Managing Science Based Regulatory Drive for Ensuring Drug Quality (260 Slides)

1. Managing Science Based Regulatory Drive
for Ensuring Drug Quality
Obaid Ali & Roohi B. Obaid
Civil Services Officers, Drug Regulatory Authority of Pakistan
Organized by
COMSATS Institute of Information Technology &
Management Association of Pakistan
at
Marriott Hotel, Karachi
03 May 2017

3. D
I
S
C
L
A
I
M
E
R
Personal Point
of View
No
Obligation
on DRAP
Knowledge &
Experience
Current
Judgment
This presentation discusses science and has nothing to do with
any commercial Product.

5. Thinking Process & Critical Thinking in
Pharmaceutical Affairs
(Case Studies)
Obaid Ali, R. Ph., Ph. D
Federal Inspector of Drugs, DRAP
Member ISPE & PDA

6. Back Mirror Messages
Gut & Ultra Sounds
Strategy to Move

7. Back Mirror Messages
Gut & Ultra Sounds
Strategy to Move

8. Do we have confidence that the incidences, tragedies
and events I am going to discuss will not happen again
Keep your thinking process open and let us know at the
end, what we have done so far

9. Thalidomide Tragedy
Teratogenic effect
that changed the
world & strategy
of regulation

10. Diethylene Glycol Tragedy
A number of tragedies
across the world
USA, Haiti, India

11. Heparin Tragedy

12. DIDP Incidence
Worst recall of Augmentin 2011
Tablets in China, Taiwan, Hong
Kong etc.
No death reported but forced to
recall
Di-iso dodecyl phthalate
(plasticizer)

13. Pyrimethamine Tragedy
Have you checked and rechecked that
this will not happen with you?

14. Vioxx Withdrawal
Rofecoxib introduced in
1999
Heart attack & Stroke
Withdrawn in 2004-05
Heavy compensation
60,000 patients alleged to be
died

15. Paracetamol Tablet & Soft Gel Capsule Failures
Huge recall
Factory close up
Loss of jobs and
market share

16. Phenyl Propanol Amine
Withdrawal
Enjoyed market for 60
years
Withdrawn in 2000
Stroke potential
01 in 0.1 to 3 million

17. Fenfluramine/ Phenteramine
Withdrawal
Wyeth product for obesity treatment
Withdrawn after 24 years
In 1997
Heart disease & Pulmonary issues
14 Billion dollar fine
Collective loss is about 21 billion
dollar

18. Aprotinin Withdrawal
Drug used to stop bleeding
during open heart surgery
killed a lot of patients
(alleged to be 22, 000)
Withdrawn in 2008

19. Baycol Withdrawal
Cerivastatin
Approved 1997
Withdrawn in 2001
30-50 deaths reported
Rhabdomyolysis
Over a billion dollar paid

20. Terfenadine Withdrawal
Hoechst product
Wthdrawan in 1997
Cardiac arrhythmia
potential caught by FDA

21. PPIs Signal of Bone problems
Incidence Sense Hypothesis Investigate Conclude

22. PPIs labels are modified
Risk of fractures of the hip, wrist, and spine with
PPIs

23. Manage Mitigate Withdrawal

24. Back Mirror Messages
Gut & Ultra Sounds
Strategy to Move

25. Trend

26. Personal experience as a 08 hour
regulator and 16 hour consumer
Contamination Consistency
Document
integrity
Stability
Dissolution Mix up Poor control Bad odor
Bad taste Discoloration
Coating
Defects

27. Metrics
Approach
Culture of
Quality

28. An environment where every person understands Product
Quality & Patient Safety
Where everyone willingly takes responsibility for patient
protection and quality of product, where patient is centre
of everything
Single most important indicator to determine the ability of
delivering the quality drugs

29. Quality
Metrics
Indicator of
operational reliability Quality Culture

30. Quality
Metrics
Lot
Acceptance
Rate
Product
Quality
Complaint
Rate
Right first
time Rate
Invalidated
OOS Rate
APR or PQR
on time Rate
CAPA Rate
Ability to
initiate
voluntary
CAPA

31. Brand Name
analysis
Trade Dress
Analysis
Signal detection

33. Expand your knowledge
Contribute and increase share in the world’s knowledge
Lets walk with grace and dignity

34. Start small,
Learn, Evolve
From ISPE
Think big,
but Start

36. Understanding of Product & Process
For Installation of Appropriate Controls
Roohi B. Obaid, R.Ph.
Civil Service Officer at DRAP
Member ISPE & PDA

