Transcript Case Studies: Richman Chemical’s Project Management

Best Practice Sourcing:
Protecting against fraud, adulteration
and interruption of supply
Presented by: Ed Richman
www.richmanchemical.com
Introduction
What can happen?
How bad can it get?
How do you reduce or eliminate risk?
Richman Chemical Inc.
www.richmanchemical.com
Learning from History
Past Catastrophes:
1. Elixir Sulfanilamide
2. Heparin
3. Tryptophan
Richman Chemical Inc.
www.richmanchemical.com
Elixir Sulfanilamide
Richman Chemical Inc.
www.richmanchemical.com
Elixir Sulfanilamide
Taste of Raspberries,
Taste of Death
Synopsis:
• Therapeutic disaster in US in 1937.
• Marketed as the new sulfa wonder drug.
• Killed over 100 people, many of whom
were children.
Richman Chemical Inc.
www.richmanchemical.com
Elixir Sulfanilamide
Taste of Raspberries,
Taste of Death
The drug, Sulfanilamide :
• Indicated for streptococcal infections.
• So successful, called “wonder drug”.
• Previously only available in tablet and
powder form.
Richman Chemical Inc.
www.richmanchemical.com
Elixir Sulfanilamide
Taste of Raspberries,
Taste of Death
(continued)
• There was an increasing
demand for the drug in liquid
form for ease of use especially
to treat sore throats in children.
• Harold Cole Watkins, the chief
chemist and pharmacist at the
S.E. Massengill Company,
found that sulfanilamide would
dissolve in diethylene glycol.
• Raspberry flavor added to
appeal to children.
Richman Chemical Inc.
www.richmanchemical.com
Elixir Sulfanilamide
Taste of Raspberries,
Taste of Death
What went wrong?
• The company tested the mixture for
flavor, appearance, and fragrance and
found it satisfactory.
• No FDA requirement for safety testing.
• In September, 1937, Massengill sent
633 shipments to 2/3 of the country.
Richman Chemical Inc.
www.richmanchemical.com
Elixir Sulfanilamide
Taste of Raspberries,
Taste of Death
(continued)
• The formulation was never tested for
toxicity.
• At the time the existing food and
drug laws did not require safety
studies on new drugs or new
formulations.
Richman Chemical Inc.
www.richmanchemical.com
Elixir Sulfanilamide
Taste of Raspberries,
Taste of Death
(continued)
• In the absence of toxicity testing,
Massengill proceeded without adequate
knowledge of the actual properties of their
product.
• Diethylene glycol, an industrial chemical
normally used as an antifreeze, is a
deadly poison.
Richman Chemical Inc.
www.richmanchemical.com
The Catastrophe Plays Out
• Tulsa, OK reports deaths to AMA
• AMA tests and determines DEG is toxic
• Public is alerted via radio and
newspapers
• FDA sends all of its 239 inspectors out to
recover product
• 97.5% of all product ever shipped is
recovered
• Massengill is not charged for the deaths
of users, only with misbranding
Richman Chemical Inc.
www.richmanchemical.com
Table 1. Elixir of sulfanilamide: Distribution, Sales, and Death Tally by State
(continued)
Richman Chemical Inc.
www.richmanchemical.com
Elixir Sulfanilamide
Taste of Raspberries,
Taste of Death
Impact on FDA Law:
• The deaths led directly to
the 1938 Food, Drug, and
Cosmetic Act after it had
languished for 5 years
without action.
• FDA then had authority to
regulate new drugs.
Richman Chemical Inc.
www.richmanchemical.com
Elixir Sulfanilamide
Taste of Raspberries,
Taste of Death
Lessons Learned:
• Watch out for Excipients
• Performance and Simplicity can
blind one to other problems
• Safety, Safety, Safety
Richman Chemical Inc.
www.richmanchemical.com
Lessons not Learned
• 1985 Spain: 5 deaths from Silver Sulfadiazine
• 1986 India: 21 deaths from Glycerin diuretic
• 1990 Nigeria: 47 children die from
Acetaminophen Syrup
• 1990-92 Bangladesh: 339 children from
Paracetamol
• 1992 Argentina 29
• 1995 Haiti 88
• 2006 Panama 219+
• 2008 Nigeria 84
Richman Chemical Inc.
www.richmanchemical.com
L-Tryptophan
• Normally safe, naturally
occurring essential amino acid
and building block for proteins
and neurotransmitters.
Richman Chemical Inc.
www.richmanchemical.com
Tryptophan
• Was marketed as a
nutritional.
• To help people sleep,
diminish pain, control
mood, and appetite.
Richman Chemical Inc.
www.richmanchemical.com
Tryptophan
Disaster in 1989
• An outbreak of eosinophilia-myalgia syndrome
(EMS), apparently never before seen, occurred.
