PQRI PODP Extractables & Leachables Workshop Leachable - - PowerPoint PPT Presentation

PQRI PODP Extractables & Leachables Workshop

William P. Beierschmitt, PhD, DABT, FATS Drug Safety Research and Development Pfizer, Inc. Leachable Evaluation of a Container Closure System - What to do When Above the Threshold

April 2018

PQRI PODP E&L Workshop April 18-19, 2018

• The PQRI thresholds were developed based upon a comprehensive

examination of the toxicological profiles of over 600 known extractables and leachables

• The available safety data for any given chemical should always be

considered when employing the PQRI qualification thresholds

• Chemical knowledge trumps the classification strategy
• Due to the rigorous process undertaken to develop and validate the

thresholds, it is reasonable to use them in cases where little or no safety data are available for a chemical

• The thresholds are not absolutes; higher levels of chemical

extractables and leachables can be qualified on an individual basis

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Background

PQRI PODP E&L Workshop April 18-19, 2018

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The PQRI Thresholds

Mutagenicity Concern? Yes – Qualify (ICH M7) No – Consider Sensitization/ Irritation Potential Sensitization/Irritation Concern? Yes – Qualify No – Consider Systemic Toxicity Systemic Toxicity Concern? Yes – Qualify No – Qualification Achieved!

PQRI PODP E&L Workshop April 18-19, 2018

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Crossing the Threshold - What Now?

PQRI PODP E&L Workshop April 18-19, 2018

• Dose - There is no such thing as a non-toxic chemical, but there is

such a thing as a non-toxic dose of it (“The dose makes the poison”)

• Route of Administration - Can affect a toxicological outcome
• Duration - Chronic, daily exposure to a chemical carries a higher

theoretical risk of causing adverse effects than short-term exposure

• Indication - What disease/condition is being treated by the drug

containing the chemical impurity influences the risk assessment

• Pediatrics - Documented age-related differences in the absorption,

distribution, metabolism and excretion can affect susceptibility

• Women of Child Bearing Potential (WOCBP) - Reproductive

toxicology endpoints should be considered if exposure is anticipated

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Crossing the Threshold - Safety Considerations

PQRI PODP E&L Workshop April 18-19, 2018

• QSAR in silico tools (if needed)
• Genetic toxicology
• Acute & multi-dose toxicity
• Carcinogenicity
• Reproductive toxicology
• Irritation and sensitization
• Human toxicity data
• Special populations (eg, pediatrics)
• Regulatory guidance information (eg, OSHA, EPA, WHO)

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Crossing the Threshold - Data Considerations

PQRI PODP E&L Workshop April 18-19, 2018

• QSAR Tools (eg, DEREK and SARAH
• In silico tools to predict mutagenicity concerns (both) and a wide

range of systemic toxicity endpoints (DEREK)

• Toxtree
• On-line tool to aid in assigning a “Cramer Class” to any given chemical;

Important when no toxicology data are available

• Each of the 3 Cramer Classes has a Threshold of Toxicological Concern

(TTC) dose below which systemic toxicity would not be expected

• Genetic Toxicology
• Must rule out mutagenicity/carcinogenicity concerns
• Insufficient data in silico analysis of the chemical is warranted

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Crossing the Threshold - Data Clarifications

PQRI PODP E&L Workshop April 18-19, 2018

• Acute Toxicology
• These data tend to only report mortality (eg, LD50 values) and not

morbidity, but they aid in determining the overall potency of a toxicant and are important to the process

• Multi-Dose Animal Toxicity
• These data are appropriate to include in every risk assessment
• Carcinogenicity
• If available can be of importance in just about every risk assessment,

especially in a chronic exposure situation

• Irritation and Sensitization
• Particularly important for parenteral products

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Crossing the Threshold - Data Clarifications

PQRI PODP E&L Workshop April 18-19, 2018

• Regulatory Guidance Information (eg, OSHA or EPA)
• While not meant to specifically address the safety of a leachable

impurity, such data (eg, OSHA Permissible Exposure Limits) are valuable since they are calculated by considering a wide range of animal and human safety information

• Human Toxicity Data
• The most critical and relevant of all data, but difficult to find!
• These data greatly strengthen the assessment, and diminish the

uncertainties with cross-species (ie, animal to human) extrapolations

• Often, if a chemical happens to be a normal constituent of the human

body (eg, an essential mineral), risk can often be assessed by calculating the additional body burden that will result from exposure

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Crossing the Threshold - Data Clarifications