37. Back Mirror Stories
Tools and approaches to
move forward
Radar and Navigation
Focus
Cont’d
1/6
2/6
3/6

38. Criticality, Risk &
Controls
Connecting the Dots
(with an Example)
Evolving Changes in
CTD
Focus 4/6
5/6
6/6

39. Back Mirror Stories1

40. Lets have a look & walk through real cases

41. 05 Feb 2017
Bupripion HCl ER

42. 2.7 lakh bottle
Dissolution failure
At 18 month of
stability

43. Does anybody want to see such news early morning?

44. Does anybody want to see such news early morning?
Are you confident it will not happen with you?

45. Does anybody want to see such news early morning?
Are you confident it will not happen with you?
Don’t assume but
keep respecting
science

46. Does anybody want to see such news early morning?
Are you confident it will not happen with you?
Don’t assume but
keep respecting
science
Understand your
product &
process

47. Does anybody want to see such news early morning?
Are you confident it will not happen with you?
Don’t assume but
keep respecting
science
Understand your
product &
process
Before it
happens

48. Drug quantity is
correct

49. Drug quantity is
correct
Drug is not available
for absorption

50. Drug quantity is
correct
Drug is not available
for absorption
Do you expect
effect?

51. Therapeutic
effect under
question

52. Therapeutic
effect under
question
Disease may progress

53. Therapeutic
effect under
question
Disease may progress
A series of
consequences
may emerge

54. Therapeutic
effect under
question
Disease may progress
A series of
consequences
may emerge

55. Therapeutic
effect under
question
Disease may progress
A series of
consequences
may emerge
Pain killers

56. Therapeutic
effect under
question
Disease may progress
A series of
consequences
may emerge
Pain killers Cardiac drug

57. Therapeutic
effect under
question
Disease may progress
A series of
consequences
may emerge
Pain killers Cardiac drug Anti epileptic drug

59. 2013
Amidate Injection
(Etomidate)

60. Degradation during
stability
Hospira & Pfizer product

61. Tools & Approaches to move forward2

62. Why How

63. Traditional
Enhanced
Approaches

64. Identify
potential
CQAs
1 Define Mfg
Process
2 Define
Control
Strategy
3

65. SystematicEvaluation&
Understanding
1
Functionalrelationshipthat
linkMA&PPtoCQAs
2
QRMtoestablish
appropriateControlStrategy
forDesignSpace
3

66. Systematic Evaluation &
Understanding
1/3

67. Functional relationship that
link MA & PP to CQAs
2/3

68. QRM to establish
appropriate Control
Strategy for Design Space
3/3

69. A systematic approach to acquiring, analyzing,
storing and disseminating information related to
product, manufacturing process and components
A Systematic process for the assessment, control,
communication and review of risk to the quality
of the drug product across the product lifecycle
Knowledge
Management
Quality Risk
Management

70. Radar & Navigation3

71. Top Reasons for Recalls

72. 125% 75%
98%
102%

73. 1
Super or sub potent formulations
Digoxin (double
thickness)
Actavis 2008

74. 1
Super or sub potent formulations
Digoxin (double
thickness)
Actavis 2008
Poor Manufacturing Control

75. 1
Super or sub potent formulations
Morphine (double size)
KV Pharmaceuticals 2008
Company closed because
they knew the problem &
failed to inform FDA
Fine of 27.6 million USD

76. 1
Super or sub potent formulations
Morphine (double size)
KV Pharmaceuticals 2008
Company closed because
they knew the problem &
failed to inform FDA
Fine of 27.6 million USD
Poor Manufacturing Control

77. 2
Particulate Contamination
Takeda, Millenium &
Janssen anti-cancer product
Particulates were seen after
reconstitution
Europe, America & Asia
Polyester like material
originated from filtration
system

78. 2
Particulate Contamination
Takeda, Millenium &
Janssen anti-cancer product
Particulates were seen after
reconstitution
Europe, America & Asia
Polyester like material
originated from filtration
system
Wrong sort of container used
to store highly acidic or
basic solution

79. 2
Particulate Contamination
Takeda, Millenium &
Janssen anti-cancer product
Particulates were seen after
reconstitution
Europe, America & Asia
Polyester like material
originated from filtration
system
Glass, silicon & stainless steel …. …in the
glass used to manufacture vials and other
containers.
wear and tear of machinery, abrasion of
stoppers and plungers …in the glass used to
manufacture vials and other containers.

