More than 400 participants represented dozens of manufacturing companies with diversified educational background & experience attended throughout the day with active participation in discussion forum of Regulatory & Quality Sciences.

1. Routine Decisions that have
Direct Impact on Product Performance
and are Hard to Detect
Warm welcome in CCK Discussion Forum

2. Sunday, 01 April 2018 at ICCBS, University of Karachi

3. Take a Breath, Look Back, See Around, Predict Future
&
Have a Dream to make Drugs Safe, Effective & of Quality

4. 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, nothing
more and nothing less

5. Limited to Generic Drugs Manufacturing Facilities & Quality
Not with Innovator Drugs or its Safety Concerns

6. Worst drug recall in recent past
2004
Vioxx
1,40, 000 suffered from heart attack, stroke
Recall cost
6 billion
2005
Bextra
Increased risk of heart attack & stroke
Criminal Fine
1.2 billion
2001
Baycol
> 100, 000 lac deaths reported
Criminal Fine
1.2 billion

7. What is eosinophilia-myalgia syndrome (EMS)?
Can anyone recall
what happened?
1989

8. L-Tryptophan
5-HT
1500 cases of
EMS & 38
deaths
L-Tryptophan
impurity was
found
responsible

9. Diptheria anti-toxin was contaminated
with live tetanus bacilli
1902
60 got polio, 89 contracted from them1955

10. 1 Labeling
2
Chemistry
Manufacturing &
Controls
3 Bioavailability
4 Manufacturing Plant

11. Before GMP Standards
Inconsistency
Mix ups Contaminated
Record
While we are dealing with life

12. Do you know about recall of 31 million
bottles of capsules?
What was the product & why it was
recalled?

13. What happened in 1930? 107 people died

14. In 1941 what happened when
sulphatiazole tablets tainted with
phenobarbital

15. PIC Tragedy of Pakistan took about 125 lives ………

16. Who cares … It is Government … it is Society … it is Industry
Scientific Perspective
Moral Perspective
Legal Perspective

17. Evolution of GMP Standards & Emergence of Drugs
Testing emerged
as a great tool
Tragedies potential
being continued

18. Evolution of GMP Standards & Emergence of Drugs
Process Control
Post marketing issues
emerged as a challenge

19. Evolution of GMP Standards & Emergence of Drugs
Dynamic changes
in Technology
Regulatory Sciences at
their best

20. Evolution of GMP Standards & Emergence of Drugs
Complex Supply
Chain
Harmonization
&
Globalization

21. Evolution of GMP Standards & Emergence of Drugs
Cross Pollination
of
Misconceptions
Mutual Reliance,
Knowledge Sharing,
Understanding &
Recognitions

22. Technology Transfer & Scale up is the biggest Challenge
Biggest Challenge
From building
to building
From old site
to new site
From one
process train to
another process
train

24. Make sure that Transfer Protocols are developed to capture the
process thoroughly
Assessment of
original information
For e.g. supplier
qualification of API,
Critical Process
Parameters,
Equipment
Comparison with
guidelines
Equipment size,
identification of
potential difference
& clear
understanding about
the impact of
difference

25. Ignorance Predictions
BelievesDeviations
Change Diversions

26. Diversions
Change
Deviations

27. Data Integrity

28. Regulatory Intent
Why?
Patient
safety
Reconstruct
activities
Product
quality
Data Integrity

29. Main Principles of Data Integrity
Organization needs to take responsibility for system & generated data
Organizational
culture should ensure
Complete
Consistent
Accurate
Paper form
Electronic form

30. You must know it
How data influence
in decisions is
actually the
criticality
Your data is used in
decisions of
Quality, Safety &
Efficacy
REMEMBER

31. Data ……..
A
L
O
A
C
Attributable to person generated data
Accurate
Original Record or Certified True Copy
Legible & Permanent
Contemporaneous

32. Data …….. Governance
Complete
Available
Consistent
Enduring
The data must be whole; a complete set
The data must be self-consistent
Durable; lasting throughout the data
lifecycle
Readily available for review & inspection
process

33. Please Remember
It is a degree to which the data is complete, consistent, accurate,
trustworthy, reliable & that these characteristics of data are
maintained throughout the lifecycle

34. Difficult to Inspect (DIP) Parenteral Dosage Forms for Particles

35. Particulates and
Sterility ….?

36. Horrible sometimes …

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

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

39. Take an area as an example of challenge

40. 2m2
• Protects body from
pathogens
• Prevents loss of
moisture
• Body temperature
regulation
Diversity
• Considerable diversity
in species
• Variation b/w different
locations on body
• Variation b/w
individuals
30 million
• Average person
sheds 1 billion skin
cells/ day
• 10% have micro-
organisms on them
Human Skin
Go in clean rooms They touch, shed, do things wrong sometimes

41. ORAL CAVITY
High population
High diversity
SKIN
Variable population
Low diversity
URETHRA/VAGINA
High population
Low diversity
GUT
High population
High diversity
People
Ecology

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

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

44. DIPs
Diminished
capability of
100% visual
inspection
Formulation
Container
system

45. DIP Formulation types
1 Lyophilized products
2 Suspensions
Opalescent to milky solutions 3
Emulsions etc. 4

46. Supplemental destructive
inspection when parenteral
product is not capable of
100% visual inspection for
particulate matter

47. Situation Appearance and
quality defects
Readily visible
particulate matter

48. Lets see Simple Math …………
Particle Size
Clinical relevance
Administration Route
Historical Process
Capability
Quick question: How many batch you manufactured & re-inspected per year

49. Destructive
Testing methods
Reconstitution & visual
inspection of solid
(lyophilized & powder)
products
Membrane Filtration /
Microscopic Examination

50. Unsafe, Inefficacious & have Incorrect
identity
NOT Deliver the same performance as
claimed
Perform inconsistently over shelf life
Made in a manner that does not ensure
quality
Will may not be available when needed

51. Real Time Case Studies;
An Opportunity to Review & Re-Learn

52. 2X mg X mg
1/2X
mg