gauge daily check

183. Description Materials Transfer
Final Effect
Wrong delivery & receive wrong materials
Visual check
Proposed
mitigation action
Design queue for starting materials based on
weighing schedule plan

184. Description Data logging
Final Effect Entry Incorrect data
Proposed
mitigation action Encoder and decoder equipment ….

185. Description Labeling
Final Effect Wrong label on weighed material pack
Proposed
mitigation action
Barcode system/ Label Control system for data entry
Combination of new business model and barcode system

186. Take Home Message
It is unacceptable as a
matter of cGMP to
continue manufacturing
drugs with shared
equipment …
Practically
Penicillin etc.
Non-pharmaceutical
products
Pesticides etc.

187. Take Home Message
It is unacceptable as a
matter of cGMP to
continue manufacturing
drugs with shared
equipment …
Practically
1. Cross-
contamination
2. Sensitivity
knowledge
3. Cleaning
techniques

188. Thank You