PQRI PODP Extractables & Leachables Workshop Leachable Evaluation of a Container Closure System - What to do When Above the Threshold William P. Beierschmitt, PhD, DABT, FATS Drug Safety Research and Development Pfizer, Inc. April 2018
Background 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 2
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! 3
Crossing the Threshold - What Now? 4
Crossing the Threshold - Safety Considerations 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 5
Crossing the Threshold - Data Considerations 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) 6
QSAR Tools (eg, DEREK and SARAH In silico tools to predict mutagenicity concerns (both) and a wide range of systemic toxicity endpoints (DEREK) Toxtree Crossing the Threshold - Data Clarifications 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 7
Crossing the Threshold - Data Clarifications 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 8
Crossing the Threshold - Data Clarifications 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 9
Crossing the Threshold - Leveraging Data 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 10
Crossing the Threshold - An Example Unknown Peak in a Parenteral Dosage Formulation 11
Crossing the Threshold - An Example 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) O MW - 182.1 g/mol 12
Crossing the Threshold - An Example 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 13
Crossing the Threshold - An Example 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 14
Crossing the Threshold - An Example 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 15
Crossing the Threshold - An Example 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 16
Crossing the Threshold - Conclusion Collectively, as a result of this examination of the available toxicology data for benzophenone, the presence of 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 17
Acknowledgements 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) 18