DEG, NDMA, OSCS, DIDP, Benzene

1. GMP & Control of DEG – 13 Nov 2022, Hotel Marriott, Karachi

2. Disclaimer
We discuss science with reproducible evidence
nothing more, nothing less
It is experience based learning expression received during last 25 years
while dealing hundreds of foreign & domestic inspections, regulatory
compliance & enforcements, dozen of meetings with international experts
(FDA, EU, Japan, Canada, MHRA) etc. etc.
Thoughts represent the current thinking of Centre for Quality Sciences
Obaid Ali & Roohi B. Obaid

3. Indonesia
Paracetamol
DEG -
Contamination
Kidney Failures
195
Deaths so
far
Is it
GMP failure
or something else?
Understand to Control
before it happens here
Professional Development is the key
Centre for Quality Sciences
Sunday, 13 Nov, 2022
Ambassador – 1, Hotel Marriott, Karachi

4. • Awareness & Magnitude in Pakistan
• Waves of Global Outbreaks
• Supply Chain Integrity
• Strength of bond b/w safety & testing?
• Capacity to construct wall
• Catch the signal from noises
• What can we do?

5. Impurity &
Contamination
Is it important to control .. Is it not important
to control.. Why it is important & Why it is
not.. How it is important
What is limitation & What is residual level ..
What is meaningful & What is meaningless ..

6. GMP
What is the purpose? What is the intent?
Consistency Contamination Mix up

7. Benzene
N. D. M. A.
Di Ethylene Glycol

8. Impurity &
Contamination
From where it comes in
the finished drug product?

9. Example
Microbial contamination, Chemical contamination or dirt etc.
Meningococcal
outbreak

10. Are we aware & can we assess the magnitude
of impurity & contamination

11. Systems … Tissues
… Cell … Genetic
information
Human body
Harmonized,
Collaborated and
well integrated
Integrated
Respond to keep
life moving on with
its best
Immunity

12. Uncontrolled
growth of abnormal
cell in the body
Cancer
Substance that
promote Cancer
(Carcinogensis)
Carcinogen
Chemical agent
harms Genetic
information
Genotoxic

13. All genotoxic are not mutagen
But
All Mutagens are genotoxic

14. Mutation can cause cancer
But
Not always necessary so ..

15. Carcinogen can promote
Carcinogenesis
It is indeed formation of Cancer

16. As many mutation can cause cancer
therefore
Also likely to be carcinogen

17. A genotoxic agent damages
cellular DNA, resulting in
mutations or cancer.
Genotoxic are known to be
potentially mutagenic or
carcinogenic when inhaled,
ingested or penetrate the skin.
Genomics

18. AFLATOXIN
Most carcinogenic substance

20. API
Transformation
Starting
material

21. Transformation Multiple Reactions
Reagent
Intermediate
Catalyst
Solvents

22. Reagent
Intermediate
Catalyst
Solvents
Impurity
Byproducts

23. Impurity
Genotoxic
Carcinogenic
May be

24. US
1937
107 deaths
South Africa
1969
7 deaths
Nigeria
1990
2008
40 deaths
84 deaths
Bangladesh
1990
2009
364 deaths
24 deaths
Haiti
1995
85 deaths
India
1986
14 deaths

25. Acetic acid increase pH
• 2 Hydroxy ethoxy acetaldehyde
• 2 Hydroxy ethoxy acetic acid
What will happen?

26. Acetic acid increase pH
• 2 Hydroxy ethoxy acetaldehyde
• 2 Hydroxy ethoxy acetic acid
What will happen?

28. Benzene

29. Benzene
108
unique
lots from
30
different
brands
analyzed.

30. Benzene
108
unique
lots from
30
different
brands
analyzed.
24 lots from 8
brands
2.24 – 17.7 ppm of
benzene

31. Benzene
108
unique
lots from
30
different
brands
analyzed.
24 lots from 8
brands
2.24 – 17.7 ppm of
benzene
14 lots from 8
brands
0.20 – 1.89 ppm of
benzene

32. Benzene
108
unique
lots from
30
different
brands
analyzed.
24 lots from 8
brands
2.24 – 17.7 ppm of
benzene
14 lots from 8
brands
0.20 – 1.89 ppm of
benzene
21 lots Detectable benzene

