best practice sourcing : protecting against fraud, adulteration and interruption of supply

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

Richman Chemical Inc.www.richmanchemical.com

Introduction

What can happen?

How bad can it get?

How do you reduce or eliminate risk?


Learning from HistoryLearning from History

Past Catastrophes:

1. Elixir Sulfanilamide

2. Heparin

3. Tryptophan


Elixir Sulfanilamide


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.



Taste of Death

The drug, Sulfanilamide :

• Indicated for streptococcal infections.

• So successful, called “wonder drug”.

• Previously only available in tablet and powder form.



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.



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.



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.



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.


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


Table 1. Elixir of sulfanilamide: Distribution, Sales, and Death Tally by State

(continued)



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.



Taste of Death

Lessons Learned:

• Watch out for Excipients

• Performance and Simplicity can blind one to other problems

• Safety, Safety, Safety


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


L-Tryptophan

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


Tryptophan

• Was marketed as a nutritional.

• To help people sleep, diminish pain, control mood, and appetite.


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.



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.



(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.



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.



(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.



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


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.



(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



ReutersApril 22, 2008



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.



Lesson learned:

• Your product is only as safe as the least honest person in your raw material sourcing channel.

• Dishonest people also lie.


Security of Supply

• War & Terrorism

• Natural Disasters

• Single Sources & Questionable back ups

• Business Disruptions


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.


Geographical Risks

Low Risk:

North America

Europe

Japan

High Risk:

China

Russia

(India)


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)

best practice sourcing : protecting against fraud, adulteration and interruption of supply

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