80. 2
Particulate Contamination
Takeda, Millenium &
Janssen anti-cancer product
Particulates were seen after
reconstitution
Europe, America & Asia
Polyester like material
originated from filtration
system
Inadequate understanding of
the product and process

81. 3
API’s Contamination
Bulk heparin in China
Over sulfated Chondroitin
Sulfate
80 deaths in USA alone
Found deliberated &
economically motivated

82. 3
API’s Contamination
Bulk heparin in China
Over sulfated Chondroitin
Sulfate
80 deaths in USA alone
Found deliberated &
economically motivated
Weak supply chain
Unknown contaminant later
named OSCS

83. 3
API’s Contamination
GSK Worthing UK facility
July 2015
Bactobran cream
containing Mupirocin
recalled

84. 3
API’s Contamination
GSK Worthing UK facility
July 2015
Bactobran cream
containing Mupirocin
recalled
API Mupirocin
contaminated with penicillin &
foreign substances during Mfg
process

85. 3
API’s Contamination
GSK Worthing UK facility
July 2015
Bactobran cream
containing Mupirocin
recalled
Inadequate Controls to
Prevent contamination

86. 3
API’s Contamination
Attix Pharmaceuticals
Canada (April 2015)
A Repackager recalled
hundreds of bulk API
cross-contaminated by
penicillin
Failed to use separate
facilities or equipments

87. 3
API’s Contamination
Attix Pharmaceuticals
Canada (April 2015)
A Repackager recalled
hundreds of bulk API
cross-contaminated by
penicillin
Failed to use separate
facilities or equipments
Inappropriate practice during operations
Personnel & material movement, use of
non-dedicated facilities

88. 3
API’s Contamination
Attix Pharmaceuticals
Canada (April 2015)
A Repackager recalled
hundreds of bulk API
cross-contaminated by
penicillin
Failed to use separate
facilities or equipments
Cleaning is not
a substitute for
segregation

89. 3
API’s Contamination
Attix Pharmaceuticals
Canada (April 2015)
A Repackager recalled
hundreds of bulk API
cross-contaminated by
penicillin
Failed to use separate
facilities or equipments
Cleaning is not
a substitute for
segregation
No safe level of
penicillin
contamination has
been determined to
be a tolerable risk

90. 3
Contamination
Misoprostol Pharmacia
Peak gave signal but
ignored (13 lots)
Later contaminant
identified to be toluene

91. 3
Contamination
Misoprostol Pharmacia
Peak gave signal but
ignored (13 lots)
Later contaminant
identified to be toluene
Loose ink in blister packaging line

92. 3
Contamination
Misoprostol Pharmacia
Peak gave signal but
ignored (13 lots)
Later contaminant
identified to be toluene
Loose ink in blister packaging line
Diethylphthalate (DEP) … from
desiccant cartridge

93. 3
Contamination
Misoprostol Pharmacia
Peak gave signal but
ignored (13 lots)
Later contaminant
identified to be toluene
Loose ink in blister packaging line
Diethylphthalate (DEP) … from
desiccant cartridge
Cause could not be assigned
whether a residue from API or
improper packaging ….

94. 4
Sterility Failure
Various drugs for potential
sterility failure found
contaminated with
pathogenic organisms
High threat for HIV, Cystic
Fibrosis or TB

95. 4
Sterility Failure
Various drugs for potential
sterility failure found
contaminated with
pathogenic organisms
High threat for HIV, Cystic
Fibrosis or TB
Poor manufacturing & environmental
control

96. 5
Contamination with TBA
Bad odour in product
J&J 2009
Pfizer 2010
TBP, a wood preservative
for pallets converted to
TBA giving bad odour

97. 5
Contamination with TBA
Bad odour in product
J&J 2009
Pfizer 2010
TBP, a wood preservative
for pallets converted to
TBA giving bad odour
Poor control and desensitized alarms,
throwing away of wake up calls, ended
up with largest recall

98. 6
Disintegration Failure
Soft gel capsule failed in
disintegration
Millions of capsules
recalled
Company shut down for
a long time

99. 6
Disintegration Failure
Soft gel capsule failed in
disintegration
Millions of capsules
recalled
Company shut down for
a long time

100. 6
Dissolution failure
100’s of batches of
Paracetamol tablet
failed in Dissolution

101. 6
Dissolution failure
100’s of batches of
Paracetamol tablet
failed in Dissolution

102. 7
Manufacturing with poor knowledge
Rivaroxaban Tablet
Failure in CDP

103. 7
Manufacturing with poor knowledge
Rivaroxaban Tablet
Failure in CDP

104. 7
Manufacturing with poor knowledge
Ramipril tablets
Process degradation
found

