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Product Quality amp Patient Safety
Compounding to Manufacturing A 21st Century Journey Avoiding the Historical Blind Alleys
USPndashIndia Workshop Quality of Chemical MedicinesImpact of Impurities and Strategies for Control
ajazajazhussaincom
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC1
Prologue
Pharmaceutical Quality for the 21st Century ndash the need to realize quality by design and reduce
reliance on testing to document quality a regulatory (FDA) and a professional journey (since
2000)
My previous presentation at a USP Conference was over 10+ years ago - in September 2004
USP Annual Scientific Meeting ndash ldquoThe Science of Qualityrdquo Iselin NJ My talk was entitled ndash
lsquoBiopharmaceutics and Drug Product Quality Performance Tests A Look Into the Futurersquo
Optimal utility of the Pharmacopoeias in the 21st Century requires understanding difference
between lsquocompoundingrsquo and lsquomanufacturingrsquo lsquomarket standardsrsquo and lsquorelease testingrsquo
identifying and addressing the historical blind spots or blind alleys and effectively educating
the user amp lsquomarketrsquo community
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC2
Outline
Current state of pharmaceutical lsquoCompoundingrsquo amp lsquoManufacturingrsquo
What are our lsquoblind alleysrsquo
Illustrative examples of lsquoblind alleysrsquo
How can one avoid these (historical) lsquoblind alleysrsquo
Closing thoughts - Pharmacopoeias championing quality by design absolutely
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC3
Current state
Compounding May 2015 Reports
FDA to develop ldquoDo not compoundrdquo and ldquoDemonstrably difficult
to compoundldquo list being developed
Compounding Center to Pay $200 Million for Meningitis
Outbreak The companyrsquos chief pharmacist is one of two people
implicated in the outbreak and charged with second-degree
murder
Experts ponder drug compounding lawrsquos impact on
ophthalmology In 2013 in the wake of infectious outbreaks
traced to steroids and repackaged intravitreal Avastin produced
at compounding pharmacies Congress passed the Drug Quality
and Security Act which included the Compounding Quality Act
Manufacturing 2015 Reports
FDA Bans Drugs Made by Indian Manufacturer Over GMP
Problems hellip All 13 of those letters have cited irregularities
with the companies data integrity practices
Vertex JampJ GSK Novartis all working on continuous
manufacturing facilities FDA supports the move as a way to
improve quality in manufacturing
Modern Manufacturing Systems Key to FDA Quality
Initiativehellip Urgedhellipfor more than a decade to adopt more
reliable and efficient advanced manufacturing technologies
capable of ensuring consistent high-quality production that
meets standards and public expectations
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC4
Reading the media headlines ndash it would appear thathellip
Today it seems we manufacture
in a pharmacy to label it
compounding
We lsquocontrolrsquo manufacturing in
modern factories using market
standards designed for
compounding
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC5
Compendial standards apply only to the units tested
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC6
Being human means ldquowe can be blind to the obvious
and we are also blind to our blindnessrdquo
Daniel Kahneman
Thinking Fast and Slow
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC7
httpwebmiteduperscipeopleadelsoncheckershadow_proofhtml
Examples of our lsquoblind spotsrsquo or lsquoblind alleysrsquoRelevant to this workshop
Market
standards for
lsquoProduct
Releasersquo
bullKeeping the system in a lsquocorrective
actionrsquo mode
bullCorrecting lsquocommon causersquo poses a
problem
bullReasons to rationalize deviant
behaviors
Analytical
Method
Validation
bullEyes open when Quality becomes a
issue for National Security
bullA calibration lsquostandardrsquo which was too
variable
bullWhat is Gauge RampR Why needed for
testing physical attributes
Impurities amp
Contaminants
bulllsquo1937 to 2007rsquo ndash 70 years to open our
eyes
bulllsquoMarket standardrsquo that the lsquomarketrsquo
didnrsquot know how to use
bullEvidence of lsquoblisters in farm animalsrsquo ndash
okay to use in humans since impurity
not identified in the USP
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC8
Few lsquoblind alleysrsquo that some of us ndash the old timers ndash have
spent time in so that the next generation can learn to avoid
lsquo1937 to 2007rsquo ndash 70 years to
open our eyes
lsquoMarket standardrsquo that which
the lsquomarketrsquo doesnrsquot know how
to use
Evidence of lsquomouth blisters in
farm animalsrsquo ndash okay to use in
human lungs since impurity not
identified in the USP
Eyes open when Quality
becomes a issue for National
Security
A calibration lsquostandardrsquo which
was too variable
What is Gauge RampR Why
needed for testing physical
attributes
Keeping the system in a
lsquocorrective actionrsquo mode
Busy correcting lsquocommon causersquo
ndash chasing our tail
Reasons to rationalize deviant
behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC9
How does one avoid these lsquoblind alleysrsquo Systems thinking System is the product of
interacting parts improving the parts taken separately will not improve the system
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC10
CEO amp
Sr Management
Culture
of Quality
Managers amp
Leaders
Effective
QMS
GXP
Compliance
All
Employees
Quality is Easy
The slice that is most
relevant for this
workshop
Closing thoughts
Then - 2004
The Process Analytical Technology Initiative PAT and
the Pharmacopeias
bull EDQM Spring Conference Cannes 3-4 May 2004
Assuring quality by design provide greater assurance
than testing to document quality
bull ldquoData derived from manufacturing process validation studies and from
in-process controls may provide greater assurance that a batch meets a
particular monograph requirement than analytical data derived from
an examination of finished units drawn from that batchrdquo (General
Notices USP 27)
bull Time to drop the may
Penalty for large sample size built in ndash time to remove
this penalty
bull With increasing sample size for content uniformity the numbers of
tablets found outside range 75-125 among a batch of 1000000
Now - 2015
Pharmacopoeias championing
quality by design absolutely
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC11
Pharmacopoeias championing quality by design
absolutely
Drug Substance and Product Monographs ndash conceptually should be a more detailed Quality Target Product Profile ndash
outlining CQArsquos relevant to safety and efficacy
CQA- Acceptance Criteria with no penalty for larger samples supporting robust estimation of variability (eliminate
passfail or attribute criteria) ndash supporting continual improvement
General chapter on how to address process related impurities - specific impurities best controlled via the regulatory
submission and cGMPs
General chapters for Critical Quality amp Material Attributes (functionality) amp their Measurement ndash with specific focus
on physical attributes amp analytical validation with considerations for Gage RampR as appropriate Use (and donrsquot
forget) the lessons learned from dissolution calibration
Educate users on the correct role and interpretation of the Pharmacopoeias - remove any perceptionsreasons to
rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC12
Additional information on our lsquolsquoblind alleysrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC13
Blind spot 1
lsquo1937 to 2007rsquo ndash70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC14
lsquo1937 to 2007rsquo 70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC15
1938 The Federal Food Drug and Cosmetic (FDC)
bull 1937 Elixir of Sulfanilamide
1962 Kefauver-Harris Drug Amendments
bull 1962 Thalidomide
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
1992 Generic Drug Enforcement Act
bull1989 L-Tryptophan
bull 1989 Generic Drug Scandal
bull 1988 Food and Drug Administration Act
bull 1984 Fines Enhancement Laws Drug Price Competition and Patent Term Restoration Act
2012 Food and Drug Administration Safety and Innovation Act (FDASIA)
bull 2007 Heparin Disaster
2013 Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA) Drug Quality and Security Act
bull 2012 The Deadly Meningitis Outbreak
lsquo1937 to 2007rsquo 70 years to open our eyesIs this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC16
Guidance for Industry Testing of
Glycerin for Diethylene Glycol
CDER May 2007 Compliance
1 Manufacturers did not perform full identity
testing on the glycerin raw material
including tests to quantify the amount of
DEG
2 Relied on the certificate of analysis (COA)
3 The origin of the glycerin was not easily
apparent from the COA
4 The COA was often a copy of a COA on the
letterhead of the distributor
5 The chain of custody or distribution history
of the glycerin was also not readily known
USP Glycerin Monograph
Type of Posting Revision Bulletin
Posting Date 04ndashFebndash2009
Official Date 01ndashMayndash2009
Because of the serious hazards associated
withhellip and in response to
recommendations set forth in the FDA
Guidance for Industry Testing of Glycerin
for Diethylene Glycol published in May
2007 USP has revised the USP Glycerin
monograph
Because diethylene glycol and ethylene
glycol are considered unacceptable toxic
substances the testing of USP Glycerin
should demonstrate the absence of these
substances
April 2007 FDA request to
USP to revise the Glycerin
monographrsquos
IDENTIFICATION section
Revision includes adding ndash
Identification test B LIMIT OF
DIETHYLENE GLYCOL AND
ETHYLENE GLYCOL to detect and
quantify DEGEG in Glycerin minus Is no
longer part of the impurity testing
ldquoLimit of DEG and Related
Compoundsrdquo minus Introduces a capillary
gas-chromatographic (GC) method with
flame ionization detection (FID) minus Limit
of NMT 010 each for diethylene
glycol and ethylene glycol is found
Is this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC17
0
5
10
15
20
25
30
35
Yea
rs
DEG Years since the previous incident
0
50
100
150
200
250
300
350
Number of Reported Deaths1937
Eli
xir
of
Sulf
anil
amid
e
2007T
ootp
aste
conta
min
atio
n0 70 years 0 70
years
Frequent reports
Mumbai Mumbai
Data from Excipient Fest Janeen Skutnik Chair ndashIPECAmericas 2009
Fair helliprdquoBecause of the serious hazards associated withhellip and in
response to recommendations set forth in the FDA Guidancerdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC18
Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning JAMA 1998279(15)1175-1180
doi101001jama279151175
Month of hospital admission for children with
acute renal failure Haiti
October 1995-October 1996
Diethylene glycol poisoning in Gurgaon India 1998Bulletin of the World Health Organization 2001 79 88ndash95
We report a second episode of poisoning occurring in 1998 in India as
a result of children ingesting diethylene glycol at least 33 children
are known to have died
At the beginning of the investigation we never imagined that
contaminated medicine was causing acute renal failure in children
A brand of cough expectorant manufactured by a local pharmaceutical
company was found by the Central Drugs Laboratory Calcutta to
contain 175 (vv) diethylene glycol
The district and state drug controller had tested many samples using
thin layer chromatography before a sample of medicine tested positive
for diethylene glycol at the Central Drugs Laboratory None of the
earlier samples was found to be contaminated
Number of reported death grossly underestimate the harm caused
When the drug safety system fails people get sick
Some die (Congressman Shimkus)
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC19
bull Some of these people are already very vulnerable
and proving the cause of harm from impurities
adulteration and counterfeits can be elusive
It is hard to detect
harm
bull Certainly the companies are obligated to ensure
a culture of quality and maintain vigilance as
well This reflects a systems approach to safety
FDA inspectors look
for a culture of quality
at manufacturing
facilities
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Prologue
Pharmaceutical Quality for the 21st Century ndash the need to realize quality by design and reduce
reliance on testing to document quality a regulatory (FDA) and a professional journey (since
2000)
My previous presentation at a USP Conference was over 10+ years ago - in September 2004
USP Annual Scientific Meeting ndash ldquoThe Science of Qualityrdquo Iselin NJ My talk was entitled ndash
lsquoBiopharmaceutics and Drug Product Quality Performance Tests A Look Into the Futurersquo
Optimal utility of the Pharmacopoeias in the 21st Century requires understanding difference
between lsquocompoundingrsquo and lsquomanufacturingrsquo lsquomarket standardsrsquo and lsquorelease testingrsquo
identifying and addressing the historical blind spots or blind alleys and effectively educating
the user amp lsquomarketrsquo community
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC2
Outline
Current state of pharmaceutical lsquoCompoundingrsquo amp lsquoManufacturingrsquo
What are our lsquoblind alleysrsquo
Illustrative examples of lsquoblind alleysrsquo
How can one avoid these (historical) lsquoblind alleysrsquo
Closing thoughts - Pharmacopoeias championing quality by design absolutely
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC3
Current state
Compounding May 2015 Reports
FDA to develop ldquoDo not compoundrdquo and ldquoDemonstrably difficult
to compoundldquo list being developed
Compounding Center to Pay $200 Million for Meningitis
Outbreak The companyrsquos chief pharmacist is one of two people
implicated in the outbreak and charged with second-degree
murder
Experts ponder drug compounding lawrsquos impact on
ophthalmology In 2013 in the wake of infectious outbreaks
traced to steroids and repackaged intravitreal Avastin produced
at compounding pharmacies Congress passed the Drug Quality
and Security Act which included the Compounding Quality Act
Manufacturing 2015 Reports
FDA Bans Drugs Made by Indian Manufacturer Over GMP
Problems hellip All 13 of those letters have cited irregularities
with the companies data integrity practices
Vertex JampJ GSK Novartis all working on continuous
manufacturing facilities FDA supports the move as a way to
improve quality in manufacturing
Modern Manufacturing Systems Key to FDA Quality
Initiativehellip Urgedhellipfor more than a decade to adopt more
reliable and efficient advanced manufacturing technologies
capable of ensuring consistent high-quality production that
meets standards and public expectations
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC4
Reading the media headlines ndash it would appear thathellip
Today it seems we manufacture
in a pharmacy to label it
compounding
We lsquocontrolrsquo manufacturing in
modern factories using market
standards designed for
compounding
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC5
Compendial standards apply only to the units tested
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC6
Being human means ldquowe can be blind to the obvious
and we are also blind to our blindnessrdquo
Daniel Kahneman
Thinking Fast and Slow
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC7
httpwebmiteduperscipeopleadelsoncheckershadow_proofhtml
Examples of our lsquoblind spotsrsquo or lsquoblind alleysrsquoRelevant to this workshop
Market
standards for
lsquoProduct
Releasersquo
bullKeeping the system in a lsquocorrective
actionrsquo mode
bullCorrecting lsquocommon causersquo poses a
problem
bullReasons to rationalize deviant
behaviors
Analytical
Method
Validation
bullEyes open when Quality becomes a
issue for National Security
bullA calibration lsquostandardrsquo which was too
variable
bullWhat is Gauge RampR Why needed for
testing physical attributes
Impurities amp
Contaminants
bulllsquo1937 to 2007rsquo ndash 70 years to open our
eyes
bulllsquoMarket standardrsquo that the lsquomarketrsquo
didnrsquot know how to use
bullEvidence of lsquoblisters in farm animalsrsquo ndash
okay to use in humans since impurity
not identified in the USP
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC8
Few lsquoblind alleysrsquo that some of us ndash the old timers ndash have
spent time in so that the next generation can learn to avoid
lsquo1937 to 2007rsquo ndash 70 years to
open our eyes
lsquoMarket standardrsquo that which
the lsquomarketrsquo doesnrsquot know how
to use
Evidence of lsquomouth blisters in
farm animalsrsquo ndash okay to use in
human lungs since impurity not
identified in the USP
Eyes open when Quality
becomes a issue for National
Security
A calibration lsquostandardrsquo which
was too variable
What is Gauge RampR Why
needed for testing physical
attributes
Keeping the system in a
lsquocorrective actionrsquo mode
Busy correcting lsquocommon causersquo
ndash chasing our tail
Reasons to rationalize deviant
behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC9
How does one avoid these lsquoblind alleysrsquo Systems thinking System is the product of
