Risk Assessment in the

Pharmaceutical Industry:
Toxicology
Dave Cragin, Ph.D., DABT
柯大卫
Professor of the International Program in
Pharmaceutical Engineering Management
北京大学
和
Adjunct Professor of Health Policy and Public
Health
University of the Sciences, Philadelphia

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Uses of Risk Assessment in the
Pharmaceutical Industry:
Toxicology

 Basis for quality standards

 Degradate limits (ADEs)
 Impurities (ADEs)

 Risk-based cleaning limits (ADEs

 Basis of chemical safety

 Determining Occupational Exposure
Limits to protect employees
 Understanding chemical hazards

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Is anything completely safe?
Completely Non-toxic?

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Is anything completely safe?
Non-toxic?
Woman drinks so much water she dies
POSTED: 10:33 p.m. EST, January 13, 2007
A woman who competed in a radio station's
contest to see how much water she could
drink without going to the bathroom died of
water intoxication.
Victim was trying to win video game console
for her children.

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The dose differentiates a poison from a
remedy

Brazilian Pit Viper

Captopril – ACE Inhibitor for heart disease,
part of snake venom
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The dose differentiates a poison from a remedy

 Poisonous lizard (Gila monster)

 Diabetes drug – Byetta derived from its venom
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 All substances are poisons;
The right dose differentiates a poison
from a remedy

Paracelsus, 1493-1541

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Terminology – Threshold
 Threshold – Dose above which health
effects are likely to occur and below
which no effects will occur.
 Exposure below the threshold = zero
risk

 Risk assessment identifies the acceptable

threshold, usually called:
 Acceptable Daily Exposure
 Occupational Exposure Limit

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 Acceptable Daily exposure: A dose
that is unlikely to cause an adverse
effect if an individual is exposed, by
any route, at or below this dose
every day for life
• Risk-Based Manufacture of Pharmaceutical
Products (RiskMaPP), ISPE, 2010

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Toxicology
Risk Assessment

 Toxicity x Exposure = Risk

 Toxicity is ½ the equation
 Toxicity is intrinsic to the substance
 You can’t change the toxicity of a
compound
 You can change exposure (through risk
management)

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Key questions for ADEs
 What is the adverse effect that
occurs at the lowest dose?
 For most drugs, the “adverse effect” is
the pharmacologic effect
 Who is most sensitive to the effect?
 Pregnant women?
 Children?

 Others?

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Key questions for ADEs
 If we protect against the effect that
occurs at the lowest dose, we
protect against other adverse effects
as well
 True for patients and employees

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Key questions for ADEs
 Are the health effects of the
chemical well established?
 Do we have human or lab animal
data?
• Animal data require more extrapolation

 If we have only animal data, which

animal/which study is best to predict
human effects?

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 Toxicology for Risk Assessment:
Part 2. Setting the contaminant limit
for a chemical in food
David Cragin, Ph.D., DABT
柯大卫
Professor of the International Program in Pharmaceutical
Engineering Management
Peking University, Beijing
北京大学
&
Adjunct Professor of Health Policy and Public Health
University of the Sciences, Philadelphia

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 Why food?

 北京大学 requested it
 China-specific real example
 Excellent example shows that ADEs are
applicable to any material
– Food or drug
– Any chemical

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 Regulatory Risk Assessment Example

 Situation: Your role is to develop a safe limit

for a possible food contaminant.
– You will set an “Acceptable Daily Exposure”
(ADE) for the chemical

– What do you need to know to set the acceptable

daily exposure for this chemical?
 Risk = Toxicity x Exposure

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 Regulatory Risk Assessment Example:
Toxicity – Questions to Consider

 Risk = Toxicity x Exposure

– Toxicity is chemical specific
 What adverse health effect occurs at the lowest dose?

– Which organ is damaged?

– Are there reproductive effects?
– Does it cause cancer?
– Other effects?
 If we protect the public from the effect that occurs at the
LOWEST dose, we protect them from other effects as
well

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 Regulatory Risk Assessment Example:
Exposure – Questions to Consider

 Risk = Toxicity x Exposure

– Which foods will contain the most of the
contaminant?
– Which of these foods do people eat the most?
 How much of the food do people eat?
– To calculate intake, should you use:
 The average daily intake of that food?

or
 The maximum daily intake of that food?

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 Regulatory Risk Assessment Example:
Exposure – Questions to Consider

 Milk and infant formula

– Which contaminant limit needs to be more protective – milk or
infant formula?
 Why?

