Bridging the Divide: Use of Simulation Studies to
Resolve the PODP Analytical
Challenge
Thomas N. Feinberg
PQRI-PODP E&L Chemistry Working Group
USP/PQRI Suitability and Compatibility for
Packaging and Delivery Systems Workshop
Rockville, MD – April 28, 2014
Outline
• Objective:
– Resolve the PODP “Analytical Challenge”
• Starting point:
– Best demonstrated practices for OINDP
– SCT to AET for extractables
– SCT to AET for leachables
• Discuss thought process for simulation study
design
– Supportive data
2
How to translate the SCT into an AET?
Differs by use:
Controlled Extraction Studies
parts-per-million in materials
concentration in extracts
Leachables/Migration Studies
concentration in formulation
Analytical Challenge
Extractables Perspective
CES Goals
• After extraction, extracts will contain many
compounds
• Compounds above the AET must be identified to
the extent that a safety assessment can be
made
• Identification methods must be suitable for such
purpose
• Sample preparation of extracts is crucial
CES Basics
• Packaging materials exposed to solvents
creates extracts
• Extracts manipulated (solvent switching) and/or
concentrated prior to instrumental analysis
• There is a minimum concentration that
instrumental analysis can identify unknowns
(non-targets)
Controlled Extraction Study AET (OINDP)
From the perspective of the level in the packaging:
SCT (µg/day) × Doses per Packaging
Estimated AET (µg/g) =
Packaging Weight (g) × Doses per day
SCT = Safety Concern Threshold = 0.15 µg/day
Purpose: identify extractables at the level indicated
Analyze the Extracts
Standard practice avoids conditions either close to
saturation limit or suboptimal to drive diffusion limit
phenomena:
Ratio of Extract Volume to Sample Volume 20-100
Estimated AET (µg/g) × ComponentDensity(g/mL)
AET (µg/mL) ≈
(20 - 100)
Sample Preparation Limitations
• Standard identification techniques (GCMS, LCMS)
need > 2-20 µg/mL for reasonable identification
(Targeted assay concentrations may be 1000-fold lower than ID
Limit)
• Parts-per-billion (ppb) impurities and laboratory
contaminants become parts-per-million (ID Limit)
when Concentration Factors exceed 100
2 µg/mL
20 µg/mL
≤ Concentration Factor ≤
AET (µg/mL)
AET (µg/mL)
Concentration Factor Comparisons
Component
Valve Elastomer
HDPE Cap
LDPE Bottle
COC Syringe Barrel
Laminate Bag
COC Syringe Barrel
LDPE Bottle
Density Package
(g/mL)
Doses
120
0.9
0.95
100
0.91
100
1.02
1
0.91
1
1.02
1
0.91
10
Doses
Package
Concentration
per Volume Weight
SCT
AET
Factor
Day
(mL)
(g)
(µg/day) (µg/g)
(minimum)
4
20
0.3
0.15
18.0
2
4
10
1.0
1.5
3.9
11
4
10
3.2
1.5
1.2
38
1.5
0.05
810
1
1
3.1
1
1000
10.0
1.5
0.015
2930
4
3
4.5
1.5
0.008
4706
1
100
50.0
1.5
0.030
1465
Facing the Analytical Challenge in a Chromatogram
Analytical Evaluation Thresholds:
 OINDP, MDI Elastomer: AET
SCT
= 18 µg/g
 PODP, B/F/S Thermoplastic: AET
600-fold lower
0
19.20
19.40
19.60
19.80
SCT
= 0.03 µg/g
20.00
Abundance
Scan 2193 (19.534 min): 3301013_Ref3_IPA_RE.D\data.ms (-2190) (-)
59.1
9000
8000
7000
6000
5000
4000
128.9
3000
2000
1000
0
240.1
184.1
0
50
100
150
200
250
317.0
489.3549.9609.1
372.2 439.1
300
350
400
450
500
697.9
550
600
650
700
550
600
650
700
m/z-->
Abundance
#95460: Hexadecanamide
59.0
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
128.0
184.0
0
50
100
150
200
255.0
250
300
350
400
450
500
m/z-->
5.00
10.00
15.00
20.00
25.00
30.0
11
PODP CES Recommendation
•SCT has limited utility for understanding
manufacturing
•Most additives are used at 100 ppm or greater
•Use “material-based” AET
for example 10 µg/g (10 ppm)
•OINDP precedence (pg 156)
“The Working Group recommends that MDI actuator/mouthpieces
have an extractables Estimated AET of 20 μg/g for an individual
organic extractable. Adequate extraction conditions should be
used ....”