• The outbreak was linked to L-tryptophan use and
L-Tryp from a single manufacturer.
• 1,500 cases and twenty-eight deaths were
eventually reported to the U.S. Centers for
Disease Control and Prevention.
Richman Chemical Inc.
www.richmanchemical.com
Tryptophan
Disaster in 1989
What went wrong?
• Showa Denko had a 50% market share and manufactured LTryptophan with a bacterial fermentation process.
•
In 1988, SD changed their manufacturing process by
substituting a genetically modified bacteria and
simultaneously reducing the charcoal quantity in their
filtration.
•
The change resulted in a 99.6% purity product.
Richman Chemical Inc.
www.richmanchemical.com
Tryptophan
Disaster in 1989
(Continued)
• No Safety tests were performed or required by FDA
as a result of the changed L-Tryptophan
manufacturing process.
• Similarly, no change in labeling or notification was
done or required.
• It took months to trace the EMS outbreak to Showa
Denko's L-Tryptophan.
• It is still in dispute whether the GM bacteria or the
reduced filtration was the prime factor.
Richman Chemical Inc.
www.richmanchemical.com
Tryptophan
Disaster in 1989
Impact on FDA:
• Provided impetus for passage of the Dietary
Supplement Health and Education Act of 1994
(DSHEA).
• Created a new regulatory framework for the
safety and labeling of dietary supplements.
Richman Chemical Inc.
www.richmanchemical.com
Tryptophan
Disaster in 1989
(Continued)
Impact on FDA:
• Requires that a manufacturer or
distributor notify FDA if it
intends to market a dietary
supplement in the U.S. that
contains a "new dietary
ingredient."
• New requirements for complete
disclosure of the manufacturer,
packer, or distributor; a
complete list of ingredients; and
the net contents on the label.
Richman Chemical Inc.
www.richmanchemical.com
Tryptophan
Disaster in 1989
Lessons Learned:
• Showa Denko learned about US
Product Liability Law!
• Purity is no guarantee of Safety.
• Process changes can have safety
consequences.
• Trace impurities can be lethal
• Biology can have a big impact with
small quantities
Richman Chemical Inc.
www.richmanchemical.com
Heparin
Contamination
The Drug:
•
•
•
Heparin is an
anticoagulant (blood
thinner).
Treats and prevents
blood clots in veins,
arteries, or lungs.
Heparin is used presurgically to reduce
the risk of blood clots.
Richman Chemical Inc.
www.richmanchemical.com
Heparin
Contamination
(Continued)
Heparin is administered to about 12 million
people in the U.S. annually.
Deathly side effects in 2008:
• Diarrhea, vomiting and severe pain in
chest and abdomen.
•
Caused 81 US deaths
Richman Chemical Inc.
www.richmanchemical.com
Heparin
Contamination
Reuters
April 22, 2008
Richman Chemical Inc.
www.richmanchemical.com
Heparin
Contamination
What went wrong?
•
80% of all active pharmaceutical
ingredients used in drugs sold in the U.S.
now originate overseas (GAO).
•
Baxter International purchased Heparin
ingredient from Changzhou SPL between
2004-2008.
•
Adulteration: Chondroitin Sulfate which
cost $4/kg was substituted for Heparin
which cost $400/kg.
•
FDA officials admitted that they had not
inspected the Changzhou SPL plant.
Richman Chemical Inc.
www.richmanchemical.com
Heparin
Contamination
Lesson learned:
• Your product is only as safe as the
least honest person in your raw
material sourcing channel.
• Dishonest people also lie.
Richman Chemical Inc.
www.richmanchemical.com
Security of Supply
• War & Terrorism
• Natural Disasters
• Single Sources & Questionable back
ups
• Business Disruptions
Richman Chemical Inc.
www.richmanchemical.com
Protection
• Know with whom you are doing business
(not just with whom you think you are).
• Audit manufacturing sites (make sure
they are the real ones).
• Foreign Regulatory is not US FDA
• Sample, test, sample, test, sample…
• Trust, but verify.
• Single sourcing has risks.
Richman Chemical Inc.
www.richmanchemical.com
Geographical Risks
Low Risk:
North America
Europe
Japan
High Risk:
China
Russia
(India)
Richman Chemical Inc.
www.richmanchemical.com
How do you Protect
Yourself?
• Big Pharma can, as it has the resources
to visit, audit, qualify, test, monitor,etc.
• If you are not Big Pharma, you probably
do not.
• The alternative: Use Richman Chemical
(and our 25 year track record).
– Proven Manufacturing Partners
– US, Canada, EU preferred
– China, India with trusted partners only (local
mangers, local ownership)
Richman Chemical Inc.
www.richmanchemical.com