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www.intertek.com1
Intertek Webinar
24th September 2013, Basel
Extractables and Leachables Testing: An Introduction and
Strategies in Current Practice
Dr. Armin Hauk
Intertek
ECA Concept Heidelberg Extractables & Leachables Seminar
14/15 May 2014 in Copenhagen
www.intertek.com2
Extractables and Leachables (E&L) Studies
1. Introduction to Extractables and Leachables (E&L) Studies
2. The strategy for a reasonable E&L Study.
3. Illustrative examples from E&L Studies.
4. The evaluation and assessment of E&L data.
www.intertek.com3
What is an Extractables and Leachables (E&L) Study?
An E&L investigation guarantees that a pharmaceutical packaging is save and does not negatively influence the drug product. In this context also “devices” like inhalers or prefilled syringes are regarded as a primary packaging system (a “container closure system”).
• Extractables: compounds released from a container/closure system into an
extraction solution in forced extraction experiments
• Leachables: compounds that leach from a container/closure system into the
“drug formulation” under normal storage conditions (as part of
the stability study)
=> Extractables are worst case Leachables
=> Leachables are a subset of Extractables
=> Leachables are effectively applied to the patients
www.intertek.com4
Why to perform E&L Studies?
Critical examples from the past – pharmaceutical packaging area (MDI) –polyaromatic hydrocarbons (PAHs), mercapto-benzothiazole and N-nitrosamines; (prefilled syringes) tungsten case & photoinitiators.
Critical examples from the past – food packaging area – ITX and other printing compounds and N-Nitrosamines.
Scientific reasons - additives and process chemicals are small molecules, some pharmaceutical formulations are quite good solvents for such extractables
To avoid surprises - degradation products of polymeric matrix or additives. Unknown compounds from manufacturing of the packaging (“NIAS”) and contaminants. Compounds migrating from printing and adhesives into the drug products.
Regulatory Guidelines – USP, EP, FDA, EMEA
www.intertek.com5
Why to perform E&L Studies?
EU-Pharmacopoeia Chapter 3, incl. Supplement 5.1, 5.2 & 5.3
USP e.g. <381> for elastomers, <661> for polymer characterization
FDA Guidance for Industry: Container Closure Systems for Packing Human Drugs and Biologics (1999)
FDA Guidance for Industry: Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products (1998)
FDA Guidance for Industry: Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products -Chemistry, Manufacturing, and Controls Documentation (2002)
Health Canada, Guidance for Industry: Pharmaceutical Quality of Inhalation and Nasal Products (2006)
EMEA CPMP/QWP/4359/03, Guideline on Plastic Immediate Packaging Materials (2005)
EMEA CPMP/QWP/2845/00, Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products (2006), in collaboration with Health Canada
EMEA CPMP/QWP/158/96, Note for Guidance on Dry Powder Inhalers
ICH Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (1999)
www.intertek.com6
How to design an E&L Study?
An E&L investigation is not one single study, it is at least divided in 4 subsequent major steps:
Step 1.) The critical assessment of the packaging system and the
properties of the pharmaceutical formulation plus an evaluation
of the guidelines.
Step 2.) The Extractables Study is a set of forced lab experiments to
extract as much as possible out of the packaging material (but
not to destroy the material). In this case the chemists & polymer
chemists “creativity” is necessary to design reasonable
experiments (..).
Step 3.) The data evaluation of the extractable study, including a tox.-
assessment. Selection of critical leachables.
Step 4.) The Leachables Study is finally performed as part of the stability
study for the drug product after appropriate method optimisation
& validation for the selected leachables.
Step 2b:
“Migration”
Eventually plus
extractables
experiments
with simulants
in original
packaging
system under
worst case
conditions &
long term
storage
www.intertek.com7
How to design an E&L Study?
Step 1.) The critical assessment of the packaging system means to sample all available data regarding the whole packaging system (here, be investigative and be suspicious). To be taken into account:
1) The Polymer Matrix: PP, PE, LDPE, HDPE, COC,
PVC, PET, PU, PC, PA, Teflon, elastomers (rubber),
laminated systems etc.