105. 7
Manufacturing with poor knowledge
Ramipril tablets
Process degradation
found

106. Criticality, Risk & Controls4/6

107. Criticality, Risk & Controls
Assess Production Process for
CPP Controls are
additional to
Standard Level of
Control
5 Step
Approach
What is
critical &
how to
control it

108. 1/5
Layout the process parameters in each step

109. 1/5
Layout the process parameters in each step
1, 2, 3, 4, 5, 6, …
List down all operations, parameters, units

110. 2/5
Compile experimental conditions
(target, proven, operating ranges) &
establish design space

111. 2/5
Purpose proven
Range 20-160
Design Space
30-150
Expected Control
Range40-140
Operating
Range
60-120
Target
80-100

112. 3/5
Understand the consequences of high
and low points of a range overlay the
likely production control capabilities

113. 3/5
Understand the consequences of high and
low points of a range overlay the likely
production control capabilities
Consequences
Going out

114. 4/5
Assess the risk of the process parameters on
quality (CQA) to determine if it is a likely CPP
and consider needed control

115. 4/5
Assess the risk of the process parameters on
quality (CQA) to determine if it is a likely CPP
and consider needed control
Severity
Probability

116. 5/5
Assess what additional work is needed to
determine if parameter is characterized as CPP

117. 5/5
Assess what additional work is needed to
determine if parameter is characterized as CPP
Impact on CQA
Risk of Failure
outside proven
Range

118. Connecting the Dots5/6

119. Why How
e.g. Saxagliptin

120. Saxagliptin
Case Study
Chirstine M.V. Moore, FDA
Stephen Liebowtiz, BMS
Lets see how Knowledge Management &
Quality Risk Management is used

121. A systematic approach to acquiring, analyzing,
storing and disseminating information related to
product, manufacturing process and components
A Systematic process for the assessment, control,
communication and review of risk to the quality
of the drug product across the product lifecycle
KM
QRM
Saxagliptin

122. Pharmaceutical
Development
Formulation
Development
Scale up
Mfg Process
Development
Saxagliptin

123. Lifecycle
Pharmaceutical
Development
Commercial
Manufacturing
Technology
Transfer
Pharmaceutical
Development
Formulation
Development
Scale up
Mfg Process
Development
Saxagliptin

124. Cyclization
Occurs in solid & solution state
Accelerate with commonly used excipients
Accelerate when processed under wet and dry
granulation
Acidic environment stabilizes
S
A
X
A
G
L
I
P
T
I
N

125. The enhanced pharmaceutical development used risk
assessment and DOE to evaluate criticality
of Process Parameters and Support Development of the
Control Strategy and Design Space
S
A
X
A
G
L
I
P
T
I
N

126. Expanded data leveraged to develop the mechanistic
model of the coating operation used to predict Process
Performance
The enhanced pharmaceutical development used risk
assessment and DOE to evaluate criticality
of Process Parameters and Support Development of the
Control Strategy and Design Space
S
A
X
A
G
L
I
P
T
I
N

127. Expanded data leveraged to develop the mechanistic
model of the coating operation used to predict Process
Performance
Product quality is assured through
Manufacturing Process Control combined with
Conventional End Product Testing
The enhanced pharmaceutical development used risk
assessment and DOE to evaluate criticality
of Process Parameters and Support Development of the
Control Strategy and Design Space
S
A
X
A
G
L
I
P
T
I
N

128. Cyclization
Occurs in solid & solution state
Accelerate with commonly used excipients
Accelerate when processed under wet and dry
granulation
Acidic environment stabilizes
S
A
X
A
G
L
I
P
T
I
N

129. Coating
contains Drug
Placebo
Tablet
Drug product
strategy
Critical
manufacturing
step ?
COATING
S
A
X
A
G
L
I
P
T
I
N

130. What may go wrong … Analysis of Variables
Steps
• Coater
Design
• Accessories
Movement
• Pan Load
• Pan Rotation
speed
• Baffle design
Spraying
• Rate
• Nozzle
design
• Air to liquid
ratio
• Nozzle tablet
distance
• Suspension
homogeneity
Drying
• Inlet
temperature
• Air volume
• Air humidity
S
A
X
A
G
L
I
P
T
I
N

131. Acquired knowledge ….
Quality
Attributes
identified after
assessment are
CU & Potency
Design space
established using
fundamental
process
understanding,
modeling & DOE
Predictive model
of CU & Potency
created for the
coating steps

132. Drug Product
Critical
Quality
Attributes
Potential
Critical Process
Parameters
Critical
Process
Parameters
Critical steps
Additional control
points beyond
standard unit
operation controls
Data Analysis to define a Control Strategy

