PQRI PODP Extractables & Leachables Workshop Derivation of the Parenteral Safety Concern Threshold (SCT)

Transcription

1 PQRI PODP Extractables & Leachables Workshop Derivation of the Parenteral Safety Concern Threshold (SCT) Presented by: Douglas J Ball, MS, DABT Toxicology Consultant April 2018

2 Agenda TTC Cramer Classification SCT derivation for OINDP SCT derivation for PDP SCT relationship to TTC SCT and Application of ICH M7 Case Study Conclusions 2

3 TTC Background The threshold of toxicological concern (TTC) is a pragmatic risk assessment tool Based on the principle of establishing a human exposure threshold value for all chemicals Exposure <TTC is a very low probability of an appreciable risk to human health TTC can be used to set acceptable daily intakes (ADIs) for chemicals with known toxicological profiles For chemicals with unknown toxicological profiles A de minimis value can be identified based on chemical structure And known toxicity of chemicals with similar structural characteristics Kroes et al,

4 TTC Values C. Hennes/ECETOC TTC Task Force,

5 TTC and Cramer Classification The Cramer Classification System is an assessment tool to qualify chemicals when exposure is >TCC consists of a decision tree of 33 questions, each answered yes or no Each answer leads to another question or to final classification into one of three classes (I, II and III) reflecting a presumption of low, moderate or serious toxicity The tree is organized into branches dealing with major chemical classifications and is intended for use with all ingested, structurally defined organic and metallo-organic substances Relies primarily on features of chemical structure Occurrence in body tissues and fluids, and natural occurrence in food The logic of the tree rests heavily on known data on metabolism and toxicity. Cramer, et al,

6 Cramer Classification Cramer Class I Cramer Class II Cramer Class III Low Toxicity Moderate Toxicity Serious Toxicity 1800 µg/day 540 µg/day 90 µg/day 30 µg/kg/day a 9 µg/kg/day a 1.5 µg/kg/day a a Based on a 60 kg human 6

7 SCT - Background The Safety Concern Threshold was first proposed by the PQRI OINDP Work team For OINDP, the SCT is 0.15 µg/day The SCT is the threshold below which a leachable would have a dose so low as to present negligible safety concerns from carcinogenic and noncarcinogenic toxic effects. Below the SCT, identification of leachables is unnecessary Ball et al,

8 SCT based on Carcinogenic Risk Carcinogenicity typically occurs at lower intakes than noncarcinogenic toxicity Thus, intakes with acceptable cancer-risk entail negligible concern for noncarcinogenic toxicity Based on quantitative risk estimates, the SCT limits carcinogenicity risk of unidentified leachables to an acceptable level (10-6 ) Similar to approach for FDA Threshold of Regulation for indirect food additives, but with some methodological differences 8

9 Carcinogenicity Risk Approaches and Assumptions to Derive OINDP SCT Based on distribution of 10-6 risk-specific doses Extrapolated from TD 50 values in Carcinogen Potency Database (CPDB) For genotoxic (SAL-positive) carcinogens Assumes potency via inhalation comparable to other routes (principally oral) Extrapolation used: Allometric dose-scaling Central risk estimates rather than upper bound Geometric mean rather than most sensitive species 9

10 SCT Derivation Based on Genotoxic Carcinogens Genotoxic (SAL-positive) carcinogens are particularly relevant for safety concern: More potent than SAL-negative carcinogens Linear extrapolation to zero risk (ie, no risk-free dose) more applicable to genotoxic carcinogens Most known human carcinogens are genotoxic Structural alerts are more predictive for genotoxins 10

11 Genotoxic Carcinogens More Potent Than Non-genotoxic Carcinogens 100% 10-6 Carcinogenicity Risk - CPDB Data Cumulative Percent 80% 60% 40% 20% 0% All SAL negative (N=178) All SAL positive (N=276) Calculations include allometric scaling factors and assume 70 kg human Risk Specific Dose (µg/day) PQRI OINDP Best Practices,

12 Why Allometric Dose-Scaling? Carcinogenic Potency in Mice and Rats Cumulative Percent. 100% 80% 60% 40% 20% 0% Rats Mice Median TD50: 12 mg/kg in Rats 38 mg/kg in Mice 120 SAL-positive chemicals in Carcinogenc Potency Database with TD 50 for both mice and rats Oral TD 50 (mg/kg/day) 12

13 SCT A Conservative Estimate of Risk Corresponds to the 37 th percentile of SAL-positive carcinogens in the CPDB Median excess cancer risk for a SAL-positive carcinogen at 0.15 µg/day is x 10-6 If <20% of random chemicals are genotoxic carcinogens, <7% of all compounds would exceed 10-6 increased cancer risk at intakes <0.15 µg/day lifetime exposure 13

14 SCT Dose level for OINDP Unknown leachables in OINDP at intakes below a SCT of 0.15 µg/day (1x10-6 risk level) present negligible concern for carcinogenic or noncarcinogenic health risks Set at 1x10-6 level to identify presence of cohort of concern chemicals PNAs, NAs, MBT Identification of leachables below this threshold is generally unnecessary Exception: some specific, highly potent leachables (eg, nitrosamines, PAHs) may need identification at lower levels Ball et al,