interacting parts improving the parts taken separately will not improve the system
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC10
CEO amp
Sr Management
Culture
of Quality
Managers amp
Leaders
Effective
QMS
GXP
Compliance
All
Employees
Quality is Easy
The slice that is most
relevant for this
workshop
Closing thoughts
Then - 2004
The Process Analytical Technology Initiative PAT and
the Pharmacopeias
bull EDQM Spring Conference Cannes 3-4 May 2004
Assuring quality by design provide greater assurance
than testing to document quality
bull ldquoData derived from manufacturing process validation studies and from
in-process controls may provide greater assurance that a batch meets a
particular monograph requirement than analytical data derived from
an examination of finished units drawn from that batchrdquo (General
Notices USP 27)
bull Time to drop the may
Penalty for large sample size built in ndash time to remove
this penalty
bull With increasing sample size for content uniformity the numbers of
tablets found outside range 75-125 among a batch of 1000000
Now - 2015
Pharmacopoeias championing
quality by design absolutely
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC11
Pharmacopoeias championing quality by design
absolutely
Drug Substance and Product Monographs ndash conceptually should be a more detailed Quality Target Product Profile ndash
outlining CQArsquos relevant to safety and efficacy
CQA- Acceptance Criteria with no penalty for larger samples supporting robust estimation of variability (eliminate
passfail or attribute criteria) ndash supporting continual improvement
General chapter on how to address process related impurities - specific impurities best controlled via the regulatory
submission and cGMPs
General chapters for Critical Quality amp Material Attributes (functionality) amp their Measurement ndash with specific focus
on physical attributes amp analytical validation with considerations for Gage RampR as appropriate Use (and donrsquot
forget) the lessons learned from dissolution calibration
Educate users on the correct role and interpretation of the Pharmacopoeias - remove any perceptionsreasons to
rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC12
Additional information on our lsquolsquoblind alleysrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC13
Blind spot 1
lsquo1937 to 2007rsquo ndash70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC14
lsquo1937 to 2007rsquo 70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC15
1938 The Federal Food Drug and Cosmetic (FDC)
bull 1937 Elixir of Sulfanilamide
1962 Kefauver-Harris Drug Amendments
bull 1962 Thalidomide
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
1992 Generic Drug Enforcement Act
bull1989 L-Tryptophan
bull 1989 Generic Drug Scandal
bull 1988 Food and Drug Administration Act
bull 1984 Fines Enhancement Laws Drug Price Competition and Patent Term Restoration Act
2012 Food and Drug Administration Safety and Innovation Act (FDASIA)
bull 2007 Heparin Disaster
2013 Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA) Drug Quality and Security Act
bull 2012 The Deadly Meningitis Outbreak
lsquo1937 to 2007rsquo 70 years to open our eyesIs this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC16
Guidance for Industry Testing of
Glycerin for Diethylene Glycol
CDER May 2007 Compliance
1 Manufacturers did not perform full identity
testing on the glycerin raw material
including tests to quantify the amount of
DEG
2 Relied on the certificate of analysis (COA)
3 The origin of the glycerin was not easily
apparent from the COA
4 The COA was often a copy of a COA on the
letterhead of the distributor
5 The chain of custody or distribution history
of the glycerin was also not readily known
USP Glycerin Monograph
Type of Posting Revision Bulletin
Posting Date 04ndashFebndash2009
Official Date 01ndashMayndash2009
Because of the serious hazards associated
withhellip and in response to
recommendations set forth in the FDA
Guidance for Industry Testing of Glycerin
for Diethylene Glycol published in May
2007 USP has revised the USP Glycerin
monograph
Because diethylene glycol and ethylene
glycol are considered unacceptable toxic
substances the testing of USP Glycerin
should demonstrate the absence of these
substances
April 2007 FDA request to
USP to revise the Glycerin
monographrsquos
IDENTIFICATION section
Revision includes adding ndash
Identification test B LIMIT OF
DIETHYLENE GLYCOL AND
ETHYLENE GLYCOL to detect and
quantify DEGEG in Glycerin minus Is no
longer part of the impurity testing
ldquoLimit of DEG and Related
Compoundsrdquo minus Introduces a capillary
gas-chromatographic (GC) method with
flame ionization detection (FID) minus Limit
of NMT 010 each for diethylene
glycol and ethylene glycol is found
Is this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC17
0
5
10
15
20
25
30
35
Yea
rs
DEG Years since the previous incident
0
50
100
150
200
250
300
350
Number of Reported Deaths1937
Eli
xir
of
Sulf
anil
amid
e
2007T
ootp
aste
conta
min
atio
n0 70 years 0 70
years
Frequent reports
Mumbai Mumbai
Data from Excipient Fest Janeen Skutnik Chair ndashIPECAmericas 2009
Fair helliprdquoBecause of the serious hazards associated withhellip and in
response to recommendations set forth in the FDA Guidancerdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC18
Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning JAMA 1998279(15)1175-1180
doi101001jama279151175
Month of hospital admission for children with
acute renal failure Haiti
October 1995-October 1996
Diethylene glycol poisoning in Gurgaon India 1998Bulletin of the World Health Organization 2001 79 88ndash95
We report a second episode of poisoning occurring in 1998 in India as
a result of children ingesting diethylene glycol at least 33 children
are known to have died
At the beginning of the investigation we never imagined that
contaminated medicine was causing acute renal failure in children
A brand of cough expectorant manufactured by a local pharmaceutical
company was found by the Central Drugs Laboratory Calcutta to
contain 175 (vv) diethylene glycol
The district and state drug controller had tested many samples using
thin layer chromatography before a sample of medicine tested positive
for diethylene glycol at the Central Drugs Laboratory None of the
earlier samples was found to be contaminated
Number of reported death grossly underestimate the harm caused
When the drug safety system fails people get sick
Some die (Congressman Shimkus)
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC19
bull Some of these people are already very vulnerable
and proving the cause of harm from impurities
adulteration and counterfeits can be elusive
It is hard to detect
harm
bull Certainly the companies are obligated to ensure
a culture of quality and maintain vigilance as
well This reflects a systems approach to safety
FDA inspectors look
for a culture of quality
at manufacturing
facilities
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Outline
Current state of pharmaceutical lsquoCompoundingrsquo amp lsquoManufacturingrsquo
What are our lsquoblind alleysrsquo
Illustrative examples of lsquoblind alleysrsquo
How can one avoid these (historical) lsquoblind alleysrsquo
Closing thoughts - Pharmacopoeias championing quality by design absolutely
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC3
Current state
Compounding May 2015 Reports
FDA to develop ldquoDo not compoundrdquo and ldquoDemonstrably difficult
to compoundldquo list being developed
Compounding Center to Pay $200 Million for Meningitis
Outbreak The companyrsquos chief pharmacist is one of two people
implicated in the outbreak and charged with second-degree
murder
Experts ponder drug compounding lawrsquos impact on
ophthalmology In 2013 in the wake of infectious outbreaks
traced to steroids and repackaged intravitreal Avastin produced
at compounding pharmacies Congress passed the Drug Quality
and Security Act which included the Compounding Quality Act
Manufacturing 2015 Reports
FDA Bans Drugs Made by Indian Manufacturer Over GMP
Problems hellip All 13 of those letters have cited irregularities
with the companies data integrity practices
Vertex JampJ GSK Novartis all working on continuous
manufacturing facilities FDA supports the move as a way to
improve quality in manufacturing
Modern Manufacturing Systems Key to FDA Quality
Initiativehellip Urgedhellipfor more than a decade to adopt more
reliable and efficient advanced manufacturing technologies
capable of ensuring consistent high-quality production that
meets standards and public expectations
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC4
Reading the media headlines ndash it would appear thathellip
Today it seems we manufacture
in a pharmacy to label it
compounding
We lsquocontrolrsquo manufacturing in
modern factories using market
standards designed for
compounding
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC5
Compendial standards apply only to the units tested
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC6
Being human means ldquowe can be blind to the obvious
and we are also blind to our blindnessrdquo
Daniel Kahneman
Thinking Fast and Slow
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC7
httpwebmiteduperscipeopleadelsoncheckershadow_proofhtml
Examples of our lsquoblind spotsrsquo or lsquoblind alleysrsquoRelevant to this workshop
Market
standards for
lsquoProduct
Releasersquo
bullKeeping the system in a lsquocorrective
actionrsquo mode
bullCorrecting lsquocommon causersquo poses a
problem
bullReasons to rationalize deviant
behaviors
Analytical
Method
Validation
bullEyes open when Quality becomes a
issue for National Security
bullA calibration lsquostandardrsquo which was too
variable
bullWhat is Gauge RampR Why needed for
testing physical attributes
Impurities amp
Contaminants
bulllsquo1937 to 2007rsquo ndash 70 years to open our
eyes
bulllsquoMarket standardrsquo that the lsquomarketrsquo
didnrsquot know how to use
bullEvidence of lsquoblisters in farm animalsrsquo ndash
okay to use in humans since impurity
not identified in the USP
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC8
Few lsquoblind alleysrsquo that some of us ndash the old timers ndash have
spent time in so that the next generation can learn to avoid
lsquo1937 to 2007rsquo ndash 70 years to
open our eyes
lsquoMarket standardrsquo that which
the lsquomarketrsquo doesnrsquot know how
to use
Evidence of lsquomouth blisters in
farm animalsrsquo ndash okay to use in
human lungs since impurity not
identified in the USP
Eyes open when Quality
becomes a issue for National
Security
A calibration lsquostandardrsquo which
was too variable
What is Gauge RampR Why
needed for testing physical
attributes
Keeping the system in a
lsquocorrective actionrsquo mode
Busy correcting lsquocommon causersquo
ndash chasing our tail
Reasons to rationalize deviant
behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC9
How does one avoid these lsquoblind alleysrsquo Systems thinking System is the product of
interacting parts improving the parts taken separately will not improve the system
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC10
CEO amp
Sr Management
Culture
of Quality
Managers amp
Leaders
Effective
QMS
GXP
Compliance
All
Employees
Quality is Easy
The slice that is most
relevant for this
workshop
Closing thoughts
Then - 2004
The Process Analytical Technology Initiative PAT and
the Pharmacopeias
bull EDQM Spring Conference Cannes 3-4 May 2004
Assuring quality by design provide greater assurance
than testing to document quality
bull ldquoData derived from manufacturing process validation studies and from
in-process controls may provide greater assurance that a batch meets a
particular monograph requirement than analytical data derived from
an examination of finished units drawn from that batchrdquo (General
Notices USP 27)
bull Time to drop the may
Penalty for large sample size built in ndash time to remove
this penalty
bull With increasing sample size for content uniformity the numbers of
tablets found outside range 75-125 among a batch of 1000000
Now - 2015
Pharmacopoeias championing
quality by design absolutely
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC11
Pharmacopoeias championing quality by design
absolutely
Drug Substance and Product Monographs ndash conceptually should be a more detailed Quality Target Product Profile ndash
outlining CQArsquos relevant to safety and efficacy
CQA- Acceptance Criteria with no penalty for larger samples supporting robust estimation of variability (eliminate
passfail or attribute criteria) ndash supporting continual improvement
General chapter on how to address process related impurities - specific impurities best controlled via the regulatory
submission and cGMPs
General chapters for Critical Quality amp Material Attributes (functionality) amp their Measurement ndash with specific focus
on physical attributes amp analytical validation with considerations for Gage RampR as appropriate Use (and donrsquot
forget) the lessons learned from dissolution calibration
Educate users on the correct role and interpretation of the Pharmacopoeias - remove any perceptionsreasons to
rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC12
Additional information on our lsquolsquoblind alleysrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC13
Blind spot 1
lsquo1937 to 2007rsquo ndash70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC14
lsquo1937 to 2007rsquo 70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC15
1938 The Federal Food Drug and Cosmetic (FDC)
bull 1937 Elixir of Sulfanilamide
1962 Kefauver-Harris Drug Amendments
bull 1962 Thalidomide
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
1992 Generic Drug Enforcement Act
bull1989 L-Tryptophan
bull 1989 Generic Drug Scandal
bull 1988 Food and Drug Administration Act
bull 1984 Fines Enhancement Laws Drug Price Competition and Patent Term Restoration Act
2012 Food and Drug Administration Safety and Innovation Act (FDASIA)
bull 2007 Heparin Disaster
2013 Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA) Drug Quality and Security Act
bull 2012 The Deadly Meningitis Outbreak
lsquo1937 to 2007rsquo 70 years to open our eyesIs this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC16
Guidance for Industry Testing of
Glycerin for Diethylene Glycol
CDER May 2007 Compliance
1 Manufacturers did not perform full identity
testing on the glycerin raw material
including tests to quantify the amount of
DEG
2 Relied on the certificate of analysis (COA)
3 The origin of the glycerin was not easily
apparent from the COA
4 The COA was often a copy of a COA on the
letterhead of the distributor
5 The chain of custody or distribution history
of the glycerin was also not readily known
USP Glycerin Monograph
Type of Posting Revision Bulletin
Posting Date 04ndashFebndash2009
Official Date 01ndashMayndash2009
Because of the serious hazards associated
withhellip and in response to
recommendations set forth in the FDA
Guidance for Industry Testing of Glycerin
for Diethylene Glycol published in May
2007 USP has revised the USP Glycerin
monograph
Because diethylene glycol and ethylene
glycol are considered unacceptable toxic
substances the testing of USP Glycerin
should demonstrate the absence of these
substances
April 2007 FDA request to
USP to revise the Glycerin
monographrsquos
IDENTIFICATION section
Revision includes adding ndash
Identification test B LIMIT OF
DIETHYLENE GLYCOL AND
ETHYLENE GLYCOL to detect and
quantify DEGEG in Glycerin minus Is no
longer part of the impurity testing
ldquoLimit of DEG and Related
Compoundsrdquo minus Introduces a capillary
gas-chromatographic (GC) method with
flame ionization detection (FID) minus Limit
of NMT 010 each for diethylene
glycol and ethylene glycol is found
Is this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC17
0
5
10
15
20
25
30
35
Yea
rs
DEG Years since the previous incident
0
50
100
150
200
250
300
350
Number of Reported Deaths1937
Eli
xir
of
Sulf
anil
amid
e
2007T
ootp
aste
conta
min
atio
n0 70 years 0 70
years
Frequent reports
Mumbai Mumbai
Data from Excipient Fest Janeen Skutnik Chair ndashIPECAmericas 2009
Fair helliprdquoBecause of the serious hazards associated withhellip and in
response to recommendations set forth in the FDA Guidancerdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC18
Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning JAMA 1998279(15)1175-1180
doi101001jama279151175
Month of hospital admission for children with
acute renal failure Haiti
October 1995-October 1996
Diethylene glycol poisoning in Gurgaon India 1998Bulletin of the World Health Organization 2001 79 88ndash95
We report a second episode of poisoning occurring in 1998 in India as
a result of children ingesting diethylene glycol at least 33 children
are known to have died
At the beginning of the investigation we never imagined that
contaminated medicine was causing acute renal failure in children
A brand of cough expectorant manufactured by a local pharmaceutical
company was found by the Central Drugs Laboratory Calcutta to
contain 175 (vv) diethylene glycol
