Product Quality & Patient Safety USP Workshop Mumbai 12 June 2015

Product Quality & Patient Safety
Compounding to Manufacturing:
A 21st Century Journey Avoiding the Historical Blind Alleys
USP–India Workshop: Quality of Chemical Medicines:
Impact of Impurities and Strategies for Control
ajaz@ajazhussain.com
12 June 2012
© Ajaz S. Hussain | Insight Advice &
Solutions LLC
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Prologue
Pharmaceutical Quality for the 21st Century – 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 – “The Science of Quality”, Iselin, NJ. My talk was entitled –
‘Biopharmaceutics and Drug Product Quality: Performance Tests, A Look Into the Future’
Optimal utility of the Pharmacopoeias in the 21st Century requires understanding difference
between ‘compounding’ and ‘manufacturing’, ‘market standards’ and ‘release testing’,
identifying and addressing the historical blind spots or blind alleys, and effectively educating
the user & ‘market’ community.
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Outline
Current state of pharmaceutical ‘Compounding’ & ‘Manufacturing’
What are our ‘blind alleys’?
Illustrative examples of ‘blind alleys’
How can one avoid these (historical) ‘blind alleys’?
Closing thoughts - Pharmacopoeias championing quality by design; absolutely
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Current state
Compounding: May 2015 Reports
FDA to develop “Do not compound” and “Demonstrably difficult
to compound“ list being developed
Compounding Center to Pay $200 Million for Meningitis
Outbreak. The company’s chief pharmacist is one of two people
implicated in the outbreak and charged with second-degree
murder.
Experts ponder drug compounding law’s 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 … All 13 of those letters have cited irregularities
with the companies' data integrity practices.
Vertex, J&J, 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
Initiative…. Urged…for 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.
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Reading the media headlines – it would appear that…
Today it seems we manufacture
in a pharmacy to label it
compounding!
We ‘control’ manufacturing in
modern factories using market
standards designed for
compounding!
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Compendial standards apply only to the units tested
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Being human means “we can be blind to the obvious,
and we are also blind to our blindness.”
Daniel Kahneman,
Thinking, Fast and Slow
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http://web.mit.edu/persci/people/adelson/checkershadow_proof.html

Examples of our ‘blind spots’ or ‘blind alleys’?
Relevant to this workshop
Market
standards for
‘Product
Release’
•Keeping the system in a ‘corrective
action’ mode
•Correcting ‘common cause’ poses a
problem.
•Reasons to rationalize deviant
behaviors?
Analytical
Method
Validation
•Eyes open when Quality becomes a
issue for National Security!
•A calibration ‘standard’ which was too
variable!
•What is Gauge R&R? Why needed for
testing physical attributes?
Impurities &
Contaminants
•‘1937 to 2007’ – 70 years to open our
eyes?
•‘Market standard’ that the ‘market’
didn’t know how to use?
•Evidence of ‘blisters in farm animals’ –
okay to use in humans, since impurity
not identified in the USP!
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Few ‘blind alleys’ that some of us – the old timers – have
spent time in so that the next generation can learn to avoid
‘1937 to 2007’ – 70 years to
open our eyes?
‘Market standard’ that which
the ‘market’ doesn’t know how
to use?
Evidence of ‘mouth blisters in
farm animals’ – 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 ‘standard’ which
was too variable!
What is Gauge R&R? Why
needed for testing physical
attributes?
Keeping the system in a
‘corrective action’ mode.
Busy correcting ‘common cause’
– chasing our tail!
Reasons to rationalize deviant
behaviors?
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How does one avoid these ‘blind alleys’? Systems thinking: System is the product of
interacting parts; improving the parts taken separately will not improve the system.
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CEO &
Sr. Management
Culture
of Quality
Managers &
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.
• EDQM Spring Conference, Cannes, 3-4 May 2004
Assuring quality by design provide greater assurance
than testing to document quality
• “Data 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 batch.” (General
Notices, USP 27)
• Time to drop the may!
Penalty for large sample size built in – time to remove
this penalty
• With increasing sample size for content uniformity the numbers of
tablets found outside range 75-125% among a batch of 1,000,000?
Now - 2015
Pharmacopoeias championing
quality by design; absolutely.
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Pharmacopoeias championing quality by design;
absolutely!
Drug Substance and Product Monographs – conceptually should be a more detailed Quality Target Product Profile –
outlining CQA’s relevant to safety and efficacy
CQA- Acceptance Criteria, with no penalty for larger samples, supporting robust estimation of variability (eliminate
pass/fail or attribute criteria) – 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 & Material Attributes (functionality) & their Measurement – with specific focus
on physical attributes & analytical validation with considerations for Gage R&R, as appropriate. Use (and don’t
forget) the lessons learned from dissolution calibration.
Educate users on the correct role and interpretation of the Pharmacopoeias - remove any perceptions/reasons to
rationalize deviant behaviors
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Additional information on our ‘‘blind alleys”
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Blind spot #1
‘1937 to 2007’ –
70 years to open
our eyes?
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‘1937 to 2007’: 70 years to open our eyes?
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1938 The Federal Food,
Drug, and Cosmetic
(FDC)
• 1937 Elixir of
Sulfanilamide
1962 Kefauver-Harris
Drug Amendments
• 1962
Thalidomide
• 1960 Color Additive
Amendment
• 1958 Food Additives
Amendment; GRAS
• 1960 Color Additive
Amendment
• 1958 Food Additives
Amendment; GRAS
1992 Generic Drug
Enforcement Act
•1989 L-Tryptophan
• 1989: Generic
Drug Scandal
• 1988 Food and Drug
Administration Act
• 1984 Fines Enhancement Laws;
Drug Price Competition and
Patent Term Restoration Act
2012 Food and Drug
Administration Safety
and Innovation Act
(FDASIA).
• 2007:
Heparin
Disaster
2013 Pandemic and
All-Hazards
Preparedness
Reauthorization Act
(PAHPRA) Drug
Quality and Security
Act.
• 2012: The
Deadly
Meningitis
Outbreak