2) Additives: e.g. phenolic antioxidants, organo-
phosphites, HALS etc.
3) Process Chemicals – dependent on the polymer and
the process
4) Printings: Solvents, binder, reactive compounds, fillers,
dyes & pigments, additives
5) Adhesives: Solvents, polymer-systems, reactive
compounds, fillers and additives.
6) Secondary Packaging Systems: Paper, cardboards,
stickers, over-wrapping foils, etc.
www.intertek.com8
How to design an E&L Study?
Step 1.) The critical assessment of the packaging system means to sample all available data regarding the whole packaging system (here, be investigative and be suspicious). To be taken into account:
The Special Case: Elastomers, especially Rubber Materials:
A quantitative analysis of 2-Mercaptobenzothiazole, 2,2’-
Dithiobis(benzothiazole), PAHs and N-Nitrosamines
is necessary (PQRI recommendation)
The Special Case: Inner coatings of metal devices (tubes):
Quantitative analysis of BADGE and its derivatives is required
(recommended by BfArM.)
Gamma- and Steam-Sterilisation Processes:
Significant difference between polymers regarding
sterilisation treatments. Samples with and without
sterilisation shall be investigated
S
NSH
S
NS S
NS
N
CH3
CH3
N O
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How to design an E&L Study?
Step 1.) The critical assessment of properties of the drug product means to establish a qualitative risk based approach for the possible interaction between packaging material and drug product
Potential interaction of packaging with drug formulation
Degree of concern
High Medium Low
High Inhalation (e.g. MDIs - organic solvents!), injectables
Sterile powders and inhalation powders
Medium
Ophthalmic solutions, transdermal ointments & patches, nasal aerosols and sprays
Low
Topical solutions and suspensions, oral solutions, lingual aerosols
Oral powders Oral tablets, capsules
www.intertek.com10
How to design an E&L Study?
Step 1.) The critical assessment of properties of the drug product means to establish a qualitative risk based approach for the possible interaction between packaging material and drug product
www.intertek.com11
How to design E&L Studies?
Step 1.) The critical assessment of properties of the drug product means to establish a quantitative risk based approach for the possible interaction between packaging material and drug product
Estimation of an analytical evaluation threshold (AET) for a MDI:
• Lowest acceptable daily dose for an extractables and leachables compound –
taking also unknowns into account - is 150 ng/day (based on PQRI).
• A typical volume of a MDI is 15 mL
• The application scenario is 0.1 mL in 3 doses per day = 0.3 mL/day
• 150 ng/day / 0.3 mL/day = 500ng/mL (concentration of extractables)
• 500ng/mL x 15 mL = 7500 ng = 7.5 µg (total released amount of an extractable)
• Assuming a part has a weight of 1 g ⇒ 7.5 µg/g (ppm) of an extractables have
to be analysable with the applied method.
• Quantitation limit for Extractables has to be better than 7.5 ppm (this is a typical
value in Extractable Studies).
www.intertek.com12
How to perform E&L Studies?
Standard set for the extraction with organic solvents of different polarity: Hexane,
Dichloromethane, Iso-propanol, Ethanol etc. plus temperature stress.
Extraction performed under reflux, in Soxleths or ultrasonic baths
(analysis with GC/MS). Caution with volatile compounds!
Standard set for aqueous extraction: Different pH-buffers, variation in salinity plus
temperature stress eventually with addition of detergents. Extraction
performed under reflux or in ultrasonic baths (analysis with LC/MS plus
GC/MS of extracts). Caution with volatile compounds and degradation
reactions!
Alternative methods, e.g.: Accelerated solvent extraction (ASE), supercritical fluid
extraction (SFE) or thermodesorption devices directly coupled with
GC/MS (TDS-GC/MS)
Step 2.) The Extractable Study is a set of forced lab experiments to extract as much as possible out of the material (but not to destroy the material).
www.intertek.com13
How to perform E&L Studies?
Step 2.) The Extractable Study is a set of forced lab experiments…what means worst case?