The district and state drug controller had tested many samples using
thin layer chromatography before a sample of medicine tested positive
for diethylene glycol at the Central Drugs Laboratory None of the
earlier samples was found to be contaminated
Number of reported death grossly underestimate the harm caused
When the drug safety system fails people get sick
Some die (Congressman Shimkus)
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC19
bull Some of these people are already very vulnerable
and proving the cause of harm from impurities
adulteration and counterfeits can be elusive
It is hard to detect
harm
bull Certainly the companies are obligated to ensure
a culture of quality and maintain vigilance as
well This reflects a systems approach to safety
FDA inspectors look
for a culture of quality
at manufacturing
facilities
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Current state
Compounding May 2015 Reports
FDA to develop ldquoDo not compoundrdquo and ldquoDemonstrably difficult
to compoundldquo list being developed
Compounding Center to Pay $200 Million for Meningitis
Outbreak The companyrsquos chief pharmacist is one of two people
implicated in the outbreak and charged with second-degree
murder
Experts ponder drug compounding lawrsquos impact on
ophthalmology In 2013 in the wake of infectious outbreaks
traced to steroids and repackaged intravitreal Avastin produced
at compounding pharmacies Congress passed the Drug Quality
and Security Act which included the Compounding Quality Act
Manufacturing 2015 Reports
FDA Bans Drugs Made by Indian Manufacturer Over GMP
Problems hellip All 13 of those letters have cited irregularities
with the companies data integrity practices
Vertex JampJ GSK Novartis all working on continuous
manufacturing facilities FDA supports the move as a way to
improve quality in manufacturing
Modern Manufacturing Systems Key to FDA Quality
Initiativehellip Urgedhellipfor more than a decade to adopt more
reliable and efficient advanced manufacturing technologies
capable of ensuring consistent high-quality production that
meets standards and public expectations
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC4
Reading the media headlines ndash it would appear thathellip
Today it seems we manufacture
in a pharmacy to label it
compounding
We lsquocontrolrsquo manufacturing in
modern factories using market
standards designed for
compounding
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC5
Compendial standards apply only to the units tested
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC6
Being human means ldquowe can be blind to the obvious
and we are also blind to our blindnessrdquo
Daniel Kahneman
Thinking Fast and Slow
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC7
httpwebmiteduperscipeopleadelsoncheckershadow_proofhtml
Examples of our lsquoblind spotsrsquo or lsquoblind alleysrsquoRelevant to this workshop
Market
standards for
lsquoProduct
Releasersquo
bullKeeping the system in a lsquocorrective
actionrsquo mode
bullCorrecting lsquocommon causersquo poses a
problem
bullReasons to rationalize deviant
behaviors
Analytical
Method
Validation
bullEyes open when Quality becomes a
issue for National Security
bullA calibration lsquostandardrsquo which was too
variable
bullWhat is Gauge RampR Why needed for
testing physical attributes
Impurities amp
Contaminants
bulllsquo1937 to 2007rsquo ndash 70 years to open our
eyes
bulllsquoMarket standardrsquo that the lsquomarketrsquo
didnrsquot know how to use
bullEvidence of lsquoblisters in farm animalsrsquo ndash
okay to use in humans since impurity
not identified in the USP
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC8
Few lsquoblind alleysrsquo that some of us ndash the old timers ndash have
spent time in so that the next generation can learn to avoid
lsquo1937 to 2007rsquo ndash 70 years to
open our eyes
lsquoMarket standardrsquo that which
the lsquomarketrsquo doesnrsquot know how
to use
Evidence of lsquomouth blisters in
farm animalsrsquo ndash okay to use in
human lungs since impurity not
identified in the USP
Eyes open when Quality
becomes a issue for National
Security
A calibration lsquostandardrsquo which
was too variable
What is Gauge RampR Why
needed for testing physical
attributes
Keeping the system in a
lsquocorrective actionrsquo mode
Busy correcting lsquocommon causersquo
ndash chasing our tail
Reasons to rationalize deviant
behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC9
How does one avoid these lsquoblind alleysrsquo Systems thinking System is the product of
interacting parts improving the parts taken separately will not improve the system
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC10
CEO amp
Sr Management
Culture
of Quality
Managers amp
Leaders
Effective
QMS
GXP
Compliance
All
Employees
Quality is Easy
The slice that is most
relevant for this
workshop
Closing thoughts
Then - 2004
The Process Analytical Technology Initiative PAT and
the Pharmacopeias
bull EDQM Spring Conference Cannes 3-4 May 2004
Assuring quality by design provide greater assurance
than testing to document quality
bull ldquoData derived from manufacturing process validation studies and from
in-process controls may provide greater assurance that a batch meets a
particular monograph requirement than analytical data derived from
an examination of finished units drawn from that batchrdquo (General
Notices USP 27)
bull Time to drop the may
Penalty for large sample size built in ndash time to remove
this penalty
bull With increasing sample size for content uniformity the numbers of
tablets found outside range 75-125 among a batch of 1000000
Now - 2015
Pharmacopoeias championing
quality by design absolutely
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC11
Pharmacopoeias championing quality by design
absolutely
Drug Substance and Product Monographs ndash conceptually should be a more detailed Quality Target Product Profile ndash
outlining CQArsquos relevant to safety and efficacy
CQA- Acceptance Criteria with no penalty for larger samples supporting robust estimation of variability (eliminate
passfail or attribute criteria) ndash supporting continual improvement
General chapter on how to address process related impurities - specific impurities best controlled via the regulatory
submission and cGMPs
General chapters for Critical Quality amp Material Attributes (functionality) amp their Measurement ndash with specific focus
on physical attributes amp analytical validation with considerations for Gage RampR as appropriate Use (and donrsquot
forget) the lessons learned from dissolution calibration
Educate users on the correct role and interpretation of the Pharmacopoeias - remove any perceptionsreasons to
rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC12
Additional information on our lsquolsquoblind alleysrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC13
Blind spot 1
lsquo1937 to 2007rsquo ndash70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC14
lsquo1937 to 2007rsquo 70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC15
1938 The Federal Food Drug and Cosmetic (FDC)
bull 1937 Elixir of Sulfanilamide
1962 Kefauver-Harris Drug Amendments
bull 1962 Thalidomide
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
1992 Generic Drug Enforcement Act
bull1989 L-Tryptophan
bull 1989 Generic Drug Scandal
bull 1988 Food and Drug Administration Act
bull 1984 Fines Enhancement Laws Drug Price Competition and Patent Term Restoration Act
2012 Food and Drug Administration Safety and Innovation Act (FDASIA)
bull 2007 Heparin Disaster
2013 Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA) Drug Quality and Security Act
bull 2012 The Deadly Meningitis Outbreak
lsquo1937 to 2007rsquo 70 years to open our eyesIs this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC16
Guidance for Industry Testing of
Glycerin for Diethylene Glycol
CDER May 2007 Compliance
1 Manufacturers did not perform full identity
testing on the glycerin raw material
including tests to quantify the amount of
DEG
2 Relied on the certificate of analysis (COA)
3 The origin of the glycerin was not easily
apparent from the COA
4 The COA was often a copy of a COA on the
letterhead of the distributor
5 The chain of custody or distribution history
of the glycerin was also not readily known
USP Glycerin Monograph
Type of Posting Revision Bulletin
Posting Date 04ndashFebndash2009
Official Date 01ndashMayndash2009
Because of the serious hazards associated
withhellip and in response to
recommendations set forth in the FDA
Guidance for Industry Testing of Glycerin
for Diethylene Glycol published in May
2007 USP has revised the USP Glycerin
monograph
Because diethylene glycol and ethylene
glycol are considered unacceptable toxic
substances the testing of USP Glycerin
should demonstrate the absence of these
substances
April 2007 FDA request to
USP to revise the Glycerin
monographrsquos
IDENTIFICATION section
Revision includes adding ndash
Identification test B LIMIT OF
DIETHYLENE GLYCOL AND
ETHYLENE GLYCOL to detect and
quantify DEGEG in Glycerin minus Is no
longer part of the impurity testing
ldquoLimit of DEG and Related
Compoundsrdquo minus Introduces a capillary
gas-chromatographic (GC) method with
flame ionization detection (FID) minus Limit
of NMT 010 each for diethylene
glycol and ethylene glycol is found
Is this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC17
0
5
10
15
20
25
30
35
Yea
rs
DEG Years since the previous incident
0
50
100
150
200
250
300
350
Number of Reported Deaths1937
Eli
xir
of
Sulf
anil
amid
e
2007T
ootp
aste
conta
min
atio
n0 70 years 0 70
years
Frequent reports
Mumbai Mumbai
Data from Excipient Fest Janeen Skutnik Chair ndashIPECAmericas 2009
Fair helliprdquoBecause of the serious hazards associated withhellip and in
response to recommendations set forth in the FDA Guidancerdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC18
Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning JAMA 1998279(15)1175-1180
doi101001jama279151175
Month of hospital admission for children with
acute renal failure Haiti
October 1995-October 1996
Diethylene glycol poisoning in Gurgaon India 1998Bulletin of the World Health Organization 2001 79 88ndash95
We report a second episode of poisoning occurring in 1998 in India as
a result of children ingesting diethylene glycol at least 33 children
are known to have died
At the beginning of the investigation we never imagined that
contaminated medicine was causing acute renal failure in children
A brand of cough expectorant manufactured by a local pharmaceutical
company was found by the Central Drugs Laboratory Calcutta to
contain 175 (vv) diethylene glycol
The district and state drug controller had tested many samples using
thin layer chromatography before a sample of medicine tested positive
for diethylene glycol at the Central Drugs Laboratory None of the
earlier samples was found to be contaminated
Number of reported death grossly underestimate the harm caused
When the drug safety system fails people get sick
Some die (Congressman Shimkus)
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC19
bull Some of these people are already very vulnerable
and proving the cause of harm from impurities
adulteration and counterfeits can be elusive
It is hard to detect
harm
bull Certainly the companies are obligated to ensure
a culture of quality and maintain vigilance as
well This reflects a systems approach to safety
FDA inspectors look
for a culture of quality
at manufacturing
facilities
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Reading the media headlines ndash it would appear thathellip
Today it seems we manufacture
in a pharmacy to label it
compounding
We lsquocontrolrsquo manufacturing in
modern factories using market
standards designed for
compounding
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC5
Compendial standards apply only to the units tested
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC6
Being human means ldquowe can be blind to the obvious
and we are also blind to our blindnessrdquo
Daniel Kahneman
Thinking Fast and Slow
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC7
httpwebmiteduperscipeopleadelsoncheckershadow_proofhtml
Examples of our lsquoblind spotsrsquo or lsquoblind alleysrsquoRelevant to this workshop
Market
standards for
lsquoProduct
Releasersquo
bullKeeping the system in a lsquocorrective
actionrsquo mode
bullCorrecting lsquocommon causersquo poses a
problem
bullReasons to rationalize deviant
behaviors
Analytical
Method
Validation
bullEyes open when Quality becomes a
issue for National Security
bullA calibration lsquostandardrsquo which was too
variable
bullWhat is Gauge RampR Why needed for
testing physical attributes
Impurities amp
Contaminants
bulllsquo1937 to 2007rsquo ndash 70 years to open our
eyes
bulllsquoMarket standardrsquo that the lsquomarketrsquo
didnrsquot know how to use
bullEvidence of lsquoblisters in farm animalsrsquo ndash
okay to use in humans since impurity
not identified in the USP
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC8
Few lsquoblind alleysrsquo that some of us ndash the old timers ndash have
spent time in so that the next generation can learn to avoid
lsquo1937 to 2007rsquo ndash 70 years to
open our eyes
lsquoMarket standardrsquo that which
the lsquomarketrsquo doesnrsquot know how
to use
Evidence of lsquomouth blisters in
farm animalsrsquo ndash okay to use in
human lungs since impurity not
identified in the USP
Eyes open when Quality
becomes a issue for National
Security
A calibration lsquostandardrsquo which
was too variable
What is Gauge RampR Why
needed for testing physical
attributes
Keeping the system in a
lsquocorrective actionrsquo mode
Busy correcting lsquocommon causersquo
ndash chasing our tail
Reasons to rationalize deviant
behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC9
How does one avoid these lsquoblind alleysrsquo Systems thinking System is the product of
interacting parts improving the parts taken separately will not improve the system
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC10
CEO amp
Sr Management
Culture
of Quality
Managers amp
Leaders
Effective
QMS
GXP
Compliance
All
Employees
Quality is Easy
The slice that is most
relevant for this
workshop
Closing thoughts
Then - 2004
The Process Analytical Technology Initiative PAT and
the Pharmacopeias
bull EDQM Spring Conference Cannes 3-4 May 2004
Assuring quality by design provide greater assurance
than testing to document quality
bull ldquoData derived from manufacturing process validation studies and from
in-process controls may provide greater assurance that a batch meets a
particular monograph requirement than analytical data derived from
an examination of finished units drawn from that batchrdquo (General
Notices USP 27)
bull Time to drop the may
Penalty for large sample size built in ndash time to remove
this penalty
bull With increasing sample size for content uniformity the numbers of
tablets found outside range 75-125 among a batch of 1000000
Now - 2015
Pharmacopoeias championing
quality by design absolutely
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC11
Pharmacopoeias championing quality by design
absolutely
Drug Substance and Product Monographs ndash conceptually should be a more detailed Quality Target Product Profile ndash
outlining CQArsquos relevant to safety and efficacy
CQA- Acceptance Criteria with no penalty for larger samples supporting robust estimation of variability (eliminate
passfail or attribute criteria) ndash supporting continual improvement
General chapter on how to address process related impurities - specific impurities best controlled via the regulatory
submission and cGMPs
General chapters for Critical Quality amp Material Attributes (functionality) amp their Measurement ndash with specific focus
on physical attributes amp analytical validation with considerations for Gage RampR as appropriate Use (and donrsquot
forget) the lessons learned from dissolution calibration
Educate users on the correct role and interpretation of the Pharmacopoeias - remove any perceptionsreasons to
rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC12
Additional information on our lsquolsquoblind alleysrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC13
Blind spot 1
lsquo1937 to 2007rsquo ndash70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC14
lsquo1937 to 2007rsquo 70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC15
1938 The Federal Food Drug and Cosmetic (FDC)
bull 1937 Elixir of Sulfanilamide
1962 Kefauver-Harris Drug Amendments
bull 1962 Thalidomide
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
1992 Generic Drug Enforcement Act
bull1989 L-Tryptophan
bull 1989 Generic Drug Scandal
bull 1988 Food and Drug Administration Act
bull 1984 Fines Enhancement Laws Drug Price Competition and Patent Term Restoration Act
2012 Food and Drug Administration Safety and Innovation Act (FDASIA)
bull 2007 Heparin Disaster
2013 Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA) Drug Quality and Security Act
bull 2012 The Deadly Meningitis Outbreak
lsquo1937 to 2007rsquo 70 years to open our eyesIs this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC16