‘1937 to 2007’: 70 years to open our eyes?
Is this characterization fair?
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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: 04–Feb–2009
Official Date: 01–May–2009
Because of the serious hazards associated
with…., 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
monograph’s
IDENTIFICATION section.
Revision includes: adding –
Identification test B. LIMIT OF
DIETHYLENE GLYCOL AND
ETHYLENE GLYCOL to detect and
quantify DEG/EG in Glycerin. − Is no
longer part of the impurity testing,
“Limit of DEG and Related
Compounds”. − Introduces a capillary
gas-chromatographic (GC) method with
flame ionization detection (FID). − Limit
of NMT 0.10% each for diethylene
glycol and ethylene glycol is found.

Is this characterization fair?
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0
5
10
15
20
25
30
35
Years
DEG: Years since the previous incident
0
50
100
150
200
250
300
350
Number of Reported Deaths1937:ElixirofSulfanilamide
2007:Tootpastecontamination
0 70 years 0 70
years
Frequent reports
Mumbai Mumbai
Data from Excipient Fest Janeen Skutnik Chair –IPECAmericas 2009

Fair …”Because of the serious hazards associated with…., and in
response to recommendations set forth in the FDA Guidance”
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Epidemic of Pediatric Deaths From Acute Renal Failure Caused by
Diethylene Glycol Poisoning. JAMA. 1998;279(15):1175-1180.
doi:10.1001/jama.279.15.1175
Month of hospital admission for children with
acute renal failure, Haiti
October 1995-October 1996.
Diethylene glycol poisoning in Gurgaon, India, 1998
Bulletin of the World Health Organization, 2001, 79: 88–95.
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 17.5% (v/v) 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)
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• 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
• 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 ‘standard’;
that which the
‘market’ didn’t
know how to use?
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Market ‘standard’; the ‘market’ didn’t know how to use?
FDA Failed to Track Substandard
Generic Medicines, Congress Told
Generic heart drugs made by some
India-based companies don’t work as
they should, said Preston Mason, a
researcher at Brigham & Women’s
Hospital in Boston who has studied
the effectiveness of copies of Pfizer
Inc. (PFE:US)’s Lipitor made both in
the U.S. and abroad. That may be
because some companies are cutting
corners to save money, he said.
Bashing Generics Study, U.S.
Regulator Says Heart Drugs Are Safe
Mansoor A. Khan, R.Ph., Ph.D. Director,
DPQR/OTR/OPQ/CDER/FDA; NIPTE
Conference, UM at Shady Grove, April 30, 2015
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FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities. Therapeutic Innovation & Regulatory Science May 27, 2014

Blind spot #3
Evidence of ‘mouth
blisters’ in farm
animals – okay to
use in humans, since
impurity not
identified in the
Pharmacopoeia!
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Evidence of ‘mouth blisters’ in farm animals – 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 –no action to
remove the impurity
because the product
meets pharmacopeia
monograph.
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Information about the FDA investigator and the facility in question not shared here.
Other similar examples… HCN in medical grade CO2, ……..

Blind spot #4
Eyes open when Quality
becomes a issue for
National Security!
A calibration ‘standard’
which was too variable!
What is Gauge R&R?
Why needed for testing
physical attributes?
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More U.S. Marines contract
Malaria
Wednesday, September 10, 2003
Posted: 9:25 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more U.S.
military personnel serving as part of
the peacekeeping mission in Liberia are
showing signs of having contracted
malaria.
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DPA/CDER/FDA 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.
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Use lessons learned on calibration.

Time to eliminate this
‘blind spot’!
Process Validation
(2011), Statistical
Confidence, Continued
Process Verification…
Quality Metrics,….
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Blind spot #5
Keeping the system in a
‘corrective action’ mode
Correcting ‘common cause’
poses a problem.
Reasons to rationalize
deviant behaviors?
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Attribute: Dissolution

Previous slide and these
data (see fig) are from one of
the top three Pharma Co.
Modified release product – 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
– what would you think?
A. Generic manufacturer has a superior
process – in control- compared to the
RLD; or
B. Your gut says – ‘data is too good to be
true’?
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600 days*
*I have inserted the “600 days’, on the figure – this is based on cases I have seen while at FDA)

Preconditions to malice or disregard
Rationalization &
Attitude
Pressure &
Incentive
Opportunity –
‘holes in the QMS”
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Risk of unintended or intended normative support for
‘testing into compliance’?
attitude
toward
performing
the behavior
Process
validation is
done so
quality is
good;
test prone
to error
“Batch failure
means I
made a
mistake”
subjective
norm
Documents
not critical;
Compendial
testing
sufficient
Local
regulators
collect & test
samples – no
issue there!
“Testing into compliance”

Remove any perception and reasons to rationalize
deviant behaviors
Educate users on the correct role and interpretation
of the Pharmacopoeias in the 21st century
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Addional information
Excipient Knowledge Management Mumbai 12 March 2015 Part 1 & 2
Culture of Quality, Data Integrity, Quality by Design: Connecting the Dots
Good Regulators of Pharmaceuticals (GRP) 22 October 2014
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Photo credits: www.bigstockphotos.com

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Product Quality & Patient Safety USP Workshop Mumbai 12 June 2015