Best Practice Sourcing: Protecting against fraud, adulteration and interruption of supply

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Best Practice SourcingProtecting against fraud,
adulteration and interruption of supply

• Presented by Ed Richman
• www.richmanchemical.com

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Introduction

• What can happen?
• How bad can it get?
• How do you reduce or eliminate risk?

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Learning from History

• Past Catastrophes
• Elixir Sulfanilamide
• Heparin
• 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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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
Reuters April 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)

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Thank You for Listening

• Ed Richman