Guidance for Industry Testing of
Glycerin for Diethylene Glycol
CDER May 2007 Compliance
1 Manufacturers did not perform full identity
testing on the glycerin raw material
including tests to quantify the amount of
DEG
2 Relied on the certificate of analysis (COA)
3 The origin of the glycerin was not easily
apparent from the COA
4 The COA was often a copy of a COA on the
letterhead of the distributor
5 The chain of custody or distribution history
of the glycerin was also not readily known
USP Glycerin Monograph
Type of Posting Revision Bulletin
Posting Date 04ndashFebndash2009
Official Date 01ndashMayndash2009
Because of the serious hazards associated
withhellip and in response to
recommendations set forth in the FDA
Guidance for Industry Testing of Glycerin
for Diethylene Glycol published in May
2007 USP has revised the USP Glycerin
monograph
Because diethylene glycol and ethylene
glycol are considered unacceptable toxic
substances the testing of USP Glycerin
should demonstrate the absence of these
substances
April 2007 FDA request to
USP to revise the Glycerin
monographrsquos
IDENTIFICATION section
Revision includes adding ndash
Identification test B LIMIT OF
DIETHYLENE GLYCOL AND
ETHYLENE GLYCOL to detect and
quantify DEGEG in Glycerin minus Is no
longer part of the impurity testing
ldquoLimit of DEG and Related
Compoundsrdquo minus Introduces a capillary
gas-chromatographic (GC) method with
flame ionization detection (FID) minus Limit
of NMT 010 each for diethylene
glycol and ethylene glycol is found
Is this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC17
0
5
10
15
20
25
30
35
Yea
rs
DEG Years since the previous incident
0
50
100
150
200
250
300
350
Number of Reported Deaths1937
Eli
xir
of
Sulf
anil
amid
e
2007T
ootp
aste
conta
min
atio
n0 70 years 0 70
years
Frequent reports
Mumbai Mumbai
Data from Excipient Fest Janeen Skutnik Chair ndashIPECAmericas 2009
Fair helliprdquoBecause of the serious hazards associated withhellip and in
response to recommendations set forth in the FDA Guidancerdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC18
Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning JAMA 1998279(15)1175-1180
doi101001jama279151175
Month of hospital admission for children with
acute renal failure Haiti
October 1995-October 1996
Diethylene glycol poisoning in Gurgaon India 1998Bulletin of the World Health Organization 2001 79 88ndash95
We report a second episode of poisoning occurring in 1998 in India as
a result of children ingesting diethylene glycol at least 33 children
are known to have died
At the beginning of the investigation we never imagined that
contaminated medicine was causing acute renal failure in children
A brand of cough expectorant manufactured by a local pharmaceutical
company was found by the Central Drugs Laboratory Calcutta to
contain 175 (vv) diethylene glycol
The district and state drug controller had tested many samples using
thin layer chromatography before a sample of medicine tested positive
for diethylene glycol at the Central Drugs Laboratory None of the
earlier samples was found to be contaminated
Number of reported death grossly underestimate the harm caused
When the drug safety system fails people get sick
Some die (Congressman Shimkus)
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC19
bull Some of these people are already very vulnerable
and proving the cause of harm from impurities
adulteration and counterfeits can be elusive
It is hard to detect
harm
bull Certainly the companies are obligated to ensure
a culture of quality and maintain vigilance as
well This reflects a systems approach to safety
FDA inspectors look
for a culture of quality
at manufacturing
facilities
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Compendial standards apply only to the units tested
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC6
Being human means ldquowe can be blind to the obvious
and we are also blind to our blindnessrdquo
Daniel Kahneman
Thinking Fast and Slow
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC7
httpwebmiteduperscipeopleadelsoncheckershadow_proofhtml
Examples of our lsquoblind spotsrsquo or lsquoblind alleysrsquoRelevant to this workshop
Market
standards for
lsquoProduct
Releasersquo
bullKeeping the system in a lsquocorrective
actionrsquo mode
bullCorrecting lsquocommon causersquo poses a
problem
bullReasons to rationalize deviant
behaviors
Analytical
Method
Validation
bullEyes open when Quality becomes a
issue for National Security
bullA calibration lsquostandardrsquo which was too
variable
bullWhat is Gauge RampR Why needed for
testing physical attributes
Impurities amp
Contaminants
bulllsquo1937 to 2007rsquo ndash 70 years to open our
eyes
bulllsquoMarket standardrsquo that the lsquomarketrsquo
didnrsquot know how to use
bullEvidence of lsquoblisters in farm animalsrsquo ndash
okay to use in humans since impurity
not identified in the USP
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC8
Few lsquoblind alleysrsquo that some of us ndash the old timers ndash have
spent time in so that the next generation can learn to avoid
lsquo1937 to 2007rsquo ndash 70 years to
open our eyes
lsquoMarket standardrsquo that which
the lsquomarketrsquo doesnrsquot know how
to use
Evidence of lsquomouth blisters in
farm animalsrsquo ndash okay to use in
human lungs since impurity not
identified in the USP
Eyes open when Quality
becomes a issue for National
Security
A calibration lsquostandardrsquo which
was too variable
What is Gauge RampR Why
needed for testing physical
attributes
Keeping the system in a
lsquocorrective actionrsquo mode
Busy correcting lsquocommon causersquo
ndash chasing our tail
Reasons to rationalize deviant
behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC9
How does one avoid these lsquoblind alleysrsquo Systems thinking System is the product of
interacting parts improving the parts taken separately will not improve the system
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC10
CEO amp
Sr Management
Culture
of Quality
Managers amp
Leaders
Effective
QMS
GXP
Compliance
All
Employees
Quality is Easy
The slice that is most
relevant for this
workshop
Closing thoughts
Then - 2004
The Process Analytical Technology Initiative PAT and
the Pharmacopeias
bull EDQM Spring Conference Cannes 3-4 May 2004
Assuring quality by design provide greater assurance
than testing to document quality
bull ldquoData derived from manufacturing process validation studies and from
in-process controls may provide greater assurance that a batch meets a
particular monograph requirement than analytical data derived from
an examination of finished units drawn from that batchrdquo (General
Notices USP 27)
bull Time to drop the may
Penalty for large sample size built in ndash time to remove
this penalty
bull With increasing sample size for content uniformity the numbers of
tablets found outside range 75-125 among a batch of 1000000
Now - 2015
Pharmacopoeias championing
quality by design absolutely
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC11
Pharmacopoeias championing quality by design
absolutely
Drug Substance and Product Monographs ndash conceptually should be a more detailed Quality Target Product Profile ndash
outlining CQArsquos relevant to safety and efficacy
CQA- Acceptance Criteria with no penalty for larger samples supporting robust estimation of variability (eliminate
passfail or attribute criteria) ndash supporting continual improvement
General chapter on how to address process related impurities - specific impurities best controlled via the regulatory
submission and cGMPs
General chapters for Critical Quality amp Material Attributes (functionality) amp their Measurement ndash with specific focus
on physical attributes amp analytical validation with considerations for Gage RampR as appropriate Use (and donrsquot
forget) the lessons learned from dissolution calibration
Educate users on the correct role and interpretation of the Pharmacopoeias - remove any perceptionsreasons to
rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC12
Additional information on our lsquolsquoblind alleysrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC13
Blind spot 1
lsquo1937 to 2007rsquo ndash70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC14
lsquo1937 to 2007rsquo 70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC15
1938 The Federal Food Drug and Cosmetic (FDC)
bull 1937 Elixir of Sulfanilamide
1962 Kefauver-Harris Drug Amendments
bull 1962 Thalidomide
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
1992 Generic Drug Enforcement Act
bull1989 L-Tryptophan
bull 1989 Generic Drug Scandal
bull 1988 Food and Drug Administration Act
bull 1984 Fines Enhancement Laws Drug Price Competition and Patent Term Restoration Act
2012 Food and Drug Administration Safety and Innovation Act (FDASIA)
bull 2007 Heparin Disaster
2013 Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA) Drug Quality and Security Act
bull 2012 The Deadly Meningitis Outbreak
lsquo1937 to 2007rsquo 70 years to open our eyesIs this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC16
Guidance for Industry Testing of
Glycerin for Diethylene Glycol
CDER May 2007 Compliance
1 Manufacturers did not perform full identity
testing on the glycerin raw material
including tests to quantify the amount of
DEG
2 Relied on the certificate of analysis (COA)
3 The origin of the glycerin was not easily
apparent from the COA
4 The COA was often a copy of a COA on the
letterhead of the distributor
5 The chain of custody or distribution history
of the glycerin was also not readily known
USP Glycerin Monograph
Type of Posting Revision Bulletin
Posting Date 04ndashFebndash2009
Official Date 01ndashMayndash2009
Because of the serious hazards associated
withhellip and in response to
recommendations set forth in the FDA
Guidance for Industry Testing of Glycerin
for Diethylene Glycol published in May
2007 USP has revised the USP Glycerin
monograph
Because diethylene glycol and ethylene
glycol are considered unacceptable toxic
substances the testing of USP Glycerin
should demonstrate the absence of these
substances
April 2007 FDA request to
USP to revise the Glycerin
monographrsquos
IDENTIFICATION section
Revision includes adding ndash
Identification test B LIMIT OF
DIETHYLENE GLYCOL AND
ETHYLENE GLYCOL to detect and
quantify DEGEG in Glycerin minus Is no
longer part of the impurity testing
ldquoLimit of DEG and Related
Compoundsrdquo minus Introduces a capillary
gas-chromatographic (GC) method with
flame ionization detection (FID) minus Limit
of NMT 010 each for diethylene
glycol and ethylene glycol is found
Is this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC17
0
5
10
15
20
25
30
35
Yea
rs
DEG Years since the previous incident
0
50
100
150
200
250
300
350
Number of Reported Deaths1937
Eli
xir
of
Sulf
anil
amid
e
2007T
ootp
aste
conta
min
atio
n0 70 years 0 70
years
Frequent reports
Mumbai Mumbai
Data from Excipient Fest Janeen Skutnik Chair ndashIPECAmericas 2009
Fair helliprdquoBecause of the serious hazards associated withhellip and in
response to recommendations set forth in the FDA Guidancerdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC18
Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning JAMA 1998279(15)1175-1180
doi101001jama279151175
Month of hospital admission for children with
acute renal failure Haiti
October 1995-October 1996
Diethylene glycol poisoning in Gurgaon India 1998Bulletin of the World Health Organization 2001 79 88ndash95
We report a second episode of poisoning occurring in 1998 in India as
a result of children ingesting diethylene glycol at least 33 children
are known to have died
At the beginning of the investigation we never imagined that
contaminated medicine was causing acute renal failure in children
A brand of cough expectorant manufactured by a local pharmaceutical
company was found by the Central Drugs Laboratory Calcutta to
contain 175 (vv) diethylene glycol
The district and state drug controller had tested many samples using
thin layer chromatography before a sample of medicine tested positive
for diethylene glycol at the Central Drugs Laboratory None of the
earlier samples was found to be contaminated
Number of reported death grossly underestimate the harm caused
When the drug safety system fails people get sick
Some die (Congressman Shimkus)
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC19
bull Some of these people are already very vulnerable
and proving the cause of harm from impurities
adulteration and counterfeits can be elusive
It is hard to detect
harm
bull Certainly the companies are obligated to ensure
a culture of quality and maintain vigilance as
well This reflects a systems approach to safety
FDA inspectors look
for a culture of quality
at manufacturing
facilities
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Being human means ldquowe can be blind to the obvious
and we are also blind to our blindnessrdquo
Daniel Kahneman
Thinking Fast and Slow
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC7
httpwebmiteduperscipeopleadelsoncheckershadow_proofhtml
Examples of our lsquoblind spotsrsquo or lsquoblind alleysrsquoRelevant to this workshop
Market
standards for
lsquoProduct
Releasersquo
bullKeeping the system in a lsquocorrective
actionrsquo mode
bullCorrecting lsquocommon causersquo poses a
problem
bullReasons to rationalize deviant
behaviors
Analytical
Method
Validation
bullEyes open when Quality becomes a
issue for National Security
bullA calibration lsquostandardrsquo which was too
variable
bullWhat is Gauge RampR Why needed for
testing physical attributes
Impurities amp
Contaminants
bulllsquo1937 to 2007rsquo ndash 70 years to open our
eyes
bulllsquoMarket standardrsquo that the lsquomarketrsquo
didnrsquot know how to use
bullEvidence of lsquoblisters in farm animalsrsquo ndash
okay to use in humans since impurity
not identified in the USP
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC8
Few lsquoblind alleysrsquo that some of us ndash the old timers ndash have
spent time in so that the next generation can learn to avoid
lsquo1937 to 2007rsquo ndash 70 years to
open our eyes
lsquoMarket standardrsquo that which
the lsquomarketrsquo doesnrsquot know how
to use
Evidence of lsquomouth blisters in
farm animalsrsquo ndash okay to use in
human lungs since impurity not
identified in the USP
Eyes open when Quality
becomes a issue for National
Security
A calibration lsquostandardrsquo which
was too variable
What is Gauge RampR Why
needed for testing physical
attributes
Keeping the system in a
lsquocorrective actionrsquo mode
Busy correcting lsquocommon causersquo
ndash chasing our tail
Reasons to rationalize deviant
behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC9
How does one avoid these lsquoblind alleysrsquo Systems thinking System is the product of
interacting parts improving the parts taken separately will not improve the system
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC10
CEO amp
Sr Management
Culture
of Quality
Managers amp
Leaders
Effective
QMS
GXP
Compliance
All
Employees
Quality is Easy
The slice that is most
relevant for this
workshop
Closing thoughts
Then - 2004
The Process Analytical Technology Initiative PAT and
the Pharmacopeias
bull EDQM Spring Conference Cannes 3-4 May 2004
Assuring quality by design provide greater assurance
than testing to document quality
bull ldquoData derived from manufacturing process validation studies and from
in-process controls may provide greater assurance that a batch meets a
particular monograph requirement than analytical data derived from
an examination of finished units drawn from that batchrdquo (General
Notices USP 27)
bull Time to drop the may
Penalty for large sample size built in ndash time to remove
this penalty
bull With increasing sample size for content uniformity the numbers of
tablets found outside range 75-125 among a batch of 1000000
Now - 2015
Pharmacopoeias championing
quality by design absolutely
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC11
Pharmacopoeias championing quality by design
absolutely
Drug Substance and Product Monographs ndash conceptually should be a more detailed Quality Target Product Profile ndash
outlining CQArsquos relevant to safety and efficacy
CQA- Acceptance Criteria with no penalty for larger samples supporting robust estimation of variability (eliminate
passfail or attribute criteria) ndash supporting continual improvement
General chapter on how to address process related impurities - specific impurities best controlled via the regulatory
submission and cGMPs
General chapters for Critical Quality amp Material Attributes (functionality) amp their Measurement ndash with specific focus
on physical attributes amp analytical validation with considerations for Gage RampR as appropriate Use (and donrsquot
forget) the lessons learned from dissolution calibration
Educate users on the correct role and interpretation of the Pharmacopoeias - remove any perceptionsreasons to
rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC12
Additional information on our lsquolsquoblind alleysrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC13
Blind spot 1