133. Changes in CTD6/6

134. Changes in CTD
An Evolving Landscape of leading Regulatory Agency
Ref: US-FDA (May 22nd 2015)

135. Established Conditions & Control Strategy

136. Established Condition (EC)

137. Established
Conditions
Product
Description
Mfg Process
Description
Facilities
and
Equipment
Elements of
associated
Control
Strategy
Changes to
the
established
conditions
MUST be
reported to
the
Regulatory
Authority
EC

138. Control Strategy (CS)

139. Current product
understanding
Current process
understanding
Planned set
of controls
Control Strategy
(Set of Controls)
Assures
Process performance &
Product quality
CS

140. What is Process Performance???
Ability of the process to RELIABLY
produce a quality product

141. Elements of Control Strategy
(ECS)

142. Drug substance Excipients
In-process
materials
Drug product
materials
Facility &
Equipment
Operating
Conditions
In-process controls
Finished product
specifications
Associated
methods &
Frequency of
monitoring
Associated
methods &
Frequency of
sampling
Associated
methods &
Frequency of
testing
Associated
methods &
Frequency of
control
Etc.
Parameters and attributes related toECS

143. ECS that can be considered part of EC
DS/DP (including in-process materials) manufacturing & testing
facilities
Source of and specifications for starting materials for biological
products
Process, including in-process tests and sequence of operations,
equipment, and process parameters and their ranges
Cont’d

144. Specifications including the tests, analytical procedures and
acceptance criteria, including specifications for the DS, other
components, in-process materials and the DP
Container closure system, components and specifications
Maintenance strategy for chemometric and/or multivariate models
(e.g. for models that have a high impact on product quality
ECS that can be considered part of EC

145. Control
Strategy
Control
Strategy
Elements
reported in an
application
Established
conditions
Relationship
of CS & EC

146. Elements of Control Strategy NOT generally considered
“Established Conditions”
Batch
Records
Development
Data
Characterization
Data
Validation
Data
Batch
Analysis
Data

147. Robust Pharmaceutical Quality System
Important, Critical and Indispensible
Recap

148. Performance
Critical to assure that Drug
Product is manufactured to
meet the attributes of
Desired
Quality

149. Capable and trustable
to fulfill label claim &
regulatory expectations

150. Closing Words
Audit
communicate &
monitor your
suppliers
Understand CQA
of your product
Understand CPP
of your process
Validate your
process

151. Closing Words
Develop a
Control
Strategy
Maintain
your
equipments
& facility
Trend and
monitor all
the
components
Modify the
Control
Strategy if
required
Maintain the
state of
control

152. Safe,
efficacious
& have
correct
identity
Deliver the
same
performance
as claimed
Perform
consistently
over shelf
life
Made in a
manner that
ensure
quality
Will be
available
when
needed

154. Pakistan’s Pharmaceutical
Scientific & Regulatory Practices
Obaid Ali, R. Ph., Ph. D
Federal Inspector of Drugs, DRAP
Member ISPE & PDA

155. Regulatory
Scientific
Way to move ahead
1
2
3

156. 1
Organizational
Competency &
Capability
2
Pre & Post-
market
Reviews
3
Compliance
&
Enforcement
Regulatory Issues
4
Harmonization
& Global
Compatibility
5
Inherent
resistance to
change

157. Organizational Competency & Capability
Educational
Support
Continuous
Training
Discussion
Forums
Scientific
Dialogues
Structure &
Willingness

158. Pre & Post Market Reviews
Subject based
Reviews
Cross
functional
Reviews
Summary of
Approval
Complete
Response
Communication
Signal
Detection &
Safety Alerts
Monitoring &
Lifecycle

159. Compliance & Enforcement
Site Visit, Tour &
Inspection
Practices
Inconsistent
Inspection
Approaches
Inspector
Discretion &
Polarization
Wrong Tools &
Prioritization
In predictive &
Insecure Working
Environment
Progressive
Roadmap
Uncertainty

160. Compliance and Inspections
Resource
Preparation for
Inspection
On manufacturing
site
Post Inspection
Focused
04 working
days
08 working
days
04 working
days
Integrated
90 working
days
55 working
days
15 working
days

161. Harmonization & Global Incompatibility
ICH PIC/S
Regional
Cooperation
MOU/MRA
Joint
Programs
Exchange
Programs

162. Inherent Resistance to Change
Incompetency Fear of loss Lack of Vision
Knowledge
Gap
Organizational
Ego

163. Product
Development
& Bio-studies
Critical
Quality
Attributes
Blindness
Chemistry,
Manufacturing
& Controls
Manufacturing
Controls &
Inherent
Believes
Major Scientific Issues

