Transcript Development and Justification of Qualification Threshold

Development and Justification
of Qualification Threshold
Ron Wolff
IPAC-RS Representative
Fellow, Life Sciences
Nektar Therapeutics
Outline
• Decision criteria
• Process for setting qualification threshold (QT)
– Comparison to non-carcinogenic reference thresholds
in a similar manner to SCT
• Consideration of irritation, hypersensitivity, age
• Relation of QT to
– Ambient particulate matter
– Examples from marketed products
Decision Criteria
• A leachable with a tolerable daily intake (TDI) at
or below the qualification threshold
– would have a dose so low as to present negligible
safety concerns from noncarcinogenic toxic effects
– would be considered qualified, so no toxicological
assessment would be required
– would require a toxicology risk assessment with a
structural alert or known class effect for
carcinogenicity/genotoxicity, irritation, or
hypersensitivity
Reference Exposure Levels (RELs)
• Definition
– Daily exposure concentration considered to present negligible
risk to human health from non-carcinogenic effects
– Usually a no-observed-adverse-effect-level (NOAEL) from
animal toxicology studies with the use of an appropriate safety
factor (usually  100)
• Sources
– US EPA
– Agency for Toxic Substances Disease Registry (ATSDR)
– California Environmental Protection Agency (CAL EPA)
Inhalation Reference Levels in Various
Databases
100%
100%
Systemic Tox (N=44)
Respiratory Tox (N=32)
80%
80%
60%
60%
40%
40%
20%
20%
0%
0%
0.0001
0.01
1
100
10000
1000000
0.0001
100%
1
100
10000
1000000
100%
Systemic Tox (N=62)
Systemic Tox (N=98)
Respiratory Tox (N=38)
80%
60%
Respiratory Tox (N=57)
60%
40%
40%
20%
20%
0%
0.0001
0.01
ATSDR Minimal Risk Level (µg/day)
California REL (µg/day)
80%
Systemic Tox (N=41)
Respiratory Tox (N=18)
0%
0.01
1
100
10000
1000000
US EPA Inhalation RfD (µg/day)
0.0001
0.01
1
100
10000
1000000
Combined Reference Value (µg/day)
Summary of Inhalation Reference
Toxicity Values (µg/day)
Respiratory Toxicity
Systemic Toxicity
median
10th %tile
median
10th %tile
CAL EPA RELs
60
1.2
5000
4.0
ATSDR MRLs
189
1.1
5426
5.4
US EPA RfDs
90
0.5
1400
4.2
Combined
120
1.5
1940
5.0
Most Compounds with Reference Levels < 5 g/day
Are Metals, Carcinogens or Identified Irritants
Compounds with Respiratory Toxicity
Compounds with Systemic Toxicity
Ref Value
(µg/
day)
Source
chromium vi (chromic acid mists)
0.086
REL RfD MRL
beryllium and compounds
0.237
RfD REL
hexamethylene diisocyanate
0.525
acrolein
chloroacetophenone, 2-
Compound
Compound
chlorinated dioxins
Ref Value
(µg/day)
Source
0.0008
REL
cadmium
0.4
REL
RfD MRL
arsenic
0.6
REL
0.583
REL RfD MRL
arsine
1.0
RfD
0.600
RfD
manganese
1.5
REL RfD MRL
toluene diisocyanate mixture
1.4
RfD REL
mercury
1.9
REL RfD MRL
glutaraldehyde
1.6
REL
chlordane
2.4
REL MRL
nickel & compounds
2.0
REL MRL
dicyclopentadiene
4.0
RfD
cobalt
2.0
MRL
nitroaniline, 2-
4.0
RfD
titanium tetrachloride
2.0
MRL
disulfoton
4.0
MRL
nickel oxide
2.0
REL
1,2-dibromoethane
4.0
RfD
antimony trioxide
4.0
RfD
1,2-dibromo-3chloropropane
4.0
RfD
chlorine
4.0
RfD REL
hydrazine
4.0
REL
chlorine dioxide
4.0
RfD
hexachlorocyclopentadiene
4.0
RfD
Note: For compounds with more than 1 source, Ref Value is geometric mean from all available sources. Ref Value = reference value.