Typical pMDI: API plus excipients, pH-buffer, Ethanol (10%), propellant (40% fluorinated HC)
Prefilled syringe: API plus excipients, pH-buffer but >90% water
Tablets: API plus some excipients, stationary phase
– no solvent and no water!
Extraction Study only with single parts possible
Extraction Study with single parts or assembled device
Extraction Study with single parts or assembled device
Extraction Study with strong organic and aqueous solvents with pH adjustment
Extraction Study with aqueous alcohol and pH adjustment
Extraction Study with organic solvents or TENAX
www.intertek.com14
How to perform E&L Studies?
Step 2: Work flow for extractables analysis (method set-up to be comprehensive)
Aqueous / organic extract
HS-GC/MS
ICP/MS
LC/MS
pH 4 Extraction GC/MS
Derivatization GC/MS
pH 12 Extraction
Derivatization
GC/MS
GC/MS
TDS-GC/MS
GC/MS
Extraction w/oDerivatisation -GC/MS
Special analytics
OrganicExtract
OrganicExtract
OrganicExtract
www.intertek.com15
How to perform E&L Studies?
Step 2: Analytical devices typically used in an Extractables study:
TDS-GC/MSD → Comprehensive screening for VOCs,
oligomers, additives, additive break-down products
and unknowns.
Headspace-GC/MSD → Qualitative & quantitative analysis of
residual solvents & volatiles in aqueous extracts.
GC/MSD → Qualitative & quantitative analysis of extracts &
derivatised extracts, specific analysis of oligomes,
additives, & additive break-down products.
LC/MS → Quantitative analysis of extracts for semi-polar
and polar compounds - screening for polar
unknowns possible, but no perfect tool for
qualitative analysis
ICP-MS → Metals from catalysts, dyes and pigments.
NMR / MS / IR → Identification & structure elucidation of
unknowns
www.intertek.com16
How to perform E&L Studies?
Typical qualitative results of an Extractables study; here polyolefin:
2. 00 4.00 6 .0 0 8. 00 10 .0 0 1 2. 00 14.00 16. 00 1 8. 00 2 0. 00 2 2. 00 2 4.00 26. 00 28 .0 0
500 000
10 000 00
15 000 00
2000 00 0
2500 00 0
3000 00 0
3500 00 0
4000 00 0
4500 00 0
5000 00 0
5500 00 0
6000 00 0
6500 00 0
7000 00 0
7500 00 0
8000 00 0
8500 00 0
9000 00 0
9500 00 0
1 e+07
Time -->
Abu ndanc e
Minor compounds are some VOCs, some typical additives, some additive degradation products
Main compounds are sets of homologue series of PE-oligomers
O
O
O
OH
O
O
4
Irganox 10107,9-Di-tert-butyl-1-oxaspiro[4.5]deca-6,9-diene-2,8-dione
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How to perform E&L Studies?
Typical qualitative results of an Extractables study; here a polysiloxane-material:
2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00
500000
1000000
1500000
2000000
2500000
3000000
3500000
4000000
4500000
5000000
5500000
6000000
6500000
7000000
7500000
8000000
8500000
9000000
9500000
1e+07
1.05e+07
1.1e+07
1.15e+07
1.2e+07
1.25e+07
1.3e+07
Time-->
Abundance
Main compounds are some non-resolved sets of homologue series of PSX-oligomers
Minor compounds are some VOCs, some additive degradation products and residuals of a polymerisation starter
O
OOH
ClCl
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How to perform E&L Studies?
“Worst case” extraction; case study 1 for non-realistic conditions
• Extractables study on multi-layer container closure system
• Extraction conditions were: aqueous solutions, 95°C, 24 h
• Sum of all identified & quantified extractables by GC/MS and LC/MS was ~20 ppm
• But the TOC of the aqueous extracts was ~120 ppm
• Reason for that difference ?
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How to perform E&L Studies?