lsquo1937 to 2007rsquo ndash70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC14
lsquo1937 to 2007rsquo 70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC15
1938 The Federal Food Drug and Cosmetic (FDC)
bull 1937 Elixir of Sulfanilamide
1962 Kefauver-Harris Drug Amendments
bull 1962 Thalidomide
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
1992 Generic Drug Enforcement Act
bull1989 L-Tryptophan
bull 1989 Generic Drug Scandal
bull 1988 Food and Drug Administration Act
bull 1984 Fines Enhancement Laws Drug Price Competition and Patent Term Restoration Act
2012 Food and Drug Administration Safety and Innovation Act (FDASIA)
bull 2007 Heparin Disaster
2013 Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA) Drug Quality and Security Act
bull 2012 The Deadly Meningitis Outbreak
lsquo1937 to 2007rsquo 70 years to open our eyesIs this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC16
Guidance for Industry Testing of
Glycerin for Diethylene Glycol
CDER May 2007 Compliance
1 Manufacturers did not perform full identity
testing on the glycerin raw material
including tests to quantify the amount of
DEG
2 Relied on the certificate of analysis (COA)
3 The origin of the glycerin was not easily
apparent from the COA
4 The COA was often a copy of a COA on the
letterhead of the distributor
5 The chain of custody or distribution history
of the glycerin was also not readily known
USP Glycerin Monograph
Type of Posting Revision Bulletin
Posting Date 04ndashFebndash2009
Official Date 01ndashMayndash2009
Because of the serious hazards associated
withhellip and in response to
recommendations set forth in the FDA
Guidance for Industry Testing of Glycerin
for Diethylene Glycol published in May
2007 USP has revised the USP Glycerin
monograph
Because diethylene glycol and ethylene
glycol are considered unacceptable toxic
substances the testing of USP Glycerin
should demonstrate the absence of these
substances
April 2007 FDA request to
USP to revise the Glycerin
monographrsquos
IDENTIFICATION section
Revision includes adding ndash
Identification test B LIMIT OF
DIETHYLENE GLYCOL AND
ETHYLENE GLYCOL to detect and
quantify DEGEG in Glycerin minus Is no
longer part of the impurity testing
ldquoLimit of DEG and Related
Compoundsrdquo minus Introduces a capillary
gas-chromatographic (GC) method with
flame ionization detection (FID) minus Limit
of NMT 010 each for diethylene
glycol and ethylene glycol is found
Is this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC17
0
5
10
15
20
25
30
35
Yea
rs
DEG Years since the previous incident
0
50
100
150
200
250
300
350
Number of Reported Deaths1937
Eli
xir
of
Sulf
anil
amid
e
2007T
ootp
aste
conta
min
atio
n0 70 years 0 70
years
Frequent reports
Mumbai Mumbai
Data from Excipient Fest Janeen Skutnik Chair ndashIPECAmericas 2009
Fair helliprdquoBecause of the serious hazards associated withhellip and in
response to recommendations set forth in the FDA Guidancerdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC18
Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning JAMA 1998279(15)1175-1180
doi101001jama279151175
Month of hospital admission for children with
acute renal failure Haiti
October 1995-October 1996
Diethylene glycol poisoning in Gurgaon India 1998Bulletin of the World Health Organization 2001 79 88ndash95
We report a second episode of poisoning occurring in 1998 in India as
a result of children ingesting diethylene glycol at least 33 children
are known to have died
At the beginning of the investigation we never imagined that
contaminated medicine was causing acute renal failure in children
A brand of cough expectorant manufactured by a local pharmaceutical
company was found by the Central Drugs Laboratory Calcutta to
contain 175 (vv) diethylene glycol
The district and state drug controller had tested many samples using
thin layer chromatography before a sample of medicine tested positive
for diethylene glycol at the Central Drugs Laboratory None of the
earlier samples was found to be contaminated
Number of reported death grossly underestimate the harm caused
When the drug safety system fails people get sick
Some die (Congressman Shimkus)
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC19
bull Some of these people are already very vulnerable
and proving the cause of harm from impurities
adulteration and counterfeits can be elusive
It is hard to detect
harm
bull Certainly the companies are obligated to ensure
a culture of quality and maintain vigilance as
well This reflects a systems approach to safety
FDA inspectors look
for a culture of quality
at manufacturing
facilities
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Examples of our lsquoblind spotsrsquo or lsquoblind alleysrsquoRelevant to this workshop
Market
standards for
lsquoProduct
Releasersquo
bullKeeping the system in a lsquocorrective
actionrsquo mode
bullCorrecting lsquocommon causersquo poses a
problem
bullReasons to rationalize deviant
behaviors
Analytical
Method
Validation
bullEyes open when Quality becomes a
issue for National Security
bullA calibration lsquostandardrsquo which was too
variable
bullWhat is Gauge RampR Why needed for
testing physical attributes
Impurities amp
Contaminants
bulllsquo1937 to 2007rsquo ndash 70 years to open our
eyes
bulllsquoMarket standardrsquo that the lsquomarketrsquo
didnrsquot know how to use
bullEvidence of lsquoblisters in farm animalsrsquo ndash
okay to use in humans since impurity
not identified in the USP
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC8
Few lsquoblind alleysrsquo that some of us ndash the old timers ndash have
spent time in so that the next generation can learn to avoid
lsquo1937 to 2007rsquo ndash 70 years to
open our eyes
lsquoMarket standardrsquo that which
the lsquomarketrsquo doesnrsquot know how
to use
Evidence of lsquomouth blisters in
farm animalsrsquo ndash okay to use in
human lungs since impurity not
identified in the USP
Eyes open when Quality
becomes a issue for National
Security
A calibration lsquostandardrsquo which
was too variable
What is Gauge RampR Why
needed for testing physical
attributes
Keeping the system in a
lsquocorrective actionrsquo mode
Busy correcting lsquocommon causersquo
ndash chasing our tail
Reasons to rationalize deviant
behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC9
How does one avoid these lsquoblind alleysrsquo Systems thinking System is the product of
interacting parts improving the parts taken separately will not improve the system
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC10
CEO amp
Sr Management
Culture
of Quality
Managers amp
Leaders
Effective
QMS
GXP
Compliance
All
Employees
Quality is Easy
The slice that is most
relevant for this
workshop
Closing thoughts
Then - 2004
The Process Analytical Technology Initiative PAT and
the Pharmacopeias
bull EDQM Spring Conference Cannes 3-4 May 2004
Assuring quality by design provide greater assurance
than testing to document quality
bull ldquoData derived from manufacturing process validation studies and from
in-process controls may provide greater assurance that a batch meets a
particular monograph requirement than analytical data derived from
an examination of finished units drawn from that batchrdquo (General
Notices USP 27)
bull Time to drop the may
Penalty for large sample size built in ndash time to remove
this penalty
bull With increasing sample size for content uniformity the numbers of
tablets found outside range 75-125 among a batch of 1000000
Now - 2015
Pharmacopoeias championing
quality by design absolutely
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC11
Pharmacopoeias championing quality by design
absolutely
Drug Substance and Product Monographs ndash conceptually should be a more detailed Quality Target Product Profile ndash
outlining CQArsquos relevant to safety and efficacy
CQA- Acceptance Criteria with no penalty for larger samples supporting robust estimation of variability (eliminate
passfail or attribute criteria) ndash supporting continual improvement
General chapter on how to address process related impurities - specific impurities best controlled via the regulatory
submission and cGMPs
General chapters for Critical Quality amp Material Attributes (functionality) amp their Measurement ndash with specific focus
on physical attributes amp analytical validation with considerations for Gage RampR as appropriate Use (and donrsquot
forget) the lessons learned from dissolution calibration
Educate users on the correct role and interpretation of the Pharmacopoeias - remove any perceptionsreasons to
rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC12
Additional information on our lsquolsquoblind alleysrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC13
Blind spot 1
lsquo1937 to 2007rsquo ndash70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC14
lsquo1937 to 2007rsquo 70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC15
1938 The Federal Food Drug and Cosmetic (FDC)
bull 1937 Elixir of Sulfanilamide
1962 Kefauver-Harris Drug Amendments
bull 1962 Thalidomide
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
1992 Generic Drug Enforcement Act
bull1989 L-Tryptophan
bull 1989 Generic Drug Scandal
bull 1988 Food and Drug Administration Act
bull 1984 Fines Enhancement Laws Drug Price Competition and Patent Term Restoration Act
2012 Food and Drug Administration Safety and Innovation Act (FDASIA)
bull 2007 Heparin Disaster
2013 Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA) Drug Quality and Security Act
bull 2012 The Deadly Meningitis Outbreak
lsquo1937 to 2007rsquo 70 years to open our eyesIs this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC16
Guidance for Industry Testing of
Glycerin for Diethylene Glycol
CDER May 2007 Compliance
1 Manufacturers did not perform full identity
testing on the glycerin raw material
including tests to quantify the amount of
DEG
2 Relied on the certificate of analysis (COA)
3 The origin of the glycerin was not easily
apparent from the COA
4 The COA was often a copy of a COA on the
letterhead of the distributor
5 The chain of custody or distribution history
of the glycerin was also not readily known
USP Glycerin Monograph
Type of Posting Revision Bulletin
Posting Date 04ndashFebndash2009
Official Date 01ndashMayndash2009
Because of the serious hazards associated
withhellip and in response to
recommendations set forth in the FDA
Guidance for Industry Testing of Glycerin
for Diethylene Glycol published in May
2007 USP has revised the USP Glycerin
monograph
Because diethylene glycol and ethylene
glycol are considered unacceptable toxic
substances the testing of USP Glycerin
should demonstrate the absence of these
substances
April 2007 FDA request to
USP to revise the Glycerin
monographrsquos
IDENTIFICATION section
Revision includes adding ndash
Identification test B LIMIT OF
DIETHYLENE GLYCOL AND
ETHYLENE GLYCOL to detect and
quantify DEGEG in Glycerin minus Is no
longer part of the impurity testing
ldquoLimit of DEG and Related
Compoundsrdquo minus Introduces a capillary
gas-chromatographic (GC) method with
flame ionization detection (FID) minus Limit
of NMT 010 each for diethylene
glycol and ethylene glycol is found
Is this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC17
0
5
10
15
20
25
30
35
Yea
rs
DEG Years since the previous incident
0
50
100
150
200
250
300
350
Number of Reported Deaths1937
Eli
xir
of
Sulf
anil
amid
e
2007T
ootp
aste
conta
min
atio
n0 70 years 0 70
years
Frequent reports
Mumbai Mumbai
Data from Excipient Fest Janeen Skutnik Chair ndashIPECAmericas 2009
Fair helliprdquoBecause of the serious hazards associated withhellip and in
response to recommendations set forth in the FDA Guidancerdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC18
Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning JAMA 1998279(15)1175-1180
doi101001jama279151175
Month of hospital admission for children with
acute renal failure Haiti
October 1995-October 1996
Diethylene glycol poisoning in Gurgaon India 1998Bulletin of the World Health Organization 2001 79 88ndash95
We report a second episode of poisoning occurring in 1998 in India as
a result of children ingesting diethylene glycol at least 33 children
are known to have died
At the beginning of the investigation we never imagined that
contaminated medicine was causing acute renal failure in children
A brand of cough expectorant manufactured by a local pharmaceutical
company was found by the Central Drugs Laboratory Calcutta to
contain 175 (vv) diethylene glycol
The district and state drug controller had tested many samples using
thin layer chromatography before a sample of medicine tested positive
for diethylene glycol at the Central Drugs Laboratory None of the
earlier samples was found to be contaminated
Number of reported death grossly underestimate the harm caused
When the drug safety system fails people get sick
Some die (Congressman Shimkus)
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC19
bull Some of these people are already very vulnerable
and proving the cause of harm from impurities
adulteration and counterfeits can be elusive
It is hard to detect
harm
bull Certainly the companies are obligated to ensure
a culture of quality and maintain vigilance as
well This reflects a systems approach to safety
FDA inspectors look
for a culture of quality
at manufacturing
facilities
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Few lsquoblind alleysrsquo that some of us ndash the old timers ndash have
spent time in so that the next generation can learn to avoid
lsquo1937 to 2007rsquo ndash 70 years to
open our eyes
lsquoMarket standardrsquo that which
the lsquomarketrsquo doesnrsquot know how
to use
Evidence of lsquomouth blisters in
farm animalsrsquo ndash okay to use in
human lungs since impurity not
identified in the USP
Eyes open when Quality
becomes a issue for National
Security
A calibration lsquostandardrsquo which
was too variable
What is Gauge RampR Why
needed for testing physical
attributes
Keeping the system in a
lsquocorrective actionrsquo mode
Busy correcting lsquocommon causersquo
ndash chasing our tail
Reasons to rationalize deviant
behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC9
How does one avoid these lsquoblind alleysrsquo Systems thinking System is the product of
interacting parts improving the parts taken separately will not improve the system
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC10
CEO amp
Sr Management
Culture
of Quality
Managers amp
Leaders
Effective
QMS
GXP
Compliance
All
Employees
Quality is Easy
The slice that is most
relevant for this
workshop
Closing thoughts
Then - 2004
The Process Analytical Technology Initiative PAT and
the Pharmacopeias
bull EDQM Spring Conference Cannes 3-4 May 2004
Assuring quality by design provide greater assurance
than testing to document quality
bull ldquoData derived from manufacturing process validation studies and from
in-process controls may provide greater assurance that a batch meets a
particular monograph requirement than analytical data derived from
an examination of finished units drawn from that batchrdquo (General
Notices USP 27)
bull Time to drop the may
Penalty for large sample size built in ndash time to remove
this penalty
bull With increasing sample size for content uniformity the numbers of
tablets found outside range 75-125 among a batch of 1000000
Now - 2015
Pharmacopoeias championing
quality by design absolutely
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC11
Pharmacopoeias championing quality by design
absolutely
Drug Substance and Product Monographs ndash conceptually should be a more detailed Quality Target Product Profile ndash
outlining CQArsquos relevant to safety and efficacy
CQA- Acceptance Criteria with no penalty for larger samples supporting robust estimation of variability (eliminate
passfail or attribute criteria) ndash supporting continual improvement
General chapter on how to address process related impurities - specific impurities best controlled via the regulatory
submission and cGMPs
General chapters for Critical Quality amp Material Attributes (functionality) amp their Measurement ndash with specific focus
on physical attributes amp analytical validation with considerations for Gage RampR as appropriate Use (and donrsquot
forget) the lessons learned from dissolution calibration
Educate users on the correct role and interpretation of the Pharmacopoeias - remove any perceptionsreasons to
rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC12
Additional information on our lsquolsquoblind alleysrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC13
Blind spot 1
lsquo1937 to 2007rsquo ndash70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC14
lsquo1937 to 2007rsquo 70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC15
1938 The Federal Food Drug and Cosmetic (FDC)
bull 1937 Elixir of Sulfanilamide
1962 Kefauver-Harris Drug Amendments
bull 1962 Thalidomide
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
1992 Generic Drug Enforcement Act
bull1989 L-Tryptophan
bull 1989 Generic Drug Scandal
bull 1988 Food and Drug Administration Act
bull 1984 Fines Enhancement Laws Drug Price Competition and Patent Term Restoration Act