33. Benzene
108
unique
lots from
30
different
brands
analyzed.
24 lots from 8
brands
2.24 – 17.7 ppm of
benzene
14 lots from 8
brands
0.20 – 1.89 ppm of
benzene
21 lots Detectable benzene
Recalls
Procter & Gamble’s Old
Spice, Secret, Pantene,
Aussie, Herbal Essences,
& Waterl<ss products,
and Sure & Brut
products

35. Methyl diazonium
RAS Oncogenes
N D M A

36. Methyl diazonium
RAS Oncogenes
N D M A
Gastric
Liver
Bladder
Prostate
Leukemia
Myeloma

37. Impurity &
Contamination
Is it important to control .. Is it not important
to control.. Why it is important & Why it is
not.. How it is important
What is limitation & What is residual level ..
What is meaningful & What is meaningless ..

38. Heparin Case Study

39. Pig
Heparin
Chondroitin
Sulfate
Tragedy

40. Anticoagulant
1916 – Dog liver to 1930 – Bovine lungs
1939 – First approved – Bovine lungs
1942 – Porcine source got approval
1996 – BSE crisis – UK
2007 – Heparin adulteration crisis
Often used in dialysis or heart surgery
What is heparin?
From where?

41. How heparin is
formulated as drug?
3000 pigs for 1 kg
heparin
Extraction
Separation
Purification
Porcine intestine
Polysaccharides complex with
resin or ammonium salt
Acid – base wash etc. etc.
Natural peptide, lipids
Bacterial endotoxin related
glycosaminoglycans

42. A pig highly pathogenic disease … Prolonged high fever,
Red discoloration of the body & Blue ears,
Reproductive failure, Pneumonia and increased
susceptibility to secondary bacterial infection.
It is caused by a virus classified as a member of the
genus Arterivirus.
PRRS
(Porcine reproductive and
respiratory syndrome)
Blue Ear Disease

43. 2 million kills /day
• 1,000 – 20,000 kg intestine processed for heparin
• 15 – 300 kg per month
• Supplied through brokers to the pharmaceuticals
Economically Motivated Adulteration (EMA)
Quantum

44. • Crisis of availability – Blue Ear Disease in pigs
• Shortage of crude heparin
• OSCS – derived from animal cartilage
• Similar structure to heparin
• Cannot be identified with test used for heparin
What happened &
why people died?

45. • Baxter International & China
• Over sulfated chondroitin sulfate
• Severe allergic reaction & low blood pressure
What happened &
why people died?

46. • High charge density
• Strong anti factor IIa activity
• Test not capable to catch difference
Why OSCS cause
allergy?

47. • Don’t rely on opaque supply chain
• Crude material with natural impurities
• Don’t use weak method
• Catch signals & real world observations
• Listen from noises to synchronize
Take Home Message

48. Simple bioassay can help in protecting the
global supply chain of heparin
Screening for the presence of poly sulfated
contaminants
Be vigilant

49. Tea Break

50. Contamination - A challenging issue
Reference: US-FDA

51. Inspections Progress
Deep Sleep

52. No regulation
before 2012 for
Foreign inspections
in FDA
Inspections of
domestic sites every
2 years
Deep Sleep

53. Inspect domestic & foreign sites in accordance
with risk based schedule
Thousand drug manufacturing facilities with no
inspection history
They completed the task
FDASIA - 2012

54. • Inadequate control on cross-contamination
• Data integrity
• Poor investigation
• Inadequate control for sterile manufacturing
Top Concern

55. • From industrial chemicals
• Di Ethylene Glycol
• Benzene
• Pesticides – Ciprofloxacin tragedy
• Etc.
Dangerous
Cross-contamination

56. Can an API firm make multiple
potent drugs including hormones on
shared equipment?
Challenge Question

57. Can operators share same dining
where people gather from cosmetics
and penicillin area both?
Challenge Question

58. Please see & note in your
notebook what’s wrong

59. 1. Passed through filter bag at the
top of fluid bed
2. Vertical drop in duct by pass – re-
enter
3. Another stay to contaminate next
batch
1
2
3

