Presented in March 2014

1. Review of Control Strategy of GMP
Obaid Ali & Roohi B. Obaid (March 2013)

2. Disclaimer and References
The views expressed in this
presentation are not necessarily of the
Drug Regulatory Authority of Pakistan
It is an informal communication that
represents the best current judgment
and does not constitute an advisory
opinion or binding or otherwise
obligate or commit the DRAP, to the
views expressed.
This presentation is designed by the
speaker after consulting international
reference documents

3. Presentation Focus
Cont’d

4. Presentation Focus

5. Back mirror challenges;
Wake up call….s

8. Regulatory Complexity

9. Why Regulations?

10. Its not just as simple as its seems to be

13. Pre-approval Inspection
Post-approval Inspection
Pre-market Review
Post-market Review
SCENE
Regulatory Background
D
R
U
G

14. SCENE
Very near to your and your beloved one’s lives
Very near to your and your beloved one’s lives
Health care profession and business
Health care profession and business
Regulations
protect
and
promote
Public Health

15. New
Generics
Primary Logical Boundaries
D R U G S

16. New
Drugs
Main Concerns
Safety
Efficacy
C
linical Sites
SupplyChain
Vigilance
Manufacturing Site

17. 1
Main Elements of Review Process for New Drugs
Toxicology & Pharmacology
Clinical Pharmacol & Bio-Pharmaceutics
Medical & Statistical
Immunological review esp. for Biologicals
Chemistry & CMC
Risk Evaluation & Mitigation Strategy
2
3
4
5
6
SCENE
5
Cross Discipline
7

18. CONCERNS
CMC review….. SMF, DMF, LIF………..CMC review….. SMF, DMF, LIF………..
SCENE
Generic or
approved
new Drug
for new site
New Drug
Main Elements of Review Process for Generic Drugs
Clinical study….Bio-studies….Dissolution
studies………Justification of waiver
Clinical study….Bio-studies….Dissolution
studies………Justification of waiver
Labeling review……Product Development……
Stability……..Shelf life
Labeling review……Product Development……
Stability……..Shelf life
Manufacturing capacity………Pre-approval
Inspection report………..history of GMP
Manufacturing capacity………Pre-approval
Inspection report………..history of GMP

19. Review Journey
Process
Design
Review
SCENE
Meetings
W
riting

20. SCENE
Review Model of the 21st
Century
CTD
International
Conference on
Harmonization
Question
based review

21. Main Challenges
ABILITY
Data Analysis and Assessment
SCENE
Identification
ofDataGenuineness
ReportW
riting

23. Consistency, mix-up, Contamination, Cross-contamination, Traceability
and Data Integrity

24. Quality
can not beobserved by everyone and/or bynaked eye or evenby product testing.

25. ………………..triggered a serious adverse reaction
by depositing itself in the bone marrow and
ending the body's resistance. The generation
of white blood cells stopped in the body.
Among the symptoms of the disease were
change in skin color/pigmentation, low platelet
count and blood vomiting.
………………..triggered a serious adverse reaction
by depositing itself in the bone marrow and
ending the body's resistance. The generation
of white blood cells stopped in the body.
Among the symptoms of the disease were
change in skin color/pigmentation, low platelet
count and blood vomiting.
Recall the painful
memories

26. Good Manufacturing Practice is
the only and absolute answer to
ensure product quality of drug for
approved drugs
Good Manufacturing Practice is
the only and absolute answer to
ensure product quality of drug for
approved drugs

27. Regulatory Mandate
………GMP under Schedule B……..
Obligatory to comply
Regulatory Mandate
………GMP under Schedule B……..
Obligatory to comply

28. GMP Expectations

29. Is the drug consistent to each other
Is it mix up free
Is it not contaminated
Is it not cross-contaminated
Is data and manufacturing history traceable
Is data reliable and genuine...........

31. Variations play
?????
Variations play
?????

32. Mix-up
A number of drug products are being manufactured in a
same manufacturing facility
Label mix up
Powder mix up
Bulk product mix up
In-process mix up
Blister mix up
Etc.

