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Review of Control Strategy of GMP
Obaid Ali & Roohi B. Obaid (March 2013)
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
Presentation Focus
Cont’d
Presentation Focus
Back mirror challenges; Wake up call….s
Regulatory Complexity
Why Regulations?
Its not just as simple as its seems to be
Pre-approval Inspection
Post-approval Inspection
Pre-market Review
Post-market Review
SCENE
Regulatory Background
D R U
G
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
New
Generics
Primary Logical Boundaries
D R U G S
New Drugs
Main Concerns
Safety
Effi
cacy
Clinical SitesS
uppl
y C
hain Vigilance
Manufacturing Site
1
Main Elements of Review Process for New Drugs
Toxicology & Pharmacology
Clinical Pharmacol & Bio-Pharmaceutics
Medical & StatisticalImmunological review esp. for BiologicalsChemistry & CMC
Risk Evaluation & Mitigation Strategy
234
56
SCENE
5
Cross Discipline7
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 waiverClinical study….Bio-studies….Dissolution studies………Justification of waiver
Labeling review……Product Development……Stability……..Shelf lifeLabeling review……Product Development……Stability……..Shelf life
Manufacturing capacity………Pre-approval Inspection report………..history of GMPManufacturing capacity………Pre-approval Inspection report………..history of GMP
Review Journey
ProcessDesign
Review
SCENE
Mee
tings
Writing
SCENE
Review Model of the 21st Century
CTD International
Conference on Harmonization
Question based review
Main Challenges
ABILITY
Data Analysis and Assessment
SCENE
Iden
tific
atio
n of
Dat
a G
enui
nene
ss
Report W
riting
Consistency, mix-up, Contamination, Cross-contamination, Traceability and Data Integrity
Quality can not be observed by every one and/or by naked eye or even by product testing.
………………..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
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
Regulatory Mandate
………GMP under Schedule B……..
Obligatory to comply
Regulatory Mandate
………GMP under Schedule B……..
Obligatory to comply
GMP Expectations
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...........
Variations play ?????
Variations play ?????
Mix-upA number of drug products are being manufactured in a
same manufacturing facility
Label mix upPowder mix upBulk product mix upIn-process mix upBlister mix up Etc.
Let’s make science visible
Case Studies
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
Investigation Failure at QCU
Another investigation after 1.5 years suggested (based on relative retention time) the unknown
contaminant as toluene
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
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
Investigation Failure at QCU
Diethylphthalate (DEP) can be a source of contamination from desiccant cartridge
J&JDec 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
J&JDec 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
J&JDec 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
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
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
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
ResultA 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
ResultA huge number of bottles were recalled
Ranbaxy 2008Batamandi
Ranbaxy 2008Batamandi
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
Ranbaxy 2008Batamandi
Ranbaxy 2008Batamandi
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
Ranbaxy 2008Batamandi
Ranbaxy 2008Batamandi
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
Ranbaxy 2008Batamandi
Ranbaxy 2008Batamandi
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
Ranbaxy 2008Batamandi
Ranbaxy 2008Batamandi
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
Ranbaxy 2008Batamandi
Ranbaxy 2008Batamandi
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
Ranbaxy 2008Batamandi
Ranbaxy 2008Batamandi
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
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
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
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
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
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.
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.
Ranbaxy 2008 Dewas
Ranbaxy 2008 Dewas
Result of such observationsConsent 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 observationsConsent Decree and Import Alert for their
products in USA until drugs can be manufactured in the facilities complying with US manufacturing
Quality Standards
Human Factor Analysis and Classification System
What considerations will enhance preventive system and control?
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
Human Factor Analysis & Classification System (HFACS)
“………records are not completed
contemporaneously”
“………records are not completed
contemporaneously”
Misguided
Malicious
Closing Message SCENE
If there is a will, there is a way
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)