PQRI PODP Extractables & Leachables...

PQRI PODP Extractables & Leachables Workshop

Presented by: Douglas J Ball, MS, DABTToxicology Consultant

Derivation of the Parenteral Safety Concern Threshold (SCT)

April 2018

PQRI PODP E&L WorkshopApril 18-19, 2018

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

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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

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Kroes et al, 2004


TTC Values

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C. Hennes/ECETOC TTC Task Force, 2010


TTC and Cramer Classification

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• 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, 1978


Cramer Classification

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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/daya 9 µg/kg/daya 1.5 µg/kg/daya

a Based on a 60 kg human

https://eurl-ecvam.jrc.ec.europa.eu/laboratories-research/predictive_toxicology/qsar_tools/toxtree

https://eurl-ecvam.jrc.ec.europa.eu/laboratories-research/predictive_toxicology/qsar_tools/toxtree


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

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Ball et al, 2007


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

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Carcinogenicity Risk Approaches and Assumptions to Derive OINDP SCT

• Based on distribution of 10-6 risk-specific doses • Extrapolated from TD50 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

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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

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Genotoxic Carcinogens More Potent Than Non-genotoxic Carcinogens

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10-6 Carcinogenicity Risk - CPDB Data

0%

20%

40%

60%

80%

100%

0.0001 0.001 0.01 0.1 1 10 100

10-6 Risk Specific Dose (µg/day)

Cum

ulat

ive

Perc

en

All SAL negative (N=178)

All SAL positive (N=276)

Calculations include allometric scaling factors and assume 70 kg human.

Cum

ulat

ive

Perc

ent

PQRI OINDP Best Practices, 2006


Why Allometric Dose-Scaling?

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Carcinogenic Potency in Mice and Rats

0%

20%

40%

60%

80%

100%

0.1 1 10 100 1000 10000

Oral TD50 (mg/kg/day)

Cum

ulat

ive

Perc

ent.

RatsMice

120 SAL-positive chemicals in Carcinogenc Potency Database with TD50 for both mice and rats

Median TD50: 12 mg/kg in Rats 38 mg/kg in Mice


SCT – A Conservative Estimate of Risk

• Corresponds to the 37th percentile of SAL-positive carcinogens in the CPDB

• Median excess cancer risk for a SAL-positive carcinogen at 0.15 µg/day is 0. 41 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

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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 non-carcinogenic 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

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Ball et al, 2007


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 alkyl-azoxy compounds) is a known or identified leachable, doses ≤1.5 µg per day may be warranted

Barber et al, 2015

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SCT Relationship to the TTC

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• 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


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

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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 multi-laminate blaster

• Vaccine will be a single 0.5 mL IM injection

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Extractable and Leachable Assessment

• A risk assessment was conducted and it was determined–Biocompatibility studies (<87>, <88>, or ISO

10993 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

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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

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Chrysene• CAS No: 218-01-9• In Silico analysis

– mutagenicity alerts (DEREK & SARAHa)

• EPA IRIS lists Chrysene as B2 probable human carcinogenb

• + in vitro mutagenicity results• + rodent carcinogenicity• RfD not determined

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a. Llhasa, Ltd; b. EPA IRIS, 2005


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

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ICH M7, 2014


Chrysene QualificationICH M7 Limit (µg/day;

duration of treatment <1 month)

Chrysene Level in DP(µg/day)

Qualified

120 18 Yes

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• ~7x margin for chrysene vs. ICH M7 limit for a mutagenic impurity in DP with less than 1 month duration

• This is a 1st 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


Maleic Anhydride• CAS No: 108-31-6• 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.

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O OO

Huels AG, Dept. of Biology/Toxicology, unpublished Report No. 1390 (1989).


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

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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

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Acknowledgements

• PQRI Toxicology Work team– Bill Beierschmitt– Steve Beck– Alisa Vespa– Tim Robison– Jackie Kunzler

• Pfizer– Krista Dobo– Cindy Magee– Russell Navens

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