 Contaminant limits are key

– We can’t change the toxicity of a chemical
– We can control exposures
 Exposure control is key to risk management
 By setting the Acceptable Daily Exposure (ADE), we can control
exposure
– True for product quality – Controlling impurity levels is key(!)
– True for workplace as well – Exposure Control is key(!)

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 Melamine
Pharmacokinetics, Metabolism and Excretion

 Rapidly absorbed
 Excreted unmetabolized
 Plasma half-life = 2.7 hours (WHO, 2008)
– What are the risk implications of rapid excretion?

– What are the risk implications for an API that is

rapid excreted?

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 Melamine
Toxicity

 Low acute toxicity

– Lethal dose for 50% of animals = 3 - 4 g/kg
 For 50 kg person = 150 – 200 g
 Lethal dose for sodium chloride (盐) = 5 g/kg

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 Melamine
Toxicity

 Very low subchronic toxicity

– United States National Toxicology Program (NTP) 13- week
subchronic study
 Male and female rats received 38–900 mg/kg body weight via
diet
– 900 mg/kg = 45 g for an adult women
 Systemic toxicity was minimal:
– Reduced body weight gain and decreased body weight
– Urinary bladder stones in most treated males, even in the lowest
dose group. The incidence of stone formation was dose related.
– No kidney failure or clinical symptoms of kidney failure were
observed from these studies

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 Melamine
Toxicity

 Low acute toxicity

 Very low subchronic toxicity

 Summary: Melamine presents a very low

hazard
– If the hazard was low, why was there a problem?

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Time Frame for Toxicity:
Acute effects
 Acute toxicity– sudden in onset,
from exposure to a relatively large
amount of material over a short
period. Usually reversible unless
lethal.
 Examples: Eye and skin irritation,
allergic response

• Chemicals with high acute toxicity:

cyanide, carbon monoxide 24
 Melamine
Toxicity

 Very low subchronic toxicity – (USFDA Summary, 2007)

– Most recent reported No-Observed-Adverse-
Effect-Levels (NOAELs):
– 63 mg/kg/day (13 weeks, oral with feed, in rats)
– 240 mg/kg/day (28 days, oral with feed, in rats)
– 417 mg/kg/day (14 days, oral with feed, in rats)
– 1600 mg/kg/day (13 weeks, oral with feed, in mice)

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 Melamine
Toxicity

 Reproductive and developmental toxicity:

 Most sensitive calculated NOAELs for oral reproductive
and developmental toxicity in rats are:
– 400 mg/kg/day (maternal)
– 1060 mg/kg/day (fetal)

 Reproductive and developmental effects

occur only at doses that effect the mother

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Time Frame for Toxicity:
Subchronic effects
 Subchronic toxicity– Delayed in
onset, from repeated exposure to a
relatively small amounts of material
over a prolonged period. May be
slowly reversible.
 Examples of subchronic effects:
reproductive effects, anemia, immune
suppression, hormonal effects

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 Melamine
Chronic Toxicity

 No data

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Time Frame for Toxicity:
Chronic effects
 Chronic toxicity– Delayed in onset,
from repeated exposure to a
relatively small amounts of material
over a lifetime. Usually irreversible
effects.
 Examples of chronic toxicity: Cancer,
heart disease, kidney disease, nerve
damage
• Example: Tobacco smoke
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 Melamine
Toxicity

 Subchronic toxicity – (USFDA Summary, 2007)

– Most recent reported No-Observed-Adverse-Effect-Levels
(NOAELs):
– 63 mg/kg/day (13 weeks, oral with feed, in rats)
– 240 mg/kg/day (28 days, oral with feed, in rats)
– 417 mg/kg/day (14 days, oral with feed, in rats)
– 1600 mg/kg/day (13 weeks, oral with feed, in mice)
 Reproductive and developmental toxicity:
 Most sensitive calculated NOAELs for oral reproductive and
developmental toxicity in rats are:
– 400 mg/kg/day (maternal)
– 1060 mg/kg/day (fetal)
 Which data to use for the ADE?

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 Melamine
Toxicity

 Use 63 mg/kg-day from rats as NOAEL

 Using this – How do we calculate the Acceptable

Daily Exposure (ADE) for humans?
– Need to account for:

 Humans might be more sensitive than rats

 Not all humans are the same
 Rat data: 13 week study, infants use formula for years
 Uncertainty about melamine effects

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 Melamine
Toxicity

 USFDA used 63 mg/kg-day from rats as NOAEL

 Using this – How do we calculate the Acceptable Daily Exposure

(ADE) for humans?
– Safety Factors
 10x Factor for interspecies extrapolation, rat to human*
– Humans may be more sensitive than rats
 10x Interindividual variability
– Not all humans are the same
 10x Due to higher uncertainty of effects on infant kidneys
– Infants might have special sensitivity
 63 mg/kg ÷ (10 x 10 x 10) = 0.063 mg/kg-day
– ADE = 0.063 mg/kg-day

*Sometimes different factors are used

– http://www.fda.gov/Food/FoodSafety/FoodContaminantsAdulteration/ChemicalContaminants/Melamine/ucm164520.htm

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 Melamine
What is an acceptable level of exposure?

 ADE = 0.063 mg/kg-day

 What is the acceptable level of exposure for
an infant?
 What is the acceptable level of exposure for
an adult?

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 Melamine
What is an acceptable level of exposure?

 ADE = 0.063 mg/kg-day

 What is the acceptable level of exposure for an
infant?
– 0.063 mg/kg-day x 3 kg/infant = 0.189 mg
melamine/infant/day
 Infant can ingest 0.189 mg of melamine everyday
 What is the acceptable level of exposure for an
adult?
– 50 kg Standard adult female body weight
 50 kg x 0.063 mg/kg-day = 3.15 mg/day

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 How do you calculate an acceptable
level of chemical in food?

 ADE = 0.063 mg/kg-day

 Infant can ingest 0.189 mg of melamine everyday
 USFDA used a worst case exposure
scenario
– Assumed all of an infant’s total daily dietary intake
is contaminated with melamine
 Infant eats 0.15 kg powdered infant formula/day

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 How do you calculate an acceptable
level of chemical in food?

 ADE = 0.063 mg/kg-day

 Infant can ingest 0.189 mg of melamine everyday
 Infant ADE = 0.189 mg melamine/day
 USFDA used a worst case exposure scenario
– Assumed all of an infant’s total daily dietary intake is
contaminated with melamine
 Infant eats 0.15 kg powdered infant formula/day
 0.189 mg/infant/day ÷ 0.15 kg of food = the food contamination level
that would provide this amount of melamine to a 3 kg infant per day
 0.189 mg melamine ÷ 0.15 kg of food = 1.26 mg melamine/kg food

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 How do you calculate an acceptable
level of chemical in food?

 FDA used a worst case exposure scenario

– Assumed all of an infant’s total daily dietary intake is
contaminated with melamine
 Infant eats 0.15 kg powdered infant formula/day
 0.189 mg/infant/day ÷ 0.15 kg of food = the food contamination level
that would provide this amount of melamine to a 3 kg infant per day
 0.189 mg melamine ÷ 0.15 kg of food = 1.26 mg melamine/kg food
 If 100% of the diet were contaminated at a level of 1.26 ppm of
melamine, an infant’s daily intake would equal 0.063 mg/kg-day.

 1.26 ppm rounded down to 1.0 ppm melamine in infant formula

– Acceptable level of melamine in formula: 1 ppm

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 Melamine presents a low hazard:
Why was there a problem?

 Acceptable level of melamine in infant

formula
– 1 ppm
 According to China Daily News October 3,
2008:
– Infant formula contained up to 6,196 ppm
melamine
– Infant formula may have also had another
nitrogen-based compound

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 Background to the Melamine Tragedy

 Any action taken to reduce one risk, creates or increases other risks
– These collateral risks are often obvious only in retrospect

 Quality standards were created to require minimum protein content in milk

– Protein content measured indirectly via Nitrogen content
– Melamine has zero nutrition value, but is 60% nitrogen by weight

 Unscrupulous individuals figured out how to fool the quality standard by adding
melamine to milk.
– According to the China Daily News, infant formula contained up to 6,196 ppm
melamine (China Daily, Oct 3, 2008)
 Health based standard was 2.5 ppm

 It’s extremely difficult to overcome the risks caused by illegal activities

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 Summary/Conclusions

 This risk assessment approach can apply to any

situation:
– Contaminant limits in drugs
– Acceptable Daily Exposures for Cleaning validation of drugs
– Contaminant limits in packaging – (may include factor for
extractables/leachables)
– Air pollution or occupational exposure limits
– Contaminant limits in water

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 Summary/Conclusions

 This risk assessment approach can apply to any

situation
– Key things to consider:
 Exposure: Who is exposed?
– Infants/adults/pregnant women?
– How often are they exposed?
– How are they exposed? (via food, water, air?)
– How much are they exposed to?
 Toxicity: What is the lowest no effect level (NOEL) for the
chemical?
– How much toxicity data do we have?
– How certain are we regarding the hazard posed?
 Exposure x Toxicity = Risk

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