Irritation
• Evaluated from the point of view that asthmatics are the most
sensitive population
• Used the RD50 database developed on inhaled irritants in mice as a
starting point
– Validated, well-accepted, extensive database of commodity chemicals
– RD50 is the concentration that produces marked effects in mice by
reducing respiratory frequency by 50%
• Confluence of data suggest that 0.001 X RD50 is a safe
concentration for most asthmatics
– Corresponds to a concentration that produces no discernible effects on
lung tissue, and thus also unlikely to elicit any bronchoconstrictor
response, since the two are correlated
– RD50 based safe dose = 0.001 X RD50 breathed for 10 minutes
Sensitivity of Asthmatics Compared to
Normal Population
• Cockcroft (Ann Allergy, 1985) studied 253 normals and 181
symptomatic asthmatics challenged with aerosolized histamine
– 25% of normals responded at a concentration of 16 mg/L
[effectively, an RD50 concentration]
– 25% of asthmatics responded at 0.2 mg/L
– No observable responses in asthmatics at 0.015 mg/L
Illustrates that 1/1000 of RD50 values is likely to pose
negligible risk for most asthmatics
RD50 Based Safe Dose in Asthmatics
is Less than Occupational Short Term
Exposure Limits (STELs)
100%
RD50 Based Non-Irritant Dose
Cumulative Percent
80%
15-min STEL
60%
40%
20%
0%
0.01
0.1
1
10
100
Inhaled Dose (ug)
1000
10000 100000
RD50 Based Safe Doses are Similar to California
RELs Designed to Protect the General Population
(Including Sensitive Sub-Populations)
Cumulative Perce nt
100%
CA Acute REL Based
80%
RD50 Based
60%
40%
20%
0%
0.1
1
10
100
Inhaled Dose (ug)
1000
10000
100000
Hypersensitivity
• Data on isocyanates used to provide perspective
• RD50 of toluene diisocyanate is 0.4 ppm
• Permissible Exposure Level (PEL) is 0.02 ppm
– Level designated to prevent induction of sensitization
• Lowest concentration eliciting responses in
sensitized subjects
– 0.001 ppm
These data and other similar examples suggest that
0.001 X RD50 is also protective of hypersensitivity
reactions
Acute Irritation and Sensitization Have
Similar Dose-Response to Chronic
Respiratory Toxicity
Estimated Safe Human Exposures for Various Toxicity Endpoints
100%
Cumulative Percent
80%
Acute
Respiratory
Irritation
Carcinogenicity
60%
Chronic
Respiratory Toxicity
40%
20%
0%
0.001
Chronic
Systemic Toxicity
0.01
0.1
1
10
100
1000
10000
100000 1000000
Inhalation Dose (µg/day)
Carcinogenicity, 10-6 Risk Specific Dose for CPDB Mutagens (N=276)
Acute Irritation, Human Equivalent RD50/1000 (N=244)
Respiratory Toxicity, Chronic Inhalation Reference Dose (N=57)
Systemic Toxicity, Chronic Inhalation Reference Dose (N=98)
Most Compounds with RD50 Based Reference
Exposure Levels < 5 g/day Can be Identified with
Structural Alerts
• Isocyanates
• Aldehydes
• Pesticides
• Nitriles
• Styrenes
Comparison of 5 g/day QT with Ambient
Particulate Exposures
• Ambient reference concentration - 18 g/m3
– Data from Portage, Wisconsin
• Cleanest environment in the “Six cities study”
• Best air quality and least cardio-respiratory disease
• Designated as the “control” city against which others were
compared
– Well below the National Air Quality Standards for PM10
(respirable fraction)
• 50 g/m3 annual average
• 150 g/m3 twenty-four hr average
QT of 5 µg/day Compared to Inhaled
Particulate in the Cleanest of the “Six Cities”
Inhaled Environmental
Particulates *
Ventilation
5 µg/day Limit as %
of Inhaled
Environmental
Particulates
Body
Mass
(kg)
(m³/day)
(m³/kg/day)
(µg/day)
(µg/kg/day)
1 year
11.5 †
5.1 †
0.4
93
8.0
5.4%
5 years
20.0 †
8.7 †
0.4
157
7.8
3.2%
10 years
33.7 †
15.3 †
0.5
275
8.2
1.8%
15 years
55.0 †
17.7 †
0.3
319
5.8
1.6%
Adult
58.0 †
17.8 †
0.3
320
5.5
1.6%
70.0 ‡
20.0 ‡
0.3
360
5.1
1.4%
Age
* Based on PM10 inhalable particle concentration of 18  g/m³ in reference city Portage WI, USA, (Dockery et al, 1993).
