120th Training Session - Unfortunate Wave of DEG Tragedy.pdf
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
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
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
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 ..
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
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
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
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
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
82.
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