33. Let’s make science visible

38. Case Studies

39. Unknown peak in Misoprostol
Unknown peak identified in 13 lots of Cytotec
tablet
A delayed (after 1.5 months) internal
investigation report suggested contamination
during handling but it was unknown contaminant

40. Investigation
Failure at QCU
Another investigation after 1.5 years suggested
(based on relative retention time) the unknown
contaminant as toluene

41. Investigation Failure at
QCU
After 1.5 years internal evaluation revealed the
probable source of toluene was related to loose ink
in blister packaging line
Firm did not considered it as a foreign substance
and argued that toluene is also used in chemical
synthesis of misoprostol oil. It was a hypothesis, no
record was available

42. Investigation
Failure at QCU
Not a single cause out of both could be assigned,
whether it was a residue from API or improper
packaging
There was no evidence that toluene is being
monitored during the stability of API
Not a single cause out of both could be assigned,
whether it was a residue from API or improper
packaging
There was no evidence that toluene is being
monitored during the stability of API

43. Investigation
Failure at QCU
Diethylphthalate (DEP) can be a source of
contamination from desiccant cartridge

44. J&J
Dec 2009
Several complaints of uncharacteristic strong
odor were received to J&J from 2008 to 2009 for
their several OTC products packaged in bottles.
J&J failed to conduct a timely, comprehensive
investigation, determine and assign a root cause

45. J&J
Dec 2009
The adverse event was reported as
gastrointestinal distress
This lead to recall of several lots of Tylenol
Arthritis Relief Caplets and several other OTC
products

46. J&J
Dec 2009
The reason was a pesticide 2,4,6
Tribromophenol (TBP) sprayed on wooden
pallets used to keep finished products during
shipping
This pesticide degraded to 2,4,6
Tribromoanisole (TBA) with a musty odor
contaminating product containers and finished
product in those containers

47. Pfizer 2010Pfizer 2010
Several lots of Lipitor (191, 000 bottles)were
recalled due to the same reason. i.e. unusual
odor/ moldy smell of 2,4,6 Tribromoanisole, a
degradant of TBP used to disinfect wooden
pallets
Several lots of Lipitor (191, 000 bottles)were
recalled due to the same reason. i.e. unusual
odor/ moldy smell of 2,4,6 Tribromoanisole, a
degradant of TBP used to disinfect wooden
pallets

48. GSK June 2011GSK June 2011
A huge recall of Augmentin syrup in China, Hong
Kong etc. contaminated with di-isodecyl
phthalate (DIDP) Plasticizer ordered by Chinese
SFDA
A huge recall of Augmentin syrup in China, Hong
Kong etc. contaminated with di-isodecyl
phthalate (DIDP) Plasticizer ordered by Chinese
SFDA

49. GSK June 2011GSK June 2011
According to Chinese SFDA, the drug was
tainted with the DIDP plasticizer which is used
to make the plastic more flexible
Result
A huge number of bottles were recalled
According to Chinese SFDA, the drug was
tainted with the DIDP plasticizer which is used
to make the plastic more flexible
Result
A huge number of bottles were recalled

50. Ranbaxy 2008
Batamandi
Ranbaxy 2008
Batamandi
Cleaning record of the equipment V-blender
contained signature of employees who
verified the cleaning of equipment, but were
not actually present at that particular time
Cleaning record of the equipment V-blender
contained signature of employees who
verified the cleaning of equipment, but were
not actually present at that particular time

51. Ranbaxy 2008
Batamandi
Ranbaxy 2008
Batamandi
This came to bright through security log
records used to control the entry of all
personnel entering or exiting the facility
This came to bright through security log
records used to control the entry of all
personnel entering or exiting the facility

52. Ranbaxy 2008
Batamandi
Ranbaxy 2008
Batamandi
The security log records showed that the
persons/supervisors who signed the
“Checked by Production Executive or
“Cleared by QA Executive” were not present
at the facility on the days equipment was
cleaned
The security log records showed that the
persons/supervisors who signed the
“Checked by Production Executive or
“Cleared by QA Executive” were not present
at the facility on the days equipment was
cleaned

53. Ranbaxy 2008
Batamandi
Ranbaxy 2008
Batamandi
Furthermore, the employee of the firm believed
that his physical presence was not necessary
during the activity and he can sign off by asking
someone to bring records to him for signature
on the batch records as to have checked the
activity
Furthermore, the employee of the firm believed
that his physical presence was not necessary
during the activity and he can sign off by asking
someone to bring records to him for signature
on the batch records as to have checked the
activity

54. Ranbaxy 2008
Batamandi
Ranbaxy 2008
Batamandi
This demonstrates the lack of understanding of
the fundamental purpose of independent
verification under cGMP.
Such verification is paramount to ensure that
procedures or works are adequately performed to
reduce the risk of human error
This demonstrates the lack of understanding of
the fundamental purpose of independent
verification under cGMP.
Such verification is paramount to ensure that
procedures or works are adequately performed to
reduce the risk of human error

55. Ranbaxy 2008
Batamandi
Ranbaxy 2008
Batamandi
Incomplete or compromised cleaning of
equipment can provide a way for cross-
contamination or inadvertent contamination
of drug products with residual cleaning agents
or solvents
Incomplete or compromised cleaning of
equipment can provide a way for cross-
contamination or inadvertent contamination
of drug products with residual cleaning agents
or solvents