2012 Food and Drug Administration Safety and Innovation Act (FDASIA)
bull 2007 Heparin Disaster
2013 Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA) Drug Quality and Security Act
bull 2012 The Deadly Meningitis Outbreak
lsquo1937 to 2007rsquo 70 years to open our eyesIs this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC16
Guidance for Industry Testing of
Glycerin for Diethylene Glycol
CDER May 2007 Compliance
1 Manufacturers did not perform full identity
testing on the glycerin raw material
including tests to quantify the amount of
DEG
2 Relied on the certificate of analysis (COA)
3 The origin of the glycerin was not easily
apparent from the COA
4 The COA was often a copy of a COA on the
letterhead of the distributor
5 The chain of custody or distribution history
of the glycerin was also not readily known
USP Glycerin Monograph
Type of Posting Revision Bulletin
Posting Date 04ndashFebndash2009
Official Date 01ndashMayndash2009
Because of the serious hazards associated
withhellip and in response to
recommendations set forth in the FDA
Guidance for Industry Testing of Glycerin
for Diethylene Glycol published in May
2007 USP has revised the USP Glycerin
monograph
Because diethylene glycol and ethylene
glycol are considered unacceptable toxic
substances the testing of USP Glycerin
should demonstrate the absence of these
substances
April 2007 FDA request to
USP to revise the Glycerin
monographrsquos
IDENTIFICATION section
Revision includes adding ndash
Identification test B LIMIT OF
DIETHYLENE GLYCOL AND
ETHYLENE GLYCOL to detect and
quantify DEGEG in Glycerin minus Is no
longer part of the impurity testing
ldquoLimit of DEG and Related
Compoundsrdquo minus Introduces a capillary
gas-chromatographic (GC) method with
flame ionization detection (FID) minus Limit
of NMT 010 each for diethylene
glycol and ethylene glycol is found
Is this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC17
0
5
10
15
20
25
30
35
Yea
rs
DEG Years since the previous incident
0
50
100
150
200
250
300
350
Number of Reported Deaths1937
Eli
xir
of
Sulf
anil
amid
e
2007T
ootp
aste
conta
min
atio
n0 70 years 0 70
years
Frequent reports
Mumbai Mumbai
Data from Excipient Fest Janeen Skutnik Chair ndashIPECAmericas 2009
Fair helliprdquoBecause of the serious hazards associated withhellip and in
response to recommendations set forth in the FDA Guidancerdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC18
Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning JAMA 1998279(15)1175-1180
doi101001jama279151175
Month of hospital admission for children with
acute renal failure Haiti
October 1995-October 1996
Diethylene glycol poisoning in Gurgaon India 1998Bulletin of the World Health Organization 2001 79 88ndash95
We report a second episode of poisoning occurring in 1998 in India as
a result of children ingesting diethylene glycol at least 33 children
are known to have died
At the beginning of the investigation we never imagined that
contaminated medicine was causing acute renal failure in children
A brand of cough expectorant manufactured by a local pharmaceutical
company was found by the Central Drugs Laboratory Calcutta to
contain 175 (vv) diethylene glycol
The district and state drug controller had tested many samples using
thin layer chromatography before a sample of medicine tested positive
for diethylene glycol at the Central Drugs Laboratory None of the
earlier samples was found to be contaminated
Number of reported death grossly underestimate the harm caused
When the drug safety system fails people get sick
Some die (Congressman Shimkus)
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC19
bull Some of these people are already very vulnerable
and proving the cause of harm from impurities
adulteration and counterfeits can be elusive
It is hard to detect
harm
bull Certainly the companies are obligated to ensure
a culture of quality and maintain vigilance as
well This reflects a systems approach to safety
FDA inspectors look
for a culture of quality
at manufacturing
facilities
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
How does one avoid these lsquoblind alleysrsquo Systems thinking System is the product of
interacting parts improving the parts taken separately will not improve the system
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC10
CEO amp
Sr Management
Culture
of Quality
Managers amp
Leaders
Effective
QMS
GXP
Compliance
All
Employees
Quality is Easy
The slice that is most
relevant for this
workshop
Closing thoughts
Then - 2004
The Process Analytical Technology Initiative PAT and
the Pharmacopeias
bull EDQM Spring Conference Cannes 3-4 May 2004
Assuring quality by design provide greater assurance
than testing to document quality
bull ldquoData derived from manufacturing process validation studies and from
in-process controls may provide greater assurance that a batch meets a
particular monograph requirement than analytical data derived from
an examination of finished units drawn from that batchrdquo (General
Notices USP 27)
bull Time to drop the may
Penalty for large sample size built in ndash time to remove
this penalty
bull With increasing sample size for content uniformity the numbers of
tablets found outside range 75-125 among a batch of 1000000
Now - 2015
Pharmacopoeias championing
quality by design absolutely
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC11
Pharmacopoeias championing quality by design
absolutely
Drug Substance and Product Monographs ndash conceptually should be a more detailed Quality Target Product Profile ndash
outlining CQArsquos relevant to safety and efficacy
CQA- Acceptance Criteria with no penalty for larger samples supporting robust estimation of variability (eliminate
passfail or attribute criteria) ndash supporting continual improvement
General chapter on how to address process related impurities - specific impurities best controlled via the regulatory
submission and cGMPs
General chapters for Critical Quality amp Material Attributes (functionality) amp their Measurement ndash with specific focus
on physical attributes amp analytical validation with considerations for Gage RampR as appropriate Use (and donrsquot
forget) the lessons learned from dissolution calibration
Educate users on the correct role and interpretation of the Pharmacopoeias - remove any perceptionsreasons to
rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC12
Additional information on our lsquolsquoblind alleysrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC13
Blind spot 1
lsquo1937 to 2007rsquo ndash70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC14
lsquo1937 to 2007rsquo 70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC15
1938 The Federal Food Drug and Cosmetic (FDC)
bull 1937 Elixir of Sulfanilamide
1962 Kefauver-Harris Drug Amendments
bull 1962 Thalidomide
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
1992 Generic Drug Enforcement Act
bull1989 L-Tryptophan
bull 1989 Generic Drug Scandal
bull 1988 Food and Drug Administration Act
bull 1984 Fines Enhancement Laws Drug Price Competition and Patent Term Restoration Act
2012 Food and Drug Administration Safety and Innovation Act (FDASIA)
bull 2007 Heparin Disaster
2013 Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA) Drug Quality and Security Act
bull 2012 The Deadly Meningitis Outbreak
lsquo1937 to 2007rsquo 70 years to open our eyesIs this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC16
Guidance for Industry Testing of
Glycerin for Diethylene Glycol
CDER May 2007 Compliance
1 Manufacturers did not perform full identity
testing on the glycerin raw material
including tests to quantify the amount of
DEG
2 Relied on the certificate of analysis (COA)
3 The origin of the glycerin was not easily
apparent from the COA
4 The COA was often a copy of a COA on the
letterhead of the distributor
5 The chain of custody or distribution history
of the glycerin was also not readily known
USP Glycerin Monograph
Type of Posting Revision Bulletin
Posting Date 04ndashFebndash2009
Official Date 01ndashMayndash2009
Because of the serious hazards associated
withhellip and in response to
recommendations set forth in the FDA
Guidance for Industry Testing of Glycerin
for Diethylene Glycol published in May
2007 USP has revised the USP Glycerin
monograph
Because diethylene glycol and ethylene
glycol are considered unacceptable toxic
substances the testing of USP Glycerin
should demonstrate the absence of these
substances
April 2007 FDA request to
USP to revise the Glycerin
monographrsquos
IDENTIFICATION section
Revision includes adding ndash
Identification test B LIMIT OF
DIETHYLENE GLYCOL AND
ETHYLENE GLYCOL to detect and
quantify DEGEG in Glycerin minus Is no
longer part of the impurity testing
ldquoLimit of DEG and Related
Compoundsrdquo minus Introduces a capillary
gas-chromatographic (GC) method with
flame ionization detection (FID) minus Limit
of NMT 010 each for diethylene
glycol and ethylene glycol is found
Is this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC17
0
5
10
15
20
25
30
35
Yea
rs
DEG Years since the previous incident
0
50
100
150
200
250
300
350
Number of Reported Deaths1937
Eli
xir
of
Sulf
anil
amid
e
2007T
ootp
aste
conta
min
atio
n0 70 years 0 70
years
Frequent reports
Mumbai Mumbai
Data from Excipient Fest Janeen Skutnik Chair ndashIPECAmericas 2009
Fair helliprdquoBecause of the serious hazards associated withhellip and in
response to recommendations set forth in the FDA Guidancerdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC18
Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning JAMA 1998279(15)1175-1180
doi101001jama279151175
Month of hospital admission for children with
acute renal failure Haiti
October 1995-October 1996
Diethylene glycol poisoning in Gurgaon India 1998Bulletin of the World Health Organization 2001 79 88ndash95
We report a second episode of poisoning occurring in 1998 in India as
a result of children ingesting diethylene glycol at least 33 children
are known to have died
At the beginning of the investigation we never imagined that
contaminated medicine was causing acute renal failure in children
A brand of cough expectorant manufactured by a local pharmaceutical
company was found by the Central Drugs Laboratory Calcutta to
contain 175 (vv) diethylene glycol
The district and state drug controller had tested many samples using
thin layer chromatography before a sample of medicine tested positive
for diethylene glycol at the Central Drugs Laboratory None of the
earlier samples was found to be contaminated
Number of reported death grossly underestimate the harm caused
When the drug safety system fails people get sick
Some die (Congressman Shimkus)
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC19
bull Some of these people are already very vulnerable
and proving the cause of harm from impurities
adulteration and counterfeits can be elusive
It is hard to detect
harm
bull Certainly the companies are obligated to ensure
a culture of quality and maintain vigilance as
well This reflects a systems approach to safety
FDA inspectors look
for a culture of quality
at manufacturing
facilities
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Closing thoughts
Then - 2004
The Process Analytical Technology Initiative PAT and
the Pharmacopeias
bull EDQM Spring Conference Cannes 3-4 May 2004
Assuring quality by design provide greater assurance
than testing to document quality
bull ldquoData derived from manufacturing process validation studies and from
in-process controls may provide greater assurance that a batch meets a
particular monograph requirement than analytical data derived from
an examination of finished units drawn from that batchrdquo (General
Notices USP 27)
bull Time to drop the may
Penalty for large sample size built in ndash time to remove
this penalty
bull With increasing sample size for content uniformity the numbers of
tablets found outside range 75-125 among a batch of 1000000
Now - 2015
Pharmacopoeias championing
quality by design absolutely
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC11
Pharmacopoeias championing quality by design
absolutely
Drug Substance and Product Monographs ndash conceptually should be a more detailed Quality Target Product Profile ndash
outlining CQArsquos relevant to safety and efficacy
CQA- Acceptance Criteria with no penalty for larger samples supporting robust estimation of variability (eliminate
passfail or attribute criteria) ndash supporting continual improvement
General chapter on how to address process related impurities - specific impurities best controlled via the regulatory
submission and cGMPs
General chapters for Critical Quality amp Material Attributes (functionality) amp their Measurement ndash with specific focus
on physical attributes amp analytical validation with considerations for Gage RampR as appropriate Use (and donrsquot
forget) the lessons learned from dissolution calibration
Educate users on the correct role and interpretation of the Pharmacopoeias - remove any perceptionsreasons to
rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC12
Additional information on our lsquolsquoblind alleysrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC13
Blind spot 1
lsquo1937 to 2007rsquo ndash70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC14
lsquo1937 to 2007rsquo 70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC15
1938 The Federal Food Drug and Cosmetic (FDC)
bull 1937 Elixir of Sulfanilamide
1962 Kefauver-Harris Drug Amendments
bull 1962 Thalidomide
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
1992 Generic Drug Enforcement Act
bull1989 L-Tryptophan
bull 1989 Generic Drug Scandal
bull 1988 Food and Drug Administration Act
bull 1984 Fines Enhancement Laws Drug Price Competition and Patent Term Restoration Act
2012 Food and Drug Administration Safety and Innovation Act (FDASIA)
bull 2007 Heparin Disaster
2013 Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA) Drug Quality and Security Act
bull 2012 The Deadly Meningitis Outbreak
lsquo1937 to 2007rsquo 70 years to open our eyesIs this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC16
Guidance for Industry Testing of
Glycerin for Diethylene Glycol
CDER May 2007 Compliance
1 Manufacturers did not perform full identity
testing on the glycerin raw material
including tests to quantify the amount of
DEG
2 Relied on the certificate of analysis (COA)
3 The origin of the glycerin was not easily
apparent from the COA
4 The COA was often a copy of a COA on the
letterhead of the distributor
5 The chain of custody or distribution history
of the glycerin was also not readily known
USP Glycerin Monograph
Type of Posting Revision Bulletin
Posting Date 04ndashFebndash2009
Official Date 01ndashMayndash2009
Because of the serious hazards associated
withhellip and in response to
recommendations set forth in the FDA
Guidance for Industry Testing of Glycerin
for Diethylene Glycol published in May
2007 USP has revised the USP Glycerin
monograph
Because diethylene glycol and ethylene
glycol are considered unacceptable toxic
substances the testing of USP Glycerin
should demonstrate the absence of these
substances
April 2007 FDA request to
USP to revise the Glycerin
monographrsquos
IDENTIFICATION section
Revision includes adding ndash
Identification test B LIMIT OF
DIETHYLENE GLYCOL AND
ETHYLENE GLYCOL to detect and
quantify DEGEG in Glycerin minus Is no
longer part of the impurity testing
ldquoLimit of DEG and Related
Compoundsrdquo minus Introduces a capillary
gas-chromatographic (GC) method with
flame ionization detection (FID) minus Limit
of NMT 010 each for diethylene
glycol and ethylene glycol is found
Is this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC17
0
5
10
15
20
25
30
35
Yea
rs
DEG Years since the previous incident
0
50
100
150
200
250
300
350
Number of Reported Deaths1937
Eli
xir
of
Sulf
anil
amid
e
2007T
ootp
aste
conta
min
atio
n0 70 years 0 70
years
Frequent reports
Mumbai Mumbai
Data from Excipient Fest Janeen Skutnik Chair ndashIPECAmericas 2009
Fair helliprdquoBecause of the serious hazards associated withhellip and in
response to recommendations set forth in the FDA Guidancerdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC18
Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning JAMA 1998279(15)1175-1180
doi101001jama279151175
Month of hospital admission for children with
acute renal failure Haiti
October 1995-October 1996
Diethylene glycol poisoning in Gurgaon India 1998Bulletin of the World Health Organization 2001 79 88ndash95
We report a second episode of poisoning occurring in 1998 in India as
a result of children ingesting diethylene glycol at least 33 children
are known to have died
At the beginning of the investigation we never imagined that
contaminated medicine was causing acute renal failure in children
A brand of cough expectorant manufactured by a local pharmaceutical
company was found by the Central Drugs Laboratory Calcutta to
contain 175 (vv) diethylene glycol
The district and state drug controller had tested many samples using
thin layer chromatography before a sample of medicine tested positive
for diethylene glycol at the Central Drugs Laboratory None of the
earlier samples was found to be contaminated