15 SCT Derivation for PDP The derivation of the SCT for Parenteral Drug Products (PDP) employed the same principles used to derive the OINDP SCT The major difference is the SCT for PDP is set at a 1x10-5 risk level For pharmaceuticals, a theoretical 1x10-5 cancer incidence is considered justified for ADI of 1.5 µg per day for an unstudied impurity (Barber) For PDP the SCT is 1.5 µg/day Most PDP consist of aqueous formulations Due to the chemical nature of leachables formed under aqueous conditions, there is no appreciable increase in cancer incidence over a lifetime of human exposure if exposure to a PDP leachable is 1.5 µg per day Thus, below the SCT of 1.5 µg per day, the dose of a leachable would be so low that the chemical would pose a negligible safety concern from mutagenic/carcinogenic and other toxic effects Of note, if a cohort of concern chemical (e.g., aflatoxin-like, N-nitroso- and alkylazoxy compounds) is a known or identified leachable, doses 1.5 µg per day may be warranted Barber et al,

16 SCT Relationship to the TTC SCT derivation similar to TTC derivation Both are derived based on carcinogenic risk SCT is not a TTC SCT used to calculate a analytical evaluation threshold to identify leachables There is no requirement that all leachables are below the SCT to be considered qualified Each identified leachable must be assessed for potential safety issues at the dose (concentration) in PDP If a safety issue is identified, the dose (concentration) of the particular leachable must be reduced to a safe level or eliminated from the PDP 16

17 SCT and the Application of ICH M7 From ICH M7: Application of this guideline to leachables associated with drug product packaging is not intended, but the safety risk assessment principles outlined in this guideline for limiting potential carcinogenic risk can be used if warranted The PQRI work team recommends that ICH M7 may be useful to qualify leachables identified as potential mutagens by in silico analyses or from in vitro mutagenicity studies 17

18 Case Study Vaccine in a PFS A new first in class anti-viral vaccine has been developed The primary Container Closure System (CCS) is the formulated vaccine (aqueous, ph neutral) in a pre-filled syringe (PFS) PFS developed specifically for this vaccine The secondary packaging consists of a multilaminate blaster Vaccine will be a single 0.5 ml IM injection 18

19 Extractable and Leachable Assessment A risk assessment was conducted and it was determined Biocompatibility studies (<87>, <88>, or ISO equivalent) required for all critical components Controlled extraction studies for critical components of the PFS and secondary packaging Leachable study on PFS Safety assessment for all leachables identified from the DP above 1.5 µg/day 19

20 Results Biocompatibility Compliant with USP <87> and <88> Results from Leachable Study Two chemical identified that require safety assessment Chrysene: from plunger stopper; 18 µg/day Maleic Anhydride: from multi-laminate blister; 8 µg/day 20

21 Chrysene CAS No: In Silico analysis mutagenicity alerts (DEREK & SARAH a ) EPA IRIS lists Chrysene as B2 probable human carcinogen b + in vitro mutagenicity results + rodent carcinogenicity RfD not determined a. Llhasa, Ltd; b. EPA IRIS,

22 Application of ICH M7 for Chrysene Qualification The TTC-based acceptable intake of 1.5 µg/day is considered to be protective for a lifetime of daily exposure To address less than lifetime (LTL) exposures to mutagenic impurities in pharmaceuticals, an approach is applied in which the acceptable cumulative lifetime dose (1.5 µg/day x 25,550 days = 38.3 mg) is uniformly distributed over the total number of exposure days during LTL exposure This would allow higher daily intake of mutagenic impurities than would be the case for lifetime exposure and still maintain comparable risk levels for daily and non-daily treatment regimens ICH M7,

23 Chrysene Qualification ICH M7 Limit (µg/day; duration of treatment <1 month) Chrysene Level in DP (µg/day) Qualified Yes ~7x margin for chrysene vs. ICH M7 limit for a mutagenic impurity in DP with less than 1 month duration This is a 1 st in class vaccine that was developed to treat a rare, yet often fatal viral infection The benefit:risk for exposing a patient to a single dose of chrysene at 18 µg/day is warranted Based on ICH M7 the carcinogenic risk to a single dose of chrysene at 18 µg/day is low 23

24 Maleic Anhydride CAS No: Maleic anhydride is highly irritating but non-corrosive to rabbit skin Highly irritating and corrosive to rabbit eyes May be highly sensitizing to guinea pigs May cause sensitization by inhalation and skin contact in humans Occupational exposure to maleic anhydride has been associated with the development of respiratory allergy or asthma. O O O Huels AG, Dept. of Biology/Toxicology, unpublished Report No (1989). 24

25 Maleic Anhydride Qualification Based on the irritation and possible sensitization potential: Reduce levels of maleic anhydride to <5 µg/day develop an alternative multi-laminate blister that contains no maleic anhydride It was not possible to consistently reduce levels of maleic anhydride to <5 µg/day An alternative multi-laminate blister was developed 25

26 Conclusions The SCT concept was originally proposed for OINDP Based on similar concepts used to develop the TTC The 1x10-6 level (0.15 µg/day) was based on the known presence of chemicals of concern in MDIs The SCT approach can be used for E&L assessment of PDP Based on several points to consider, the SCT for PDP is based on a 1x10-5 level (1.5 µg/day) The SCT of 1.5 µg/day is used to set the AET concentration for PDP The principles of ICH M7 can be used to qualify leachables identified as mutagens It is Important to recognize, dose levels provided in ICH M7 does not alter the SCT for PDP 26

27 Acknowledgements PQRI Toxicology Work team Bill Beierschmitt Steve Beck Alisa Vespa Tim Robison Jackie Kunzler Pfizer Krista Dobo Cindy Magee Russell Navens 27

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