† Estimates based on measurements for different ages of ventilation rate at various activity levels and percentage of daily time spent at
those activity levels (Roy, 1992)
‡ Standard estimates used by US EPA for risk assessment
Perspective for Exposures to Children
• 5 g/day QT
– Represents a minor additional load compared to daily environmental
exposure for any age group, including children
• Comparisons of toxicokinetics in adults and children are within the
toxicokinetic safety factor of 3.16 greater than 90% of the time
• Comparison of deposition of particles and gases in adults vs
children are within the toxicokinetic safety factor of 3.16
Therefore, the standard intraspecies safety factor of 10
(toxicokinetic factor of 3.16 x toxicodynamic factor of 3.16) appears
to be adequate to account for possible differences between adults
and children, however additional research in this area is warranted
Comparison of 5 µg/day QT with ICH Thresholds
Type
Active
Ingredient
Product
Maximum
Dose *
(µg/day)
ICH Qualification Threshold
Drug Substance
Drug Product
basis
(µg/day)
basis
(µg/day)
FORADIL
DPI
formoterol fumarate
20
0.15%
0.03
1%
0.2
SEREVENT
MDI-DPI
salmeterol xinafoate
100
0.15%
0.15
1%
1.0
FLONASE
NAS
fluticasone propionate
200
0.15%
0.30
1%
2.0
ATROVENT
MDI
ipratropium bromide
216
0.15%
0.32
1%
2.2
ATROVENT
NAS
ipratropium bromide
252
0.15%
0.38
1%
2.5
BECONASE AQ
NAS
beclomethasone dipropionate
336
0.15%
0.50
1%
3.4
QVAR
MDI
beclomethasone dipropionate
512
0.15%
0.77
1%
5.1
ASTELIN
NAS
azelastine hydrochloride
1,096
0.15%
1.6
1%
11.0
VANCERIL 84
MDI
beclomethasone dipropionate
1,260
0.15%
1.9
1%
12.6
PULMICORT
DPI
budesonide
1,280
0.15%
1.9
1%
12.8
PROVENTIL HFA
MDI
albuterol sulfate
1,296
0.15%
1.9
1%
13.0
AZMACORT
MDI
triamcinolone acetonide
1,600
0.15%
2.4
1%
16.0
FLOVENT
MDI-DPI
fluticasone propionate
2,000
0.15%
3.0
1%
20.0
AEROBID
MDI
flunisolide
2,000
0.15%
3.0
1%
20.0
MAXAIR
MDI
pirbuterol acetate
2,400
0.15%
3.6
1%
24.0
INTAL
MDI
cromolyn sodium
6,400
0.15%
9.6
≤50 µg
50.0
TILADE
MDI
nedocromil sodium
14,000
0.15%
21
0.50%
70.0
RELENZA
DPI
zanamivir
20,000
0.15%
30
0.50%
100
IMITREX
NAS
sumatriptan
40,000
0.15%
60
0.50%
200
NICOTROL NS
NAS
nicotine
40,000
0.15%
60
0.50%
200
Median
1,448
1.9
* Based on dose delivered from mouthpiece or actuator when reported. "Every 4 hours" is assumed to allow up to 6 times daily.
Abbreviations: DPI = dry powder inhaler; MDI = metered dose inhaler; NAS = nasal spray
12.9
OINDP L&E Threshold Perspective
• Recommended thresholds based on dose inhaled by
patients
– Rather than a percentage (%) as in ICH Guidelines
• 5 g/day QT
– Recommendations intermediate between API and drug product ranges
– Relevance maximized based on considerations of
• Total daily intake
• Structural alerts
• Conservative risk assessment
Summary
• A Qualification Threshold (QT) of 5 µg/day meets the
criterion of a dose that is sufficiently low as to
present negligible safety concerns for
noncarcinogenic toxic effects.
• Consideration of possible irritancy and
hypersensitivity suggest that 5 µg/day will
adequately protect sensitive sub-populations
• The risk assessment must include structural alert
information to provide case-by-case assessments
for metals, isocyanates, aldehydes, nitriles, and
styrenes whose levels are below the QT