Best Practice Sourcing : Protecting against fraud, adulteration and interruption of supply
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Transcript of Best Practice Sourcing : Protecting against fraud, adulteration and interruption of supply
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Best Practice SourcingBest Practice Sourcing:Protecting against fraud, Protecting against fraud,
adulteration and interruption of adulteration and interruption of
supplysupply Presented by: Ed RichmanPresented by: Ed Richman
www.richmanchemical.comwww.richmanchemical.com
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Richman Chemical Inc.www.richmanchemical.com
Introduction
What can happen?
How bad can it get?
How do you reduce or eliminate risk?
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Learning from HistoryLearning from History
Past Catastrophes:
1. Elixir Sulfanilamide
2. Heparin
3. Tryptophan
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Elixir Sulfanilamide
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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.
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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.
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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.
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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.
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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.
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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.
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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
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Table 1. Elixir of sulfanilamide: Distribution, Sales, and Death Tally by State
(continued)
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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.
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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
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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
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L-Tryptophan
• Normally safe, naturally occurring essential amino acid and building block for proteins and neurotransmitters.
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Tryptophan
• Was marketed as a nutritional.
• To help people sleep, diminish pain, control mood, and appetite.
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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.
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Tryptophan Disaster in 1989
What went wrong?• Showa Denko had a 50% market share and manufactured L-
Tryptophan 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.
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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.
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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.
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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.
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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
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HeparinContamination
The Drug:• Heparin is an
anticoagulant (blood thinner).
• Treats and prevents blood clots in veins, arteries, or lungs.
• Heparin is used pre-surgically to reduce the risk of blood clots.
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HeparinContamination
(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
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HeparinContamination
ReutersApril 22, 2008
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HeparinContamination
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.
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HeparinContamination
Lesson learned:
• Your product is only as safe as the least honest person in your raw material sourcing channel.
• Dishonest people also lie.
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Security of Supply
• War & Terrorism
• Natural Disasters
• Single Sources & Questionable back ups
• Business Disruptions
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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.
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Geographical Risks
Low Risk:
North America
Europe
Japan
High Risk:
China
Russia
(India)
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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)