56. Ranbaxy 2008
Batamandi
Ranbaxy 2008
Batamandi
The deficiencies in equipment cleaning and
batch production and control records
threaten the concerns related to the
conduct, adequacy and oversight of Quality
System of the firm especially the integrity
and reliability of records
The deficiencies in equipment cleaning and
batch production and control records
threaten the concerns related to the
conduct, adequacy and oversight of Quality
System of the firm especially the integrity
and reliability of records

57. Ranbaxy 2008
Dewas
Ranbaxy 2008
Dewas
Persons from QC moved freely collecting
samples between beta-lactam and non-beta-
lactam manufacturing blocks
Persons from QC moved freely collecting
samples between beta-lactam and non-beta-
lactam manufacturing blocks

58. Ranbaxy 2008
Dewas
Ranbaxy 2008
Dewas
Persons working in beta-lactam API
warehouses were moving freely on the
manufacturing campus
Persons working in beta-lactam API
warehouses were moving freely on the
manufacturing campus

59. Ranbaxy 2008
Dewas
Ranbaxy 2008
Dewas
Persons working in beta-lactam API
warehouses were moving freely on the
manufacturing campus
Persons working in beta-lactam API
warehouses were moving freely on the
manufacturing campus

60. Ranbaxy 2008
Dewas
Ranbaxy 2008
Dewas
Persons working in Cephalosporin API
dispensing area were observed with powder
on their gowns and coming in direct contact
with outer surface of a bulk material bag that
was placed on transport equipment that can
enter in non-beta-lactam areas
Persons working in Cephalosporin API
dispensing area were observed with powder
on their gowns and coming in direct contact
with outer surface of a bulk material bag that
was placed on transport equipment that can
enter in non-beta-lactam areas

61. Ranbaxy 2008
Dewas
Ranbaxy 2008
Dewas
Surface monitoring (sampling/testing) for
residual traces of penicillin type beta-lactams is
not performed in the Penem Block where
penem sterile parenterals are manufactured or
in Block where multiple cephalosporin finished
products are manufactured.
Surface monitoring (sampling/testing) for
residual traces of penicillin type beta-lactams is
not performed in the Penem Block where
penem sterile parenterals are manufactured or
in Block where multiple cephalosporin finished
products are manufactured.

62. Ranbaxy 2008
Dewas
Ranbaxy 2008
Dewas
Surface monitoring for residual traces of
cephalosporin type beta-lactams is not
performed in the General Block where
multiple non-beta-lactam finished products
are manufactured or in the Penem Block
where sterile parenterals are manufactured.
Surface monitoring for residual traces of
cephalosporin type beta-lactams is not
performed in the General Block where
multiple non-beta-lactam finished products
are manufactured or in the Penem Block
where sterile parenterals are manufactured.

63. Ranbaxy 2008
Dewas
Ranbaxy 2008
Dewas
Result of such observations
Consent Decree and Import Alert for their
products in USA until drugs can be manufactured
in the facilities complying with US manufacturing
Quality Standards
Result of such observations
Consent Decree and Import Alert for their
products in USA until drugs can be manufactured
in the facilities complying with US manufacturing
Quality Standards

64. Human Factor Analysis and
Classification System

65. What considerations will
enhance preventive system
and control?

67. Human Factor Analysis & Classification System
(HFACS)

68. Human Factor Analysis & Classification System
(HFACS)

69. Human Factor Analysis & Classification System
(HFACS)

70. Human Factor Analysis & Classification System
(HFACS)

71. Human Factor Analysis & Classification System
(HFACS)

72. Human Factor Analysis & Classification System
(HFACS)

73. Human Factor Analysis & Classification System
(HFACS)

74. Human Factor Analysis & Classification System
(HFACS)

75. Human Factor Analysis & Classification System
(HFACS)

76. Human Factor Analysis & Classification System
(HFACS)

77. Human Factor Analysis & Classification System
(HFACS)

78. Human Factor Analysis & Classification System
(HFACS)

79. Human Factor Analysis & Classification System
(HFACS)

80. Human Factor Analysis & Classification System
(HFACS)

81. Human Factor Analysis & Classification System
(HFACS)

82. Human Factor Analysis & Classification System
(HFACS)

83. Human Factor Analysis & Classification System
(HFACS)

84. Human Factor Analysis & Classification System
(HFACS)

85. Human Factor Analysis & Classification System
(HFACS)

86. Human Factor Analysis & Classification System
(HFACS)

87. Human Factor Analysis & Classification System
(HFACS)
“………records are not
completed
contemporaneously”
“………records are not
completed
contemporaneously”
Misguided
Malicious

88. Closing Message
SCENE
If there is a will, there is a way

89. If everyone is moving forward together, then
success takes care of itself
(Henry Ford)
If everyone is moving forward together, then
success takes care of itself
(Henry Ford)

90. oarohama@gmail.com