Number of reported death grossly underestimate the harm caused
When the drug safety system fails people get sick
Some die (Congressman Shimkus)
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC19
bull Some of these people are already very vulnerable
and proving the cause of harm from impurities
adulteration and counterfeits can be elusive
It is hard to detect
harm
bull Certainly the companies are obligated to ensure
a culture of quality and maintain vigilance as
well This reflects a systems approach to safety
FDA inspectors look
for a culture of quality
at manufacturing
facilities
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Pharmacopoeias championing quality by design
absolutely
Drug Substance and Product Monographs ndash conceptually should be a more detailed Quality Target Product Profile ndash
outlining CQArsquos relevant to safety and efficacy
CQA- Acceptance Criteria with no penalty for larger samples supporting robust estimation of variability (eliminate
passfail or attribute criteria) ndash supporting continual improvement
General chapter on how to address process related impurities - specific impurities best controlled via the regulatory
submission and cGMPs
General chapters for Critical Quality amp Material Attributes (functionality) amp their Measurement ndash with specific focus
on physical attributes amp analytical validation with considerations for Gage RampR as appropriate Use (and donrsquot
forget) the lessons learned from dissolution calibration
Educate users on the correct role and interpretation of the Pharmacopoeias - remove any perceptionsreasons to
rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC12
Additional information on our lsquolsquoblind alleysrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC13
Blind spot 1
lsquo1937 to 2007rsquo ndash70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC14
lsquo1937 to 2007rsquo 70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC15
1938 The Federal Food Drug and Cosmetic (FDC)
bull 1937 Elixir of Sulfanilamide
1962 Kefauver-Harris Drug Amendments
bull 1962 Thalidomide
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
1992 Generic Drug Enforcement Act
bull1989 L-Tryptophan
bull 1989 Generic Drug Scandal
bull 1988 Food and Drug Administration Act
bull 1984 Fines Enhancement Laws Drug Price Competition and Patent Term Restoration Act
2012 Food and Drug Administration Safety and Innovation Act (FDASIA)
bull 2007 Heparin Disaster
2013 Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA) Drug Quality and Security Act
bull 2012 The Deadly Meningitis Outbreak
lsquo1937 to 2007rsquo 70 years to open our eyesIs this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC16
Guidance for Industry Testing of
Glycerin for Diethylene Glycol
CDER May 2007 Compliance
1 Manufacturers did not perform full identity
testing on the glycerin raw material
including tests to quantify the amount of
DEG
2 Relied on the certificate of analysis (COA)
3 The origin of the glycerin was not easily
apparent from the COA
4 The COA was often a copy of a COA on the
letterhead of the distributor
5 The chain of custody or distribution history
of the glycerin was also not readily known
USP Glycerin Monograph
Type of Posting Revision Bulletin
Posting Date 04ndashFebndash2009
Official Date 01ndashMayndash2009
Because of the serious hazards associated
withhellip and in response to
recommendations set forth in the FDA
Guidance for Industry Testing of Glycerin
for Diethylene Glycol published in May
2007 USP has revised the USP Glycerin
monograph
Because diethylene glycol and ethylene
glycol are considered unacceptable toxic
substances the testing of USP Glycerin
should demonstrate the absence of these
substances
April 2007 FDA request to
USP to revise the Glycerin
monographrsquos
IDENTIFICATION section
Revision includes adding ndash
Identification test B LIMIT OF
DIETHYLENE GLYCOL AND
ETHYLENE GLYCOL to detect and
quantify DEGEG in Glycerin minus Is no
longer part of the impurity testing
ldquoLimit of DEG and Related
Compoundsrdquo minus Introduces a capillary
gas-chromatographic (GC) method with
flame ionization detection (FID) minus Limit
of NMT 010 each for diethylene
glycol and ethylene glycol is found
Is this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC17
0
5
10
15
20
25
30
35
Yea
rs
DEG Years since the previous incident
0
50
100
150
200
250
300
350
Number of Reported Deaths1937
Eli
xir
of
Sulf
anil
amid
e
2007T
ootp
aste
conta
min
atio
n0 70 years 0 70
years
Frequent reports
Mumbai Mumbai
Data from Excipient Fest Janeen Skutnik Chair ndashIPECAmericas 2009
Fair helliprdquoBecause of the serious hazards associated withhellip and in
response to recommendations set forth in the FDA Guidancerdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC18
Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning JAMA 1998279(15)1175-1180
doi101001jama279151175
Month of hospital admission for children with
acute renal failure Haiti
October 1995-October 1996
Diethylene glycol poisoning in Gurgaon India 1998Bulletin of the World Health Organization 2001 79 88ndash95
We report a second episode of poisoning occurring in 1998 in India as
a result of children ingesting diethylene glycol at least 33 children
are known to have died
At the beginning of the investigation we never imagined that
contaminated medicine was causing acute renal failure in children
A brand of cough expectorant manufactured by a local pharmaceutical
company was found by the Central Drugs Laboratory Calcutta to
contain 175 (vv) diethylene glycol
The district and state drug controller had tested many samples using
thin layer chromatography before a sample of medicine tested positive
for diethylene glycol at the Central Drugs Laboratory None of the
earlier samples was found to be contaminated
Number of reported death grossly underestimate the harm caused
When the drug safety system fails people get sick
Some die (Congressman Shimkus)
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC19
bull Some of these people are already very vulnerable
and proving the cause of harm from impurities
adulteration and counterfeits can be elusive
It is hard to detect
harm
bull Certainly the companies are obligated to ensure
a culture of quality and maintain vigilance as
well This reflects a systems approach to safety
FDA inspectors look
for a culture of quality
at manufacturing
facilities
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Additional information on our lsquolsquoblind alleysrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC13
Blind spot 1
lsquo1937 to 2007rsquo ndash70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC14
lsquo1937 to 2007rsquo 70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC15
1938 The Federal Food Drug and Cosmetic (FDC)
bull 1937 Elixir of Sulfanilamide
1962 Kefauver-Harris Drug Amendments
bull 1962 Thalidomide
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
1992 Generic Drug Enforcement Act
bull1989 L-Tryptophan
bull 1989 Generic Drug Scandal
bull 1988 Food and Drug Administration Act
bull 1984 Fines Enhancement Laws Drug Price Competition and Patent Term Restoration Act
2012 Food and Drug Administration Safety and Innovation Act (FDASIA)
bull 2007 Heparin Disaster
2013 Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA) Drug Quality and Security Act
bull 2012 The Deadly Meningitis Outbreak
lsquo1937 to 2007rsquo 70 years to open our eyesIs this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC16
Guidance for Industry Testing of
Glycerin for Diethylene Glycol
CDER May 2007 Compliance
1 Manufacturers did not perform full identity
testing on the glycerin raw material
including tests to quantify the amount of
DEG
2 Relied on the certificate of analysis (COA)
3 The origin of the glycerin was not easily
apparent from the COA
4 The COA was often a copy of a COA on the
letterhead of the distributor
5 The chain of custody or distribution history
of the glycerin was also not readily known
USP Glycerin Monograph
Type of Posting Revision Bulletin
Posting Date 04ndashFebndash2009
Official Date 01ndashMayndash2009
Because of the serious hazards associated
withhellip and in response to
recommendations set forth in the FDA
Guidance for Industry Testing of Glycerin
for Diethylene Glycol published in May
2007 USP has revised the USP Glycerin
monograph
Because diethylene glycol and ethylene
glycol are considered unacceptable toxic
substances the testing of USP Glycerin
should demonstrate the absence of these
substances
April 2007 FDA request to
USP to revise the Glycerin
monographrsquos
IDENTIFICATION section
Revision includes adding ndash
Identification test B LIMIT OF
DIETHYLENE GLYCOL AND
ETHYLENE GLYCOL to detect and
quantify DEGEG in Glycerin minus Is no
longer part of the impurity testing
ldquoLimit of DEG and Related
Compoundsrdquo minus Introduces a capillary
gas-chromatographic (GC) method with
flame ionization detection (FID) minus Limit
of NMT 010 each for diethylene
glycol and ethylene glycol is found
Is this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC17
0
5
10
15
20
25
30
35
Yea
rs
DEG Years since the previous incident
0
50
100
150
200
250
300
350
Number of Reported Deaths1937
Eli
xir
of
Sulf
anil
amid
e
2007T
ootp
aste
conta
min
atio
n0 70 years 0 70
years
Frequent reports
Mumbai Mumbai
Data from Excipient Fest Janeen Skutnik Chair ndashIPECAmericas 2009
Fair helliprdquoBecause of the serious hazards associated withhellip and in
response to recommendations set forth in the FDA Guidancerdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC18
Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning JAMA 1998279(15)1175-1180
doi101001jama279151175
Month of hospital admission for children with
acute renal failure Haiti
October 1995-October 1996
Diethylene glycol poisoning in Gurgaon India 1998Bulletin of the World Health Organization 2001 79 88ndash95
We report a second episode of poisoning occurring in 1998 in India as
a result of children ingesting diethylene glycol at least 33 children
are known to have died
At the beginning of the investigation we never imagined that
contaminated medicine was causing acute renal failure in children
A brand of cough expectorant manufactured by a local pharmaceutical
company was found by the Central Drugs Laboratory Calcutta to
contain 175 (vv) diethylene glycol
The district and state drug controller had tested many samples using
thin layer chromatography before a sample of medicine tested positive
for diethylene glycol at the Central Drugs Laboratory None of the
earlier samples was found to be contaminated
Number of reported death grossly underestimate the harm caused
When the drug safety system fails people get sick
Some die (Congressman Shimkus)
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC19
bull Some of these people are already very vulnerable
and proving the cause of harm from impurities
adulteration and counterfeits can be elusive
It is hard to detect
harm
bull Certainly the companies are obligated to ensure
a culture of quality and maintain vigilance as
well This reflects a systems approach to safety
FDA inspectors look
for a culture of quality
at manufacturing
facilities
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Blind spot 1
lsquo1937 to 2007rsquo ndash70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC14
lsquo1937 to 2007rsquo 70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC15
1938 The Federal Food Drug and Cosmetic (FDC)
bull 1937 Elixir of Sulfanilamide
1962 Kefauver-Harris Drug Amendments
bull 1962 Thalidomide
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
1992 Generic Drug Enforcement Act
bull1989 L-Tryptophan
bull 1989 Generic Drug Scandal
bull 1988 Food and Drug Administration Act
bull 1984 Fines Enhancement Laws Drug Price Competition and Patent Term Restoration Act
2012 Food and Drug Administration Safety and Innovation Act (FDASIA)
bull 2007 Heparin Disaster
2013 Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA) Drug Quality and Security Act
bull 2012 The Deadly Meningitis Outbreak
lsquo1937 to 2007rsquo 70 years to open our eyesIs this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC16
Guidance for Industry Testing of
Glycerin for Diethylene Glycol
CDER May 2007 Compliance
1 Manufacturers did not perform full identity
testing on the glycerin raw material
including tests to quantify the amount of
DEG
2 Relied on the certificate of analysis (COA)
3 The origin of the glycerin was not easily
apparent from the COA
4 The COA was often a copy of a COA on the
letterhead of the distributor
5 The chain of custody or distribution history
of the glycerin was also not readily known
USP Glycerin Monograph
Type of Posting Revision Bulletin
Posting Date 04ndashFebndash2009
Official Date 01ndashMayndash2009
Because of the serious hazards associated
withhellip and in response to
recommendations set forth in the FDA
Guidance for Industry Testing of Glycerin
for Diethylene Glycol published in May
2007 USP has revised the USP Glycerin
monograph
Because diethylene glycol and ethylene
glycol are considered unacceptable toxic
substances the testing of USP Glycerin
should demonstrate the absence of these
substances
April 2007 FDA request to
USP to revise the Glycerin
monographrsquos
IDENTIFICATION section
Revision includes adding ndash
Identification test B LIMIT OF
DIETHYLENE GLYCOL AND
ETHYLENE GLYCOL to detect and
quantify DEGEG in Glycerin minus Is no
longer part of the impurity testing
ldquoLimit of DEG and Related
Compoundsrdquo minus Introduces a capillary
gas-chromatographic (GC) method with
flame ionization detection (FID) minus Limit
of NMT 010 each for diethylene
glycol and ethylene glycol is found
Is this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC17
0
5
10
15
20
25
30
35
Yea
rs
DEG Years since the previous incident
0
50
100
150
200
250
300
350
Number of Reported Deaths1937
Eli
xir
of
Sulf
anil
amid
e
2007T
ootp
aste
conta
min
atio
n0 70 years 0 70
years
Frequent reports
Mumbai Mumbai
Data from Excipient Fest Janeen Skutnik Chair ndashIPECAmericas 2009
Fair helliprdquoBecause of the serious hazards associated withhellip and in
response to recommendations set forth in the FDA Guidancerdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC18
Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning JAMA 1998279(15)1175-1180
doi101001jama279151175
Month of hospital admission for children with
acute renal failure Haiti
October 1995-October 1996
Diethylene glycol poisoning in Gurgaon India 1998Bulletin of the World Health Organization 2001 79 88ndash95
We report a second episode of poisoning occurring in 1998 in India as
a result of children ingesting diethylene glycol at least 33 children
are known to have died
At the beginning of the investigation we never imagined that
contaminated medicine was causing acute renal failure in children
A brand of cough expectorant manufactured by a local pharmaceutical
company was found by the Central Drugs Laboratory Calcutta to
contain 175 (vv) diethylene glycol
The district and state drug controller had tested many samples using
thin layer chromatography before a sample of medicine tested positive
for diethylene glycol at the Central Drugs Laboratory None of the
earlier samples was found to be contaminated
Number of reported death grossly underestimate the harm caused
When the drug safety system fails people get sick
Some die (Congressman Shimkus)
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC19
bull Some of these people are already very vulnerable
and proving the cause of harm from impurities
adulteration and counterfeits can be elusive
It is hard to detect
harm
bull Certainly the companies are obligated to ensure
a culture of quality and maintain vigilance as
well This reflects a systems approach to safety
FDA inspectors look
for a culture of quality
at manufacturing
facilities
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
lsquo1937 to 2007rsquo 70 years to open our eyes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC15
1938 The Federal Food Drug and Cosmetic (FDC)
bull 1937 Elixir of Sulfanilamide
1962 Kefauver-Harris Drug Amendments
bull 1962 Thalidomide
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
bull 1960 Color Additive Amendment
bull 1958 Food Additives Amendment GRAS
1992 Generic Drug Enforcement Act
bull1989 L-Tryptophan
bull 1989 Generic Drug Scandal
bull 1988 Food and Drug Administration Act
bull 1984 Fines Enhancement Laws Drug Price Competition and Patent Term Restoration Act
2012 Food and Drug Administration Safety and Innovation Act (FDASIA)
bull 2007 Heparin Disaster
2013 Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA) Drug Quality and Security Act
bull 2012 The Deadly Meningitis Outbreak
lsquo1937 to 2007rsquo 70 years to open our eyesIs this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC16
Guidance for Industry Testing of
Glycerin for Diethylene Glycol
CDER May 2007 Compliance
1 Manufacturers did not perform full identity
testing on the glycerin raw material
including tests to quantify the amount of
DEG
2 Relied on the certificate of analysis (COA)
3 The origin of the glycerin was not easily
apparent from the COA
