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

1. Best Practice Sourcing:Protecting against fraud, adulteration and interruption of supply Presented by: Ed Richman www.richmanchemical.com

2. Introduction What can happen? How bad can it get? How do you reduce or eliminate risk?

3. Learning from History Past Catastrophes: • Elixir Sulfanilamide • Heparin • Tryptophan

4. Elixir Sulfanilamide

5. Elixir SulfanilamideTaste 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.

6. Elixir SulfanilamideTaste 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.

7. Elixir SulfanilamideTaste 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.

8. Elixir SulfanilamideTaste 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.

9. Elixir SulfanilamideTaste 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.

10. Elixir SulfanilamideTaste 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.

11. 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

12. Table 1. Elixir of sulfanilamide: Distribution, Sales, and Death Tally by State (continued)

13. Elixir SulfanilamideTaste 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.

14. Elixir SulfanilamideTaste of Raspberries, Taste of Death Lessons Learned: • Watch out for Excipients • Performance and Simplicity can blind one to other problems • Safety, Safety, Safety

15. 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

16. L-Tryptophan • Normally safe, naturally occurring essential amino acid and building block for proteins and neurotransmitters. 

17. Tryptophan • Was marketed as a nutritional. • To help people sleep, diminish pain, control mood, and appetite.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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

24. 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.

25. 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

26. HeparinContamination Reuters April 22, 2008

27. 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.

28. HeparinContamination Lesson learned: • Your product is only as safe as the least honest person in your raw material sourcing channel. • Dishonest people also lie.

29. Security of Supply • War & Terrorism • Natural Disasters • Single Sources & Questionable back ups • Business Disruptions

30. 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.

31. Geographical Risks Low Risk: North America Europe Japan High Risk: China Russia (India)

32. 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)