60. Case Study
Reference: Redica

61. Beta Lactam
Packaging
Non-Beta Lactam
Packaging
Common Area
of personnel

62. Product was recalled
Manufacturing was stopped
Decontamination & renovation of facility
Warning was issued
Take Home Message

63. Case Study
Contamination due to inadequate cleaning

64. Process equipment duct are usually contaminated with
residue from multiple drugs
Visible residue of fluid bed dryer and tablet coaters
often ring alarm
From
Inspector’s Diary

65. Don’t assume that cross-contamination or
contamination is uniformly distributed
Don’t do wrong risk assessment on the basis of testing
From
Inspector’s Diary

66. Rust on product contact surfaces
Water traps during mantling without allowing drying
From
Inspector’s Diary

67. Equipment erroneously labeled clean
Equipment use and cleaning log book deficiencies
Documentation of failed visual inspection
From
Inspector’s Diary

68. Failure to follow cleaning procedure
Availability of cleaning SOPs
Incomplete equipment dis-assembly
From
Inspector’s Diary

69. Inadequate cleaning validation
Incorrect preparation of detergent
Improper equipment storage
From
Inspector’s Diary

70. Incorrect performance of surface swabbing
Monitoring of cleaning effectiveness
From
Inspector’s Diary

71. Have you identified all cross-contamination hazards
(chemical, microbiological, physical)
Are cleaning procedures detailed enough?
Are they easy to follow?
Do it contain pictures to help operators?
Self – evaluation for
cleaning

72. How do you ensure personnel are properly trained &
always follow the validated cleaning procedure?
How do you know that they are rinsing the equipment
for the correct number of minutes?
How do you control the human variability?
Self – evaluation for
cleaning

73. How do you monitor equipment cleaning effectiveness?
How often do you have justification for the frequency
of your cleaning effectiveness or cleaning monitoring
program?
Self – evaluation for
cleaning

74. How often do you validate your cleaning process based
on data that you are gathering?
Do you have any cleaning program?
Self – evaluation for
cleaning

75. Why do these deficiencies continue to emerge?
How can companies evaluate their cleaning practices?
How do you know that drug will not harm?
Assure Yourself

76. The filling machine and HEPA filter located directly
above the filling machine in the filling room were
significantly discolored with an unknown substance
Read & share what
you understood
It was due to fumigation agent. Discolored HEPA
filters are now recolored
FDA
Firm

77. The filling machine and HEPA filter located directly
above the filling machine in the filling room were
significantly discolored with an unknown substance
Read & share what
you understood
It was due to fumigation agent. Discolored HEPA
filters are now recolored
FDA
Firm
Evidence & justification demonstrating
the source of staining was missing
Assessment of the impact of the residue
on the performance of HEPA was missing
Impact of contamination hazard on drug
product and patient was missing

78. DIDP Case Study

79. Dibutyl phthalate (DBP) &
Di(2-ethylhexyl) phthalate (DEHP)
Avoid the use of these two specific
phthalates as excipients
Phthalates
FDA Point of View

80. As a plasticizer in enteric-coatings of solid oral
drug products to maintain flexibility
As softeners of plastics, solvents in perfumes,
Additives to nail polish, as well as in lubricants
and insect repellents
Phthalates
Uses

81. Epidemiological studies suggest that certain phthalates
may affect reproductive and developmental outcomes.
Other studies have confirmed the presence of DBP and
DEHP in amniotic fluid, breast milk, urine, and serum
Phthalates
Till date data in
humans are less clear

83. Plasticizer
DIDP & DINP
Di-iso Decyl Phthalate – 5.5 ppm
& Nonyl Phthalate – 5.7 ppm
Recalled Augmentin found contaminated that was
manufactured in GSK Worthing, England, 2011
Abrasion of poly vinyl chloride plastic tubing used to transfer powder &
granules during tablet production

84. Phthalates are endocrine disruptors – may
disrupt hormonal system and cause cancer
including breast cancer
Can damage liver, kidney, lungs &
reproductive system
Phthalates

85. • Short shelf life
• Metabolize and removed through urine
and stool in 24 hours (Anderson – 2001)
Phthalates – Removal
from body

86. Drinking straws, sealants used in food
packaging, toys, flooring, gloves, garden
hoses
Phthalates
(DINP)
From where it
comes in