understanding of product & process for installation of appropriate controls (12 april 2017)
TRANSCRIPT
Understanding of Product & Process
For Installation of Appropriate Controls
Roohi B. Obaid, R. Ph.Civil Services Officer
Member ISPE & PDA
12 April 2017
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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.
Why How
Why Howe.g. Saxagliptin
Lets have a look & walk through real cases
05 Feb 2017
Bupripion HCl ER
2.7 lakh bottle
Dissolution failure
At 18 month of
stability
Does anybody want to see such news early morning?
Does anybody want to see such news early morning?
Are you confident it will not happen with you?
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
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
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
Drug assay is
compliant
Drug assay is
compliant
Drug is not available
for absorption
Drug assay is
compliant
Drug is not available
for absorption
Do you expect
effect?
Therapeutic
effect under
question
Therapeutic
effect under
questionDisease may progress
Therapeutic
effect under
questionDisease may progress
A series of
consequences
may emerge
Therapeutic
effect under
questionDisease may progress
A series of
consequences
may emerge
Therapeutic
effect under
questionDisease may progress
A series of
consequences
may emerge
Pain killers
Therapeutic
effect under
questionDisease may progress
A series of
consequences
may emerge
Pain killers Cardiac drug
Therapeutic
effect under
questionDisease may progress
A series of
consequences
may emerge
Pain killers Cardiac drug Anti epileptic drug
2013
Amidate Injection
(Etomidate)
Degradation during
stability
Hospira & Pfizer product
Top Reasons for Recalls
1
Super or sub potent formulations
Digoxin (double
thickness)
Actavis 2008
1
Super or sub potent formulations
Digoxin (double
thickness)
Actavis 2008Poor Manufacturing Control
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
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
2
Particulate Contamination
Takeda, Millenium &
Janssen anti-cancer product
Particulates were seen after
reconstitution
Europe, America & Asia
Polyester like material
originated from filtration
system
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
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.
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
3
API’s Contamination
Bulk heparin in China
Over sulfated Chondroitin
Sulfate
80 deaths in USA alone
Found deliberated &
economically motivated
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
3
API’s Contamination
GSK Worthing UK facility
July 2015
Bactobran cream
containing Mupirocin
recalled
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
3
API’s Contamination
GSK Worthing UK facility
July 2015
Bactobran cream
containing Mupirocin
recalled
Inadequate Controls to
Prevent contamination
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
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
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
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
3
Contamination
Misoprostol Pharmacia
Peak gave signal but
ignored (13 lots)
Later contaminant
identified to be toluene
3
Contamination
Misoprostol Pharmacia
Peak gave signal but
ignored (13 lots)
Later contaminant
identified to be toluene
Loose ink in blister packaging line
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
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 ….
4
Sterility Failure
Various drugs for potential
sterility failure found
contaminated with
pathogenic organisms
High threat for HIV, Cystic
Fibrosis or TB
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
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
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
6
Disintegration Failure
Soft gel capsule failed in
disintegration
Millions of capsules
recalled
Company shut down for
a long time
6
Disintegration Failure
Soft gel capsule failed in
disintegration
Millions of capsules
recalled
Company shut down for
a long time
6
Dissolution failure
100’s of batches of
Paracetamol tablet
failed in Dissolution
6
Dissolution failure
100’s of batches of
Paracetamol tablet
failed in Dissolution
7
Manufacturing with poor knowledge
Rivaroxaban Tablet
Failure in CDP
7
Manufacturing with poor knowledge
Rivaroxaban Tablet
Failure in CDP
7
Manufacturing with poor knowledge
Ramipril tablets
Process degradation
found
7
Manufacturing with poor knowledge
Ramipril tablets
Process degradation
found
Able Laboratories, NJ
A story of Generic Manufacturing Company’s
Collapse
1999 to 2005
Enormous growth & expansion
17 - 55% per share
1999 to 2005
Enormous growth & expansion
17 - 55% per share
2005 - Major recall due to falsification of data
Flouting, altering or manipulation & reporting
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
Lets hear and watch the way Leaders
come forward to protect trust
These are the norms of moral business
Closing Words
Audit communicate &
monitor your suppliers
Understand CQA of your product
Understand CPP of your process
Validate your process
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
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