#F:
500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600m/z
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
Rela
tive A
bundance
755.7
6
711.7
4
871.8
7
799.8
4
915.9
2
959.8
9
667.7
3
843.8
5827.8
4
595.6
6
1003.9
3
1075.9
7
1031.9
1
551.6
9
639.7
1
987.9
4
1119.9
9
783.8
2
1192.0
5
1163.9
9
623.7
5
1324.0
9
1236.0
2
887.8
7
1280.0
4
1395.9
5
943.8
7
1147.9
8
1440.1
0
1252.0
2
1076.9
7
507.6
0
960.9
1
1352.0
2
1484.1
5
1441.1
4
1281.0
6
1412.0
8
683.7
4
844.8
5
800.8
4
739.7
7
756.8
4
712.8
0
1513.2
21528.1
8
1512.2
4
1557.2
31572.2
81573.2
21600.2
1
579.6
8
596.7
4
640.7
7
552.7
3
479.6
0
1613.1
3
508.6
9523.6
2
641.7
4
480.6
7
RO
R'n
RO
R'n
=> Very complex mixture of homologue series of high molecular weight compounds could be seen in the baseline of the chromatogram
• LC/ MS screening
www.intertek.com20
How to perform E&L Studies?
• “Extraction kinetics” of the TOC (H2O, 95°C):
TOC-Formation
0 5 10 15 20 25 30t [h]
TO
C
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How to perform E&L Studies?
• “Extraction kinetics” of the high molecular weight compounds (H2O, 95°C)
Formation of compounds with MW 944-988
0
50000
100000
150000
200000
250000
300000
350000
0 5 10 15 20 25 30
t [h]
LC
/MS
are
a (
neg
. m
od
e)
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How to perform E&L Studies?
• “Extraction kinetics” of low molecular weight compounds (H2O, 95°C):
RT 9.9 min, m/z = 150
0
10000
20000
30000
40000
50000
60000
70000
80000
0 5 10 15 20 25 30
t [h]
GC
/MS
are
a
RT 12.8, m/z = 73
0
20000
40000
60000
80000
100000
120000
0 5 10 15 20 25 30
t [h]
GC
/MS
are
a
www.intertek.com23
How to perform E&L Studies?
“Worst case” extraction; case study 2 for non-realistic conditions
• Metal parts (MDI canister or Al-tubes) are coated with epoxy-resins.
• Problem with such coatings: BADGE and its derivatives.
• Until now data from food migration studies - carried out under standard conditions 10d at 40°C with e.g. 95% ethanol or olive oil - were accepted.
• Extractables studies were also carried out with alcohols (ethanol, iso-propanol).
• Publication from team of Mrs. Lipperheide (BfArM) showed that pharmaceutical formulations are quite better solvents for BADGE and its derivatives as alcohols and olive oil.
J. B. Haverkamp, U. Lipke, Th. Zapf, R. Galensa and C. Lipperheide
(2008) Contamination of semi-solid dosage forms by leachables from
aluminium tubes. European Journal of Pharmaceutics and
Biopharmaceutics, 70, 921-928.
www.intertek.com24
How to perform E&L Studies?
“Worst case” extraction; case study 2 for non-realistic conditions
RT:0.09 - 18.13SM:7G
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Time (min)
0
10
20
30
40
50
60
70
80
90
100
Rela
tive A
bundance
0
10
20
30
40
50
60
70
80
90
100
Rela
tive A
bundance 8.21
10.5110.8910.38
9.86 11.099.7211.22
11.809.07
12.22 14.8014.30 17.6412.85 17.1815.66
7.557.32
6.435.934.814.153.320.81 2.532.07
11.72
14.8917.7616.2810.82 13.4312.3110.53
9.769.200.91 8.246.766.435.404.813.623.022.13
ACN extract
Water/iso-propanol extract (50+50)
cyclo-di-BADGE
BADGE related compounds
HPLC-APCI(+)-MS (TIC, m/z 400-2000)
cyclo-tetra-BADGE, di-BADGE*BPA,
BADGE*BuEtOH, BADGE*tBuPh
www.intertek.com25
How to perform E&L Studies?
