This presentation discusses the importance of understanding pharmaceutical products and processes in order to prevent quality issues and recalls. It provides several examples of recent drug recalls that occurred due to a lack of control or understanding of the product and manufacturing process. These issues include super or sub potent formulations, particulate contamination, active pharmaceutical ingredient contamination, sterility failures, and dissolution or disintegration failures. The presentation emphasizes that companies must validate their manufacturing processes, maintain strict controls, monitor all aspects of production, and be prepared to modify their strategies as needed to ensure safe, effective drugs are consistently produced.

1. Understanding of Product & Process
For Installation of Appropriate Controls
Roohi B. Obaid, R. Ph.
Civil Services Officer
Member ISPE & PDA
12 April 2017

2. D
I
S
C
L
A
I
M
E
R
Not the view
of DRAP
Current
judgment
No
obligation
on DRAP
Regulatory
experience
This presentation discusses science and has nothing to do with
any commercial Product.

3. Why How

4. Why How
e.g. Saxagliptin

5. Lets have a look & walk through real cases

6. 05 Feb 2017
Bupripion HCl ER

7. 2.7 lakh bottle
Dissolution failure
At 18 month of
stability

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

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

10. 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

11. 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

12. 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

13. Drug assay is
compliant

14. Drug assay is
compliant
Drug is not available
for absorption

15. Drug assay is
compliant
Drug is not available
for absorption
Do you expect
effect?

16. Therapeutic
effect under
question

17. Therapeutic
effect under
question
Disease may progress

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

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

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

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

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

23. 2013
Amidate Injection
(Etomidate)

24. Degradation during
stability
Hospira & Pfizer product

25. Top Reasons for Recalls

26. 1
Super or sub potent formulations
Digoxin (double
thickness)
Actavis 2008

27. 1
Super or sub potent formulations
Digoxin (double
thickness)
Actavis 2008
Poor Manufacturing Control

28. 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

29. 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

30. 2
Particulate Contamination
Takeda, Millenium &
Janssen anti-cancer product
Particulates were seen after
reconstitution
Europe, America & Asia
Polyester like material
originated from filtration
system

31. 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

32. 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.

33. 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

34. 3
API’s Contamination
Bulk heparin in China
Over sulfated Chondroitin
Sulfate
80 deaths in USA alone
Found deliberated &
economically motivated

35. 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

36. 3
API’s Contamination
GSK Worthing UK facility
July 2015
Bactobran cream
containing Mupirocin
recalled

37. 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

38. 3
API’s Contamination
GSK Worthing UK facility
July 2015
Bactobran cream
containing Mupirocin
recalled
Inadequate Controls to
Prevent contamination

39. 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

40. 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

41. 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

42. 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

43. 3
Contamination
Misoprostol Pharmacia
Peak gave signal but
ignored (13 lots)
Later contaminant
identified to be toluene

44. 3
Contamination
Misoprostol Pharmacia
Peak gave signal but
ignored (13 lots)
Later contaminant
identified to be toluene
Loose ink in blister packaging line

45. 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

46. 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 ….

47. 4
Sterility Failure
Various drugs for potential
sterility failure found
contaminated with
pathogenic organisms
High threat for HIV, Cystic
Fibrosis or TB

48. 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

49. 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

50. 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

51. 6
Disintegration Failure
Soft gel capsule failed in
disintegration
Millions of capsules
recalled
Company shut down for
a long time

52. 6
Disintegration Failure
Soft gel capsule failed in
disintegration
Millions of capsules
recalled
Company shut down for
a long time

53. 6
Dissolution failure
100’s of batches of
Paracetamol tablet
failed in Dissolution

54. 6
Dissolution failure
100’s of batches of
Paracetamol tablet
failed in Dissolution

55. 7
Manufacturing with poor knowledge
Rivaroxaban Tablet
Failure in CDP

56. 7
Manufacturing with poor knowledge
Rivaroxaban Tablet
Failure in CDP

57. 7
Manufacturing with poor knowledge
Ramipril tablets
Process degradation
found

58. 7
Manufacturing with poor knowledge
Ramipril tablets
Process degradation
found

59. Able Laboratories, NJ
A story of Generic Manufacturing Company’s
Collapse

60. 1999 to 2005
Enormous growth & expansion
17 - 55% per share

61. 1999 to 2005
Enormous growth & expansion
17 - 55% per share
2005 - Major recall due to falsification of data
Flouting, altering or manipulation & reporting

62. 1999 to 2005
Enormous growth & expansion
17 - 55% per share
2005 - Major recall due to falsification of data
Flouting, altering or manipulation & reporting
2007 - Charged
All drugs withdrawn, company shut down

64. Lets hear and watch the way Leaders
come forward to protect trust
These are the norms of moral business

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

66. 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

67. 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