164. Shelf Life
& Stability
Claims
Labeling,
Promises &
Negligence
Post
marketing
Surveillance
& Vigilance
Quality
Metrics &
Culture
Major Scientific Issues

165. Product
Development &
Bio-studies
Product Understanding
Process Understanding
Chemistry, Manufacturing
& Controls/CTD
Bioequivalence, BCS & Comparative
Dissolution Profile

166. Critical Quality
Attributes
Blindness
Operational Excellence Misuse
Wrongly Applied Six/Lean Sigma Approach
Dissolution, Content Uniformity, Sterility Etc. Tests
Waiver from End Product Testing
Aseptic Operations without Media Fill, Smoke
Studies Etc.

167. Chemistry,
Manufacturing &
Controls
Drug Master File & Supplier Qualification
Scale up, Process Controls & Manufacturing
Bulk Holding, Container Closure & Stability
Transportations & Storage

168. Manufacturing
Controls &
Inherent Believes
Processing, Technology & Maintenance in
Manufacturing to demonstrate Consistency
Contamination, Cross-contamination reasonably
Heavy, Crossed Traffic Flow & Mix up potentials
Tracking, Tracing, Reliability & Integrity

169. Shelf life &
Stability Claims
Retest & Stability Studies
Meaningless Batch Sizes used for Stability
Contrary Testing Frequency with the agreed ICH
Walking with Misconceptions & Believes without
Science

170. Labeling
Promises &
Negligence
Labels contrary to Innovators
Hiding of Facts & Potential Threats
Absence of Boxed Warnings & Black Box Warning
Smart Promotion of Off Label Use

171. Post Marketing
Surveillance &
Vigilance
Quality Attributes
Complaints Management
Pharmaco-epidemiology
Pharmaco-ecomomics

172. Quality Metrics
& Culture
Indicators of Operational Reliability
Patient is Centre of Everything
Leadership Emphasis on Quality
Employee Empowerment in Decision Making

173. Regulatory Issues & Way to move Forward

174. Simplification
in Regulations
Optimization
Initiatives
Centralized
Submissions
Scientific Issues & Way to move Forward
Third Party
Inspections
Data
Standardization

175. Simplification
in
Regulations
Clear Regulations
Science based
Risk based
Predictive & Certain

176. Optimization
Initiatives
Identify & Cut Overlapping
Align with Global Language
Focus on Science & Risk
Be Smart & Progressive

177. Centralized
Submissions
Online & Computerized
Question based & Uniform
Cross Functions Integration
Efficiency Monitoring

178. Third Party
Inspections
Focus on Importing Country
Prioritization Scale
Reliance & Confidence
MOUs & MRAs

179. Data
Standardization
Common Regulatory Language
Common Format
Reliable Tools
Within ICH Guidance

180. Scientific Issues & Way to move Forward

181. Assess
Capacity &
Capability
Develop
Compliance
Strategy
Secure State
of Control
Scientific Issues & Way to move Forward
Adopt
Innovation &
Emerging
Regulatory
Sciences
Keep Wheel of
Change
Moving

182. Assess Capacity &
Capability
Be Honest First
Analyze Mfg Facilities
Analyze Quality System
Design a Clear Roadmap

183. Develop Compliance
Strategy
Identify Resources
Design Plan Strategy
Empowerment & Proceeding
Review & Critical Review

184. Secure State of
Control
Deviation & Changes
Continuous Update
Expanding Detecting Ability
Be Predictive & Proactive

185. Adopt Innovation &
Emerging Regulatory
Sciences
Knowledge Management
Strengthening the Process
Regulatory Expectations
Dashboard & Back Mirror

186. Keep Wheel of
Change Moving
Change as a Strength
Complain as a Opportunity
Integrity as a Principle
Culture of Quality

188. Emerging Challenges in
Pharmaceutical Manufacturing
Obaid Ali, R. Ph., Ph. D
Federal Inspector of Drugs, DRAP
Member ISPE & PDA

189. Applicant needs to prove for a Trustable CMC
1

190. Can your application demonstrate
You fully understand the Product & Process
Control on Excipients & In-process
A robust & consistent Manufacturing Process

191. The way to move and prove through
ICH Module 2 (2.3), Module 3 (Quality Part)
Substantial data navigates & supports final decisions
Well organized & logical flow of information

192. Remember Integration of Regulatory Tools is a new Approach
Manufacturing facility & process review
Application reviews
Systematic Assessment