“Comprehensive overview”, relevance of back-extractions
16.50 17.00 17.50 18.00 18.50 19.00 19.50 20.00 20.50 21.00 21.50 22.00 22.50
16.50 17.00 17.50 18.00 18.50 19.00 19.50 20.00 20.50 21.00 21.50 22.00 22.50
16.50 17.00 17.50 18.00 18.50 19.00 19.50 20.00 20.50 21.00 21.50 22.00 22.50
16.50 17.00 17.50 18.00 18.50 19.00 19.50 20.00 20.50 21.00 21.50 22.00 22.50
16.50 17.00 17.50 18.00 18.50 19.00 19.50 20.00 20.50 21.00 21.50 22.00 22.50
16.50 17.00 17.50 18.00 18.50 19.00 19.50 20.00 20.50 21.00 21.50 22.00 22.50
16.50 17.00 17.50 18.00 18.50 19.00 19.50 20.00 20.50 21.00 21.50 22.00 22.50
16.50 17.00 17.50 18.00 18.50 19.00 19.50 20.00 20.50 21.00 21.50 22.00 22.50
16.50 17.00 17.50 18.00 18.50 19.00 19.50 20.00 20.50 21.00 21.50 22.00 22.50
16.50 17.00 17.50 18.00 18.50 19.00 19.50 20.00 20.50 21.00 21.50 22.00 22.50
16.50 17.00 17.50 18.00 18.50 19.00 19.50 20.00 20.50 21.00 21.50 22.00 22.5016.50 17.00 17.50 18.00 18.50 19.00 19.50 20.00 20.50 21.00 21.50 22.00 22.50
16.50 17.00 17.50 18.00 18.50 19.00 19.50 20.00 20.50 21.00 21.50 22.00 22.50
16.50 17.00 17.50 18.00 18.50 19.00 19.50 20.00 20.50 21.00 21.50 22.00 22.50
16.50 17.00 17.50 18.00 18.50 19.00 19.50 20.00 20.50 21.00 21.50 22.00 22.50
16.50 17.00 17.50 18.00 18.50 19.00 19.50 20.00 20.50 21.00 21.50 22.00 22.50
16.50 17.00 17.50 18.00 18.50 19.00 19.50 20.00 20.50 21.00 21.50 22.00 22.50
pH of aqueous extract: pH adjustment before
organic back-extraction:
3
3
10
7
7
10
basic
acidic
acidic
basic
acidic
basic
R
O
OH
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How to perform E&L Studies?
“Comprehensive overview”, relevance of derivatised extracts
12.0 12.5 13.0 13.5 14.0 14.5 15.0 15.5 16.0
ab
c
d
e
fg h
i k
m
n
12.0 12.5 13.0 13.5 14.0 14.5 15.0 15.5 16.0
ab
c
d
e
fg h
i k
m
n
Trimethylsilyl erucamide (unsat. C22 fatty acid amide)n
Octadecanoic acid 2,3-bis[(trimethylsilyl)oxy]propyl esterm
unknown (m/z = 73, 191, 223, 257, 433, 507, 536)k
Hexadecanoic acid 2,3-bis[(trimethylsilyl)oxy]propyl esteri
Trimethylsilyl linoleic acid amideh
Trimethylsilyl oleic acid amideg
Trimethylsilyl octadecanoatef
Trimethylsilyl hexadecenoic acid amidee
Trimethylsilyl trans-9-octadecenoated
Trimethylsilyl hexadecanoatec
Trimethylsilyl trans-9-hexadecenoateb
Trimethylsilyl tetradecanoatea
Trimethylsilyl erucamide (unsat. C22 fatty acid amide)n
Octadecanoic acid 2,3-bis[(trimethylsilyl)oxy]propyl esterm
unknown (m/z = 73, 191, 223, 257, 433, 507, 536)k
Hexadecanoic acid 2,3-bis[(trimethylsilyl)oxy]propyl esteri
Trimethylsilyl linoleic acid amideh
Trimethylsilyl oleic acid amideg
Trimethylsilyl octadecanoatef
Trimethylsilyl hexadecenoic acid amidee
Trimethylsilyl trans-9-octadecenoated
Trimethylsilyl hexadecanoatec
Trimethylsilyl trans-9-hexadecenoateb
Trimethylsilyl tetradecanoatea
NH
O
Si
NH
O
Si
Trimethylsilyl oleic acid amide
Trimethylsilyl linoleic acid amide
F3C
N
O SiMe3
SiMe3
BSTFA (N,O-bis(trimethylsilyl)- trifluoroacetamide)
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How to perform E&L Studies?
