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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