193. Post Approval Changes & Variations
2

194. Keep Policy simple, no matter how complex Change is
Minor: no need to report, just notify periodically
Major: submit & do not implement w/o approval
Moderate: notify to agency before implementation

195. Common Changes
Container closure system
Stability Protocol & Expiration Date
Site Specifications Process
Components & Composition

196. Alteration in overage …. From
approved batch formula to adjust
manufacturing losses

197. Alteration in overage …. From
approved batch formula to adjust
manufacturing losses
Minor

198. Extension of Product expiry based on
an Approved Stability Protocol

199. Extension of Product expiry based on
an Approved Stability Protocol
Minor

200. Addition of a new API Supplier

201. Addition of a new API Supplier
….
Moderate
….

202. Change in synthesis route of a drug
substance

203. Change in synthesis route of a drug
substance
Major

204. Equipment of different operating
principles
(e.g. tray dryer vs. fluid bed dryer)

205. Equipment of different operating
principles
(e.g. tray dryer vs. fluid bed dryer)
Major

206. Addition of a new flavor or color

207. Addition of a new flavor or color
Major

208. Change from a glass ampoule to a
glass vial with elastomeric closure in
sterile drug product

209. Change from a glass ampoule to a
glass vial with elastomeric closure in
sterile drug product
Major

210. Case Studies

211. Alternate Drug Product Manufacturing Site for an IR Product

212. Alternate Drug Product Manufacturing Site for an IR Product
GMP Inspection is
NOT required to
assess suitability

213. Alternate Drug Product Manufacturing Site for an IR Product
Denied
GMP Inspection is
NOT required to
assess suitability

214. Deletion of Blend Uniformity Analysis for a low dose drug (0.5 mg)

215. Deletion of Blend Uniformity Analysis for a low dose drug (0.5 mg)

216. Deletion of Blend Uniformity Analysis for a low dose drug (0.5 mg)
Denied

217. Variations & Common
Challenging Deficiencies

218. Compendia monograph compliance with Critical Quality Attributes
Method equivalency to Pharmacopeia
Revised API Specifications … method validation
Splitability data for scored tablets
Variations and Common Challenging Deficiencies

219. Variations and Common Challenging Deficiencies
Science & Risk
to assess
Product Quality
&
Potential Impact
of Change
Take Home Message
Demonstrate
Product Quality
&
Process
Understanding

220. Applied Science of Risk
3

221. Applied Science of Risk (with simple approach)
Product Quality
(CQAs & BE
impacted)
DS Inherent
Properties
Formulation
Variables &
Excipient CMAs
Manufacture
Process Steps &
Parameters
Container
Closure System
Assay Low Low Low Low
CU High High High Low
Dissolution Low Low Low Low
Deg. Products Low Low Low Low
Bioequivalence Low Medium Medium Low

222. Challenge to Develop Tools for Setting the Priority
Risk is not Contagious or Equal
esp. in Generics
Robustness of Formulation &
Compliance of Manufacturing site

223. Quickly capture Quality Attributes (Time is everything)
Minimum time
Limited time
Assure job done
1
2
3
Mitigate
CQA

224. Lets try to understand what may go wrong (1/5)
C
U
1) Design
Innovator Similar API & Excipients
Generic X Similar API & Excipients
Generic Y No strategies

225. Lets try to understand what may go wrong (2/5)
C
U
2) Process
Innovator CPPs understood & controlled
Generic X No strategies
Generic Y No strategies

226. Lets try to understand what may go wrong (3/5)
C
U
3) Measurement
Innovator Stratified Sampling in Commercial Batches
Generic X Traditional CU USP
Generic Y Traditional CU USP

227. Lets try to understand what may go wrong (4/5)
C
U
Design, Process & Measurement
Innovator
Generic X
Generic Y

228. Lets try to understand what may go wrong (4/5)
It is now common sense
which product & which site
is a priority for enhanced
quality surveillance

229. Applied Science of Risk
Use Tools to
Capture
Quality Snapshot
Data Driven
Dialogues, Discussion
&
Decisions
Take Home Message

230. Proposed Product Manufacturing Classification System
Right
particle
Best
process
Difficult
API
Good
API

231. Direct Compression
Grind drug
Intra-granular
excipients
Compression

232. Roller Compaction
Grind drug
Intra-
granular
excipients
Roller
compaction
Extra-
granular
excipient
Compression

233. Wet Granulation
Grind drug
Intra-
granular
excipients
Granulation Wet Screen
DryingDry Screen
Extra-
granular
excipient
Compression