igloo stopper silicone tubingsilicone gaskets
rubber gaskets
syringe plungersinjection/infusion stoppers
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Example for results from an Extractables study: Rubber material
2.00 4.00 6.00 8.00 10.0012.0014.0016.0018.0020.0022.0024.0026.00
14.00 15.00 16.00 17.00 18.00 19.00 20.00 21.00 22.00 23.00 24.00
10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00
10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00
10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00
10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00
m/z = 55
m/z = 57
m/z = 97
m/z = 99
n
n
55
57
97
99
isopropyl
end group
tert-butyl
end group
How to perform E&L Studies?
www.intertek.com29
Br
2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00
500000
1000000
1500000
2000000
2500000
3000000
3500000
4000000
4500000
5000000
5500000
6000000
6500000
7000000
7500000
8000000
8500000
9000000
9500000
1e+07
1.05e+07
1.1e+07
Time-->
Abundance
TIC: 11124_6720GC_1a.D\data.ms
2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00
500000
1000000
1500000
2000000
2500000
3000000
3500000
4000000
4500000
5000000
5500000
6000000
6500000
7000000
7500000
8000000
8500000
9000000
9500000
1e+07
1.05e+07
1.1e+07
Time-->
Abundance
TIC: 11124_6722GS_1a.D\data.ms
Thermodesorption-GC/MS chromatograms of two bromobutyl stoppers
BHT
C21H40
Isomers of C21H39Br
C13H24
Isomers of C13H23Br
C21H40
Isomers of C21H39Br
C13H24
Isomers of C13H23Br
Hexane Methylcyclopentane Cyclohexane
Hexane Methylcyclopentane Cyclohexane
Example for results from an Extractables study: Rubber material
How to perform E&L Studies?
www.intertek.com30
Example for results from an Extractables study: Rubber material
MercaptobenzothiazoleOrganic rubber extract after back extraction
How to perform E&L Studies?
www.intertek.com31
Quantification approaches in an Extractables study:
• Individual quantification with references
• Quantification by a qualified medium response factor
• Quantification by the “bottom line” approach
2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00
500000
1000000
1500000
2000000
2500000
3000000
3500000
4000000
4500000
5000000
5500000
6000000
6500000
7000000
7500000
8000000
8500000
9000000
9500000
1e+07
Time-->
Abundance
How to perform E&L Studies?
www.intertek.com32
Leachabels Check
Experiment, e.g. with
placebo, under conditions of
accelareted stabi.-test
Extraction experiment 2 – more realistic set-up, e.g. with organic/aquoeous solvents
Extraction experiment 1 – worst case extractions, e.g. with strong solvents
TDS-GC/MS screening, comprehensive overview of Extractables
Step 3.) The data evaluation of the extractable study, including a tox.-assessment. Finally selection of critical leachables.
Final list of relevant
extractables
How to interpret Extractables Results?
www.intertek.com33
Daily dose depended
assessment
With published tox-data
With estimated or derived tox-data
Final list of relevant
extractables
Step 3.) The data evaluation of the extractable study, including a tox.-assessment. Finally selection of critical leachables.
How to interpret Extractables Results?
www.intertek.com34
How to interpret Extractables Results?
Step 3.) The data evaluation of the extractable study, including a tox.-assessment. Selection of critical leachables.
Threshold values from Guidelines which can be applied to Extractables
• PQRI: "Justification of Thresholds for Leachables in Orally Inhaled and Nasal
Drug Products“; a Safety Concern Threshold SCT is defined for potential
carcinogenic compounds with 0.15µg/day and for non-carcinogenic 5µg/day.
• EMAE: CHPM/QWP/251344/2006; Guideline on the Limits of Genotoxic
Impurities; a Threshold of Toxicological