Presented in Seminar organized by Morgan at Hotel Marriott, Karachi

1. Pharmaceutical Regulations Drive
Obaid Ali, R. Ph. Ph. D. & Roohi B. Obaid
Civil Services Officer, Government of Pakistan
14th April 2016, Thursday, Karachi

2. DISCLAIMER
Not the view of DRAP
Current judgment
No obligation on DRAP
Regulatory experience
It has nothing to do with
any specific commercial
product
It is just a knowledge
sharing exercise nothing
more than that

3. The quality and especially the sterility of
products manufactured cannot be assured

4. The quality and especially the sterility of
products manufactured cannot be assured
April 2016

5. Background
Inspector’s Eyes
From History
Pariculates

6. Background

8. A strict definition of sterility is the
complete absence of life or inability to
reproduce
• Cont’d
However, sterility as defined in the
pharmaceutical industry has a more
complex technical definition, and is
expressed in quantitative terms

9. The probability definition for sterility derives
from the fact that microbial death follows a
geometric progression .i.e. the cells do not all
die at once when exposed to lethal conditions
• Cont’d
The US FDA defines sterilization as the
“reduction of a microbial population to 10° (or
one cell) plus an additional 6 log-cycles”

10. Sterility is defined as the “probability of a non-sterile
unit (PNSU) in a lot or batch of product”
PNSU is also referred to as the “Sterility Assurance
Level” or SAL
A product is considered sterile when the probability of a
non-sterile unit is < 1 in 1, 000, 000 units; or a SAL of
10-6

11. Managing an Aseptic Processing
Area (APA)

12. Drug
Product
Sterilization
Process
Sterile
Drug
Containers
Sterilization
Process
Sterile
Container
Excipient
Sterilization
Process
Sterile
Excipient
Closures
Sterilization
Process
Sterile
Closures
Contact
Surface
Sterilization
Process
Sterile Contact
Surface
S
t
e
r
i
l
e
D
P
Managing of all these steps is a real challenge for personnel

13. Working in an Aseptic Processing
Area (APA)

14. Personnel
Knowledge
Ability
Skill

15. Atypical
Job
Heavy
gowning
Physical
Exhaustion
Technical
understanding

16. Very
important
Educational
background
K, A, S
Personal
attributes

17. Grade A
Grade B
Grade C
Grade D

18. Process,
Facilities
&
Design
Personnel
with
appropriate
K,A,S
Training
(Knowledge
based &
performance)
Monitoring
performance
Effective
CAPAs
Aseptic
Process
Connecting the Dots

19. Inspector’s Eyes

20. Build Quality
Be proactive …. Rigorous thinking with logical, systematic &
science based approaches to improve effectiveness & efficiency
of decision making

21. Build Quality
Be proactive …. Rigorous thinking with logical, systematic &
science based approaches to improve effectiveness & efficiency
of decision making
Personnel &
material flow
Air flow pattern
evaluation
Aseptic operations
Disinfectant/
Sanitization
Cleaning efficiency
EM Plan

22. Lets understand
GMP Inspection & Inspector’s Interest

23. Quality
Materials
Production
Laboratory
Control
Facilities &
Equipment
Packaging
& Labeling

24. Quality
Review/ap
proved
procedure
Document
ation of
operation
execution
Investigation
Deviations
&
Complaints
Failures

25. Production
Control
Strategy
for change
Process
validation
Investigation
of
discrepancy
Missing &
incomplete
records
In-process
controls

26. Laboratory
Control
Control
Strategy
for change
Source of
microbial
contamina
tion
Investigation
of
discrepancy
Retention
of raw data
In-
adequate
sampling

27. Facilities &
Equipment
Contamin
ation
Cleaning
procedure
Investigation
of
discrepancy
Equipment
qualificatio
n
Control
strategy
for change

28. Materials
Identity
test
Authentici
ty of COA
Investigation
of
discrepancy
Control
strategy for
change in
handling of
materials
Release of
material

29. Packaging &
Labeling
Potential of
mislabeling
Mix up
potential
Investigation
of
discrepancy
Control
strategy for
change
Packaging
validation

30. …… Inspector’s eyes looking for ……
Systems that allow inferior product to the market

31. Quality Management System
Production & Control Strategy
Potential adulteration boulevard
Consistency affairs

32. Contamination affairs
Identification & Traceability avenues
Reliability & reproducibility of results
Genuineness & accuracy of data

33. Validation Policy, Plan, Protocol, Report
& Raw Data
Reports & Reviews
Developmental reports & Change
Controls
Deviation, non-conformance, incidents