234. Biopharmaceutical Evaluation Affairs
From Fiction to Reality
4

235. Performance
should be the
same way

236. No Worse
Performance
should be the
same way

237. No Worse
No Better
Performance
should be the
same way

238. Please make it clear
They are not
clinical studies
Nothing to do
with Safety &
Efficacy of
molecule
Evaluating the
Similarity of
Trends
&
Kinetics

239. Bioequivalence & Generic Drugs
Pharmaceutical Equivalent & Bioequivalent
Pharmaceutical Equivalence
Does not mean equivalent performance

240. Pharmaceutical Equivalence
Same active ingredient
Same dosage form
Same route of administration
Identical in strength or concentration

241. Generics not necessarily identical
Excipients Difference
Manufacturing Differences
Formulation Difference
Shape, color difference

242. Assessment of Manufacturing Facility
5

243. Maintain System & Making Change
Product & process
design with scientific
understanding is
critical
Knowledge Management
Product Development
Technology Transfer
Process Validation
Commercial Manufacturing

244. Prioritization for Pre-Approval Inspection
Product risk
factors
• Known issues
with innovator
Mfg Process
risk factors
• Complexity of
mfg
Facility risk
factors
• Fragile GMP

245. Basic Process Design (Process Validation)
CQA
Identification
Appropriate
Manufacturing Process
Suitable Control
Strategy
Impurity levels
Content Uniformity
Dissolution
Reactions
Equipment
Environmental
assessment
In process &
release testing
Proven Acceptable
Range/Normal
Operating Range

246. Process Qualification (Process Validation)
Building Design & Facilities
Understand &
incorporate
Material
Invariability
Process Performance
Qualification
Appropriateness &
Capability of Equipment
Fully evolved control
strategy for
commercialization
Protocol design, execution
& interpretation

247. Pre-Approval Inspection
Readiness
Conformance to
Application
Data Integrity
Equipment
Procedures
Quality
Management
Processes
Equipment scale
Process as
proposed
Submitted
information, raw
data & accuracy

248. Justification for commercial scale & process design not adequate
Commercial scale equipment not qualified, method not validated
Common Observations on Readiness (PAI)
Serious GMP deficiencies

249. Commercial scale equipment listed not available on-site
Implemented process does not match with the reported one
Common Observations on Conformance to Application (PAI)
Manufacturing process changes not reported

250. Averaging to hide fail results in data
Common Observations on Data Integrity (PAI)
Unknown
impurities
Retesting till
desired results
Not representative holding
studies
Use of trial
injections
Lack of audit trails
Failing results attributed to
analyst error

251. Continued Process Verification
Active proof that
state of control is
maintained
throughout the
process
Understanding of
process & risk to
develop a strategy
for monitoring
Variability potential
in manufacturing &
incoming material
properties
assessment

252. Process Performance Qualification batches & reports
Stability & Shelf Life
Component Supplier Qualification
Post-Approval Inspection

253. Determination of cGMP Compliance & Quality Culture
Investigations to determine root causes & strengthen the quality
Deficiencies, Non-compliance & Violations
Surveillance Inspection

254. Aging Manufacturing Facilities & with Old Approaches
Lets unfold to understand
Uncertainty
6

255. Aging (Facility, Process, Analytics) and its Drivers
Due to lack of proactive Improvement Programs
Investment into appropriate Maintenance Plan
Area/
Flow
Equipment AnalyticsProcess

256. Specific Risks of Older Factories
Inefficient Processes
Inappropriate material & personnel flows
Antiquated or obsolete ventilation system
Old equipment no longer meeting current requirements

257. Major change in facility! Does it worth?
Utilities HVAC (air changes etc), Water, Piping etc.
Systems Quality Policies & Compatibility
Premises Design, construction & maintainability
Flow Material, personnel, trafficking

258. Ways to keep align with modernization
Time wastage in quality documentation & administrative procedures?
Do you have adequate trained personnel in the maintenance unit?
Are adequate SOPs and maintenance protocols in place?
Analyze your number of defect rates, deviations?

259. Enhancing robustness
Improving production reliability
Adoption of new technologies leads to
Lowering costs

260. Take Home Message
Keep an eye on ways
of Improvement
Always stay on the ball
regarding technology
Continuously adapt to
the changes
Implement improvement procedures,
perform risk assessment, analysis, set up
actions & document efforts
Keep abreast of new technologies &
processes. Work with your supplier to try to
improve your machinery on the shop floor
Try to implement a culture of quality and
improvement. The only constant thing is
change