4 The COA was often a copy of a COA on the
letterhead of the distributor
5 The chain of custody or distribution history
of the glycerin was also not readily known
USP Glycerin Monograph
Type of Posting Revision Bulletin
Posting Date 04ndashFebndash2009
Official Date 01ndashMayndash2009
Because of the serious hazards associated
withhellip and in response to
recommendations set forth in the FDA
Guidance for Industry Testing of Glycerin
for Diethylene Glycol published in May
2007 USP has revised the USP Glycerin
monograph
Because diethylene glycol and ethylene
glycol are considered unacceptable toxic
substances the testing of USP Glycerin
should demonstrate the absence of these
substances
April 2007 FDA request to
USP to revise the Glycerin
monographrsquos
IDENTIFICATION section
Revision includes adding ndash
Identification test B LIMIT OF
DIETHYLENE GLYCOL AND
ETHYLENE GLYCOL to detect and
quantify DEGEG in Glycerin minus Is no
longer part of the impurity testing
ldquoLimit of DEG and Related
Compoundsrdquo minus Introduces a capillary
gas-chromatographic (GC) method with
flame ionization detection (FID) minus Limit
of NMT 010 each for diethylene
glycol and ethylene glycol is found
Is this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC17
0
5
10
15
20
25
30
35
Yea
rs
DEG Years since the previous incident
0
50
100
150
200
250
300
350
Number of Reported Deaths1937
Eli
xir
of
Sulf
anil
amid
e
2007T
ootp
aste
conta
min
atio
n0 70 years 0 70
years
Frequent reports
Mumbai Mumbai
Data from Excipient Fest Janeen Skutnik Chair ndashIPECAmericas 2009
Fair helliprdquoBecause of the serious hazards associated withhellip and in
response to recommendations set forth in the FDA Guidancerdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC18
Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning JAMA 1998279(15)1175-1180
doi101001jama279151175
Month of hospital admission for children with
acute renal failure Haiti
October 1995-October 1996
Diethylene glycol poisoning in Gurgaon India 1998Bulletin of the World Health Organization 2001 79 88ndash95
We report a second episode of poisoning occurring in 1998 in India as
a result of children ingesting diethylene glycol at least 33 children
are known to have died
At the beginning of the investigation we never imagined that
contaminated medicine was causing acute renal failure in children
A brand of cough expectorant manufactured by a local pharmaceutical
company was found by the Central Drugs Laboratory Calcutta to
contain 175 (vv) diethylene glycol
The district and state drug controller had tested many samples using
thin layer chromatography before a sample of medicine tested positive
for diethylene glycol at the Central Drugs Laboratory None of the
earlier samples was found to be contaminated
Number of reported death grossly underestimate the harm caused
When the drug safety system fails people get sick
Some die (Congressman Shimkus)
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC19
bull Some of these people are already very vulnerable
and proving the cause of harm from impurities
adulteration and counterfeits can be elusive
It is hard to detect
harm
bull Certainly the companies are obligated to ensure
a culture of quality and maintain vigilance as
well This reflects a systems approach to safety
FDA inspectors look
for a culture of quality
at manufacturing
facilities
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
lsquo1937 to 2007rsquo 70 years to open our eyesIs this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC16
Guidance for Industry Testing of
Glycerin for Diethylene Glycol
CDER May 2007 Compliance
1 Manufacturers did not perform full identity
testing on the glycerin raw material
including tests to quantify the amount of
DEG
2 Relied on the certificate of analysis (COA)
3 The origin of the glycerin was not easily
apparent from the COA
4 The COA was often a copy of a COA on the
letterhead of the distributor
5 The chain of custody or distribution history
of the glycerin was also not readily known
USP Glycerin Monograph
Type of Posting Revision Bulletin
Posting Date 04ndashFebndash2009
Official Date 01ndashMayndash2009
Because of the serious hazards associated
withhellip and in response to
recommendations set forth in the FDA
Guidance for Industry Testing of Glycerin
for Diethylene Glycol published in May
2007 USP has revised the USP Glycerin
monograph
Because diethylene glycol and ethylene
glycol are considered unacceptable toxic
substances the testing of USP Glycerin
should demonstrate the absence of these
substances
April 2007 FDA request to
USP to revise the Glycerin
monographrsquos
IDENTIFICATION section
Revision includes adding ndash
Identification test B LIMIT OF
DIETHYLENE GLYCOL AND
ETHYLENE GLYCOL to detect and
quantify DEGEG in Glycerin minus Is no
longer part of the impurity testing
ldquoLimit of DEG and Related
Compoundsrdquo minus Introduces a capillary
gas-chromatographic (GC) method with
flame ionization detection (FID) minus Limit
of NMT 010 each for diethylene
glycol and ethylene glycol is found
Is this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC17
0
5
10
15
20
25
30
35
Yea
rs
DEG Years since the previous incident
0
50
100
150
200
250
300
350
Number of Reported Deaths1937
Eli
xir
of
Sulf
anil
amid
e
2007T
ootp
aste
conta
min
atio
n0 70 years 0 70
years
Frequent reports
Mumbai Mumbai
Data from Excipient Fest Janeen Skutnik Chair ndashIPECAmericas 2009
Fair helliprdquoBecause of the serious hazards associated withhellip and in
response to recommendations set forth in the FDA Guidancerdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC18
Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning JAMA 1998279(15)1175-1180
doi101001jama279151175
Month of hospital admission for children with
acute renal failure Haiti
October 1995-October 1996
Diethylene glycol poisoning in Gurgaon India 1998Bulletin of the World Health Organization 2001 79 88ndash95
We report a second episode of poisoning occurring in 1998 in India as
a result of children ingesting diethylene glycol at least 33 children
are known to have died
At the beginning of the investigation we never imagined that
contaminated medicine was causing acute renal failure in children
A brand of cough expectorant manufactured by a local pharmaceutical
company was found by the Central Drugs Laboratory Calcutta to
contain 175 (vv) diethylene glycol
The district and state drug controller had tested many samples using
thin layer chromatography before a sample of medicine tested positive
for diethylene glycol at the Central Drugs Laboratory None of the
earlier samples was found to be contaminated
Number of reported death grossly underestimate the harm caused
When the drug safety system fails people get sick
Some die (Congressman Shimkus)
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC19
bull Some of these people are already very vulnerable
and proving the cause of harm from impurities
adulteration and counterfeits can be elusive
It is hard to detect
harm
bull Certainly the companies are obligated to ensure
a culture of quality and maintain vigilance as
well This reflects a systems approach to safety
FDA inspectors look
for a culture of quality
at manufacturing
facilities
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Is this characterization fair
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC17
0
5
10
15
20
25
30
35
Yea
rs
DEG Years since the previous incident
0
50
100
150
200
250
300
350
Number of Reported Deaths1937
Eli
xir
of
Sulf
anil
amid
e
2007T
ootp
aste
conta
min
atio
n0 70 years 0 70
years
Frequent reports
Mumbai Mumbai
Data from Excipient Fest Janeen Skutnik Chair ndashIPECAmericas 2009
Fair helliprdquoBecause of the serious hazards associated withhellip and in
response to recommendations set forth in the FDA Guidancerdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC18
Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning JAMA 1998279(15)1175-1180
doi101001jama279151175
Month of hospital admission for children with
acute renal failure Haiti
October 1995-October 1996
Diethylene glycol poisoning in Gurgaon India 1998Bulletin of the World Health Organization 2001 79 88ndash95
We report a second episode of poisoning occurring in 1998 in India as
a result of children ingesting diethylene glycol at least 33 children
are known to have died
At the beginning of the investigation we never imagined that
contaminated medicine was causing acute renal failure in children
A brand of cough expectorant manufactured by a local pharmaceutical
company was found by the Central Drugs Laboratory Calcutta to
contain 175 (vv) diethylene glycol
The district and state drug controller had tested many samples using
thin layer chromatography before a sample of medicine tested positive
for diethylene glycol at the Central Drugs Laboratory None of the
earlier samples was found to be contaminated
Number of reported death grossly underestimate the harm caused
When the drug safety system fails people get sick
Some die (Congressman Shimkus)
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC19
bull Some of these people are already very vulnerable
and proving the cause of harm from impurities
adulteration and counterfeits can be elusive
It is hard to detect
harm
bull Certainly the companies are obligated to ensure
a culture of quality and maintain vigilance as
well This reflects a systems approach to safety
FDA inspectors look
for a culture of quality
at manufacturing
facilities
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Fair helliprdquoBecause of the serious hazards associated withhellip and in
response to recommendations set forth in the FDA Guidancerdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC18
Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning JAMA 1998279(15)1175-1180
doi101001jama279151175
Month of hospital admission for children with
acute renal failure Haiti
October 1995-October 1996
Diethylene glycol poisoning in Gurgaon India 1998Bulletin of the World Health Organization 2001 79 88ndash95
We report a second episode of poisoning occurring in 1998 in India as
a result of children ingesting diethylene glycol at least 33 children
are known to have died
At the beginning of the investigation we never imagined that
contaminated medicine was causing acute renal failure in children
A brand of cough expectorant manufactured by a local pharmaceutical
company was found by the Central Drugs Laboratory Calcutta to
contain 175 (vv) diethylene glycol
The district and state drug controller had tested many samples using
thin layer chromatography before a sample of medicine tested positive
for diethylene glycol at the Central Drugs Laboratory None of the
earlier samples was found to be contaminated
Number of reported death grossly underestimate the harm caused
When the drug safety system fails people get sick
Some die (Congressman Shimkus)
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC19
bull Some of these people are already very vulnerable
and proving the cause of harm from impurities
adulteration and counterfeits can be elusive
It is hard to detect
harm
bull Certainly the companies are obligated to ensure
a culture of quality and maintain vigilance as
well This reflects a systems approach to safety
FDA inspectors look
for a culture of quality
at manufacturing
facilities
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
When the drug safety system fails people get sick
Some die (Congressman Shimkus)
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC19
bull Some of these people are already very vulnerable
and proving the cause of harm from impurities
adulteration and counterfeits can be elusive
It is hard to detect
harm
bull Certainly the companies are obligated to ensure
a culture of quality and maintain vigilance as
well This reflects a systems approach to safety
FDA inspectors look
for a culture of quality
at manufacturing
facilities
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Blind spot 2
Market lsquostandardrsquo that which the lsquomarketrsquo didnrsquot know how to use
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC20
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Market lsquostandardrsquo the lsquomarketrsquo didnrsquot know how to use
FDA Failed to Track Substandard Generic Medicines Congress Told
Generic heart drugs made by some
India-based companies donrsquot work as
they should said Preston Mason a
researcher at Brigham amp Womenrsquos
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc (PFEUS)rsquos Lipitor made both in
the US and abroad That may be
because some companies are cutting
corners to save money he said
Bashing Generics Study US Regulator Says Heart Drugs Are Safe
Mansoor A Khan RPh PhD Director
DPQROTROPQCDERFDA NIPTE
Conference UM at Shady Grove April 30 2015
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC21
FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities Therapeutic Innovation amp Regulatory Science May 27 2014
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Blind spot 3
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in humans since impurity not identified in the Pharmacopoeia
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC22
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Evidence of lsquomouth blistersrsquo in farm animals ndash okay to use in
humans since impurity not identified in the Pharmacopoeia
An FDA Investigator
at a API facility in
India noted
Returned goods
from a customer - a
farm using the API
to treat cows
Cows developing
blister investigation
of cause = process
related impurity
API used in a
inhalation product for
humans ndashno action to
remove the impurity
because the product
meets pharmacopeia
monograph
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC23
Information about the FDA investigator and the facility in question not shared here
Other similar exampleshellip HCN in medical grade CO2 helliphellip
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Blind spot 4
Eyes open when Quality becomes a issue for National Security
A calibration lsquostandardrsquo which was too variable
What is Gauge RampR Why needed for testing physical attributes
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC24
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
More US Marines contract
MalariaWednesday September 10 2003
Posted 925 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more US military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC25
DPACDERFDA Memo B J Westenberger 17 October 2003
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Food and Drug Administration
Center for Drug Evaluation and Research
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE (ACPS)
May 3 2005
Dissolution Measurement System Current State and Opportunities for Improvement
Dr Lucinda Buhse Director Division of Pharmaceutical Analysis CDER FDA
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC26
Use lessons learned on calibration
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Time to eliminate this
lsquoblind spotrsquo
Process Validation (2011) Statistical Confidence Continued Process Verificationhellip Quality Metricshellip
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC27
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Blind spot 5
Keeping the system in a lsquocorrective actionrsquo mode
Correcting lsquocommon causersquo poses a problem
Reasons to rationalize deviant behaviors
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC28
Attribute Dissolution
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Previous slide and these
data (see fig) are from one of
the top three Pharma Co
Modified release product ndash a RLD for which several generics have been approved
If a generic company at a foreign facility report no deviations and consistently releases their batches in five days or less ndash what would you think
A Generic manufacturer has a superior process ndash in control- compared to the RLD or
B Your gut says ndash lsquodata is too good to be truersquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC29
600 days
I have inserted the ldquo600 daysrsquo on the figure ndash this is based on cases I have seen while at FDA)
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Preconditions to malice or disregard
Rationalization amp
Attitude
Pressure amp
Incentive
Opportunity ndash
lsquoholes in the QMSrdquo
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC30
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC31
Risk of unintended or intended normative support for
lsquotesting into compliancersquo
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good
test prone
to error
ldquoBatch failure
means I
made a
mistakerdquo
subjective
norm
Documents
not critical
Compendial
testing
sufficient
Local
regulators
collect amp test
samples ndash no
issue thereldquoTesting into compliancerdquo
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC32
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 amp 2
Culture of Quality Data Integrity Quality by Design Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
12 June 2012copy Ajaz S Hussain | Insight Advice amp
Solutions LLC33
Photo credits wwwbigstockphotoscom