34. OOS, CAPA, OOT
Trainings & Effectiveness
Storage, Transportation
Human practice in aseptic areas

35. Sterility Failures
Media Fills
Rejects, Reworks, Re-process
Equipment repairing

36. Utilities & Plumbing Connections
Equipment logs
Maintenance Records
Cleaning Records

37. Observed Practice vs. Validated Practices
Personnel observed vs. Expected
behavior
In-process store
SOP in place

38. Calibration stickers
Non-validated analytical
methods
Growth promotion negative
controls

39. Degree of product
& process
understanding
Robustness of
Quality System
controlling the
process
Manufacturer’
ability to manage
risk associated
with product
quality

40. From History

41. Equipment and utensils are not cleaned and maintained at
appropriate intervals to prevent contamination

42. Equipment and utensils are not cleaned and maintained at
appropriate intervals to prevent contamination
HEPA, their supporting grid work, filter screens and screen tracks
possessed varying amount of discolored, chipping paint,
multicolored coalescing droplets and clumps of dark materials

43. Aging infrastructure
Regular Assessment, Repair, Expertise,
Risk Management
Conformance to Standards
compliant,
competent in
microbial
risk
assessment?
Culture

44. • Inherent human
characteristic
Employee
behaviors
• Absent or lagging change
or behavior
Documentation
• Expertise, Knowledge,
Communication
Oversight
Key Compliance Root Cause Themes

45. • Human factors
Equipment
design
• Appropriate, regularity,
expertise & know-how
Equipment
adjustment
• Risk Mitigation Activities
absentEnvironment
Key Compliance Root Cause Themes

46. sterile preservative-free
ibuprofin L-lysine at
17 mg/mL in a single-
use glass vial
in premature infants no
more than 32 weeks
gestational age
Two batches of this
product were
voluntarily recalled by
the manufacturer,
Lundbeck
interaction between the
product and the Type I
borosilicate glass vial
It substitutes for the
aluminum oxide
forming an ibuprofen
aluminum hydroxide
salt as particulate
Case

47. Particulates ….?

48. There were 55 recalls
in the United States
in 2014 due to
foreign particles

49. Sources of Particulate Matter in Injectable Drug Products
Environment
Packaging
materials
Solution &
formulation
components
Product-
packaging
interactions
Process
generated
particles

50. Clinical Effects of Injected Particulate Matter
Phlebitis
Pulmonary
emboli
Pulmonary
granulomas
Immune
system
dysfunction
Pulmonary
dysfunction
Infarction Death

51. Clinical Effects of Injected Particulate Matter
Patient risk associated with injected particulate matter
depends upon a number factors such as:
• Route of administration
• Particle size and shape
• Number of particles injected
• Particle composition
• Patient population

52. Route of Administration
The route influences the
deposition of the injected particles
The total particle load administered
The overall risk to the patient

53. The risk of systemic reaction
is low, if the administration is
via IM or SC route as
• The delivered volume (overall
particle load) is relatively small
• The ability of particles to migrate
far from injection site is negligible
The IV route carries the
maximum possibility of
• Delivering greater volume of fluids
• Broader dissemination &
deposition of particulate matter
throughout the body
Route of Administration

54. Intravenous Route of Administration
Particles
injected
IV
Venous system
(veins ↑ in size
in direction of
blood flow)
Heart
Pulmonary
artery
Lungs
Capillary
diameter 6-8 um
Particles > 6-8 um
remain in
pulmonary
capillaries
Smaller particles
deposit in organs
e.g. liver & spleen
Cont’d

55. Intravenous Route of Administration
Processed by the
phagocytic cells of the
reticulo-endothelial
system
Phagocytic overload of the
reticulo-endothelial system
by large number of particles
has potential to block the
system
Lead to secondary
infections in a
debilitated host

56. Intra-arterial Route of Administration
Particles injected IA
Arteries ↓ in
size in direction
of blood flow
Large particles
pass through
arterioles &
capillaries
May cause
occlusion
affecting blood
flow
Smaller particles are capable of
blocking terminal arterial vessels
More detrimental than
larger particles
Large particles occlude
arterioles due to ↓
collateral blood supply
available to the affected
tissue
Cont’d

57. Intra-arterial Route of Administration
Intravascular Injection of
corticosteroid formulation
containing particles is linked with
adverse CNS sequelae in humans
versus non-particulate steroid
formulations
A study on pigs injected in vertebral
artery with particulate or non-particulate
based steroids showed brain stem edema
& significant tissue damage in pigs
receiving particulate containing steroids

58. Particle Size and Shape
The shape as well as size of particle is important in
determination of potential for harm
The total particle load is also an important factor to
consider
Various animal studies with particulate containing
injections showed deposition in lungs and liver, as
well as in spleen & kidneys
Cont’d

59. Particle Size and Shape
Adverse event reports & autopsy results are the only
source of information about the effect of larger
particles on patient populations
Visible particulate matter composed of calcium salt
precipitates in drug admixtures have caused a number
of serious clinical events

60. Patient Population
Patients with
existing tissue
damage e.g. trauma,
surgery or sepsis
Critically ill patients Neonates
At highest
risk

61. Thank you