Switching Gears
Leachables Perspective
Leachable/Migration Study Goals
• After exposure, drug products may contain many
compounds both product related and packaging
related
• Packaging related compounds above the AET
must be identified to the extent that a safety
assessment can be made
• Identification methods must be suitable for such
purpose
• Sample preparation is crucial
Leachable/Migration Basics
• Drug products exposed to packaging materials
creates leachables
• Drug products manipulated (solvent switching)
and/or concentrated prior to instrumental
analysis
• There is a minimum concentration that
instrumental analysis can identify unknowns
Leachables Study AET
Estimated AET (µg/mL) =
SCT (µg/day) × Doses per Packaging
Packaging Volume (mL) × Doses per day
SCT = Safety Concern Threshold
Purpose: identify leachables at the level indicated
Compare: MDI Leachables Study AET
0.15 µg/day × 120 doses/package
AET (µg/mL) =
20 mL/package × 4 doses/day
AET (µg/mL) = 0.23 µg/mL
2 - 20µg/mL
Concentration Factor ≈
= 9 − 87
(0.23µg/mL)
SVP Leachables Study AET
1.5 µg/day × 10 doses/package
AET (µg/mL) =
100 mL/package × 1 dose/day
AET (µg/mL) = 0.15 µg/mL
2 - 20µg/mL
Concentration Factor ≈
= 13 − 130
(0.15µg/mL)
Consider Packaged DP as a CES System
• Exposing packaging material under controls of:
–
–
–
–
time
temperature
relative humidity
solution characteristics
Packaged Drug Products as CES
Component
Valve Elastomer
HDPE Cap
LDPE Bottle
COC Syringe Barrel
COC Syringe Barrel
Laminate Bag
LDPE Bottle
Density
(g/mL)
0.9
0.95
0.91
1.02
1.02
0.91
0.91
Package
Doses
Doses
per Day
120
4
100
4
100
4
1
1
1
4
1
1
10
1
Volume
Package
SCT
(mL)
Weight (g) (µg/day)
20
0.3
0.15
10
1.0
1.5
10
3.2
1.5
1
3.1
1.5
3
4.5
1.5
1000
10.0
1.5
100
50.0
1.5
AET
Volume-to(µg/g)
Sample Ratio
180.0
72
39.1
10
11.5
3
0.48
0.3
0.08
1
0.15
91
0.30
2
Formulation/Packaging Immiscibility
• Packaging materials are more
like lipids than water
• logPaverage ≈ 3.5
• Limited solubility
• Extraction driver favorable for
“sink” condition
• Same results regardless of
amount of sample
21
CES as Leachables Predictor
lipophilic
Leachables
polar
H-bonding
Simulation
SVP Example
• 50 grams of LDPE (density = 0.91 g/mL)
• Additive in LDPE = 100 ppm, 5000 µg total
• 100 mL of aqueous product
• log Kw ≈ logP > 3
• Solubility (Sw) < 1 µg/mL
Leachable < Min[Sw ,
Concentration in Polymer 5000 µg
,
]
log Kw
100 mL
10
• At equilibrium, same concentration, Sw = 1 µg/mL
SVP Sample Prep
Sw (µg/mL) ≈ 1 µg/mL
100 mL product volume to 1 mL sample volume = 100 µg/mL
1000 mL simulation volume to 1 mL sample volume = 1000 µg/mL
10-fold easier to identify
Simulation Study Guidelines
– “Flexible” AET
• Based on SCT
• Product Volume to Component Volume modified,
with justification
– Simplify the simulant
• High purity reagents allow high concentration factors
– Accelerate storage conditions
– Identify to AET
25
Model System Construction
Model System Simulation Study Design
1.5 µg/day × 10 doses/package
AET (µg/mL) =
100 mL/package × 1 dose/day
AET (µg/mL) = 0.15 µg/mL
2 - 20µg/mL
Concentration Factor ≈
= 13 − 130
(0.15µg/mL)
Simulation Study Design
Drug Product
Simulation Study
pH 2.5 buffered phosphate
same
CRT/ambient RH
40 °C/ambient RH
100 mL per container
100 mL per container
50 g packaging
50 g packaging
upright orientation
inverted orientation
2 years
6 months
Non-Target Simulation Study Analytics
Leachables
Technology
Volatile Organic
Headspace GC-MS
Semi-Volatile Organic
GC-MS
Polar Organic
(Non-Volatile Organic)
Elemental Impurities
LC-MS
ICP-MS
Element
182W
107Ag
95Mo
88Sr
79Br
75As
69Ga
65Cu
59Co
55Mn
47Ti
39K
27Al
23Na
7Li
Concentration (µg/mL)
Simulation Study: ICP-MS Example Data
1.200
1.000
0.800
0.600
0.400
0.200
0.000
Simulation Study: Expanded Scale
pH 2.5
0.050
0.040
0.035
0.030
0.025
0.020
0.015
0.010
0.005
Element
182W
107Ag
95Mo
88Sr
79Br
75As
69Ga
65Cu
59Co
55Mn
47Ti
39K
27Al
23Na
0.000
7Li
Concentration (µg/mL)
0.045
pH 2.5 Migration
1200.00
1000.00
800.00
Conc (arb units)
79Br
11B
7Li
600.00
24Mg
29Si
208Pb
66Zn
400.00
200.00
0.00
0
1
2
3
4
Months
5
6
7
Conclusions
• Use leachables AET based on SCT. Dose volume per
day for SVP and LVP leads to “Analytical Challenge”
• Use extractables AET based on material consideration
• Resolution of leachables “Analytical Challenge” may be
assisted by careful construction of a “Simulation Study”
• Assumptions for “Simulation Study” can be confirmed by
actual product testing under actual long-term storage at
actual end of shelf-life
These may be targeted assays
This would be a regulatory decision
• Construction of appropriate justifications will be
discussed further in future PQRI training
35