PQRI PODP E&L Workshop April 18-19, 2018

• Human safety data are the most relevant, but if not available the

assessment will have to rely on animal work and QSAR

• Safe doses in animal studies (e.g. NOAEL values) are typically divided

by “safety factors” to enable inter-species data extrapolation

• eg, a factor of 10 for each unknown parameter
• Alternatively, some toxicologists calculate a Permitted Daily Exposure

(PDE) value for a chemical based upon the ICH algorithm to estimate a safe dose in humans Ultimately, using all data, the toxicologist must decide if there are sufficient data to support a safety position for potential exposure of humans to the chemical impurity in question

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Crossing the Threshold - Leveraging Data

PQRI PODP E&L Workshop April 18-19, 2018

Unknown Peak in a Parenteral Dosage Formulation

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Crossing the Threshold - An Example

PQRI PODP E&L Workshop April 18-19, 2018

• A parenteral dosage form prescription medication (ie, pre-filled

syringe) with an acute intermittent dosing regimen to inoculate against an infectious disease

• During stability testing of the product an unknown peak was

detected

• Peak subsequently identified as benzophenone (CAS #119-61-9)

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Crossing the Threshold - An Example

O

MW - 182.1 g/mol

PQRI PODP E&L Workshop April 18-19, 2018

• Benzophenone is a photo-initiator widely used in the food and

pharmaceutical industries for the purpose of UV curing of inks and label coatings applied to product packaging

• The literature confirms that leaching of this chemical into

pharmaceutical products and food from packaging is not unusual (Fang et al., Amer. Pharm. Rev., 2006)

• Important consideration from a quality perspective
• A human parenteral total daily dose of 60 µg/day is calculated for

benzophenone, or 1.2 µg/kg/day for a 50 kg individual

• This exceeds all 3 PQRI thresholds (ie, 1.5, 5.0 and 50 µg/day)
• A robust regulatory-ready risk assessment supporting the safety of

this leachable impurity (all endpoints) is needed

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Crossing the Threshold - An Example

PQRI PODP E&L Workshop April 18-19, 2018

• Benzophenone was negative in both bacteria and mammalian cell

mutagenicity assays both with and without metabolic activation

• It is not a mutagen
• Acute intraperitoneal LD50 value of benzophenone in mice is

reported as 727 mg/kg

• ~600,000-fold safety margin
• In a 3-month toxicity study conducted in rats with benzophenone,

the No-Observed-Adverse-Effect-Level (NOAEL) was 20 mg/kg/day

• ~17,000-fold safety margin
• Benzophenone was determined not to be a sensitizer or an irritant in

studies conducted in animals

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Crossing the Threshold - An Example

PQRI PODP E&L Workshop April 18-19, 2018

• In carcinogenicity studies conducted in rodents, benzophenone did

not cause carcinogenic effects deemed clearly relevant to humans

• Collective evidence benzophenone is not a mutagenic carcinogen
• Consistent with its widespread use and acceptance as both an indirect

food additive and one directly added to food as a flavoring agent

• One estimate of the of the average intake of benzophenone from

food sources is 330 µg/day

• As a food additive, the European Food Safety Authority has

calculated a Tolerable Daily Intake (TDI) value of 30 μg/kg/day for benzophenone

• A 25-fold safety margin

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Crossing the Threshold - An Example

PQRI PODP E&L Workshop April 18-19, 2018

• In reproductive toxicology studies conducted in animals with

benzophenone, there was no evidence of teratogenicity (rabbits and rats) or adverse affects on fertility (rats)

• The American Industrial Hygiene Association (AIHA) developed an

8-hour Workplace Environmental Exposure Level (WEEL) of 0.5 μg/L for benzophenone, which would result in a total acceptable daily pulmonary dose of about 69 μg/kg/day for a 50 kg individual in the workplace

(0.5 µg/L x 480 min x 20 L/min ÷ 50 kg x 5 ÷ 7 = 69 µg/kg/day)

• ~ 58-fold safety margin

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Crossing the Threshold - An Example

PQRI PODP E&L Workshop April 18-19, 2018

“Collectively, as a result of this examination of the available toxicology data for benzophenone, the presence

• f this leachable in this acute intermittent use parenteral

product is deemed to pose negligible chemical risk to humans under the conditions described in this assessment”

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Crossing the Threshold - Conclusion

PQRI PODP E&L Workshop April 18-19, 2018

Douglas J. Ball (Drug Safety Research & Development) Krista Dobo (Drug Safety Research & Development) Pamela Heard (Drug Safety Research & Development) Cindy Magee (Analytical Research & Development) Jessica Whritenour (Drug Safety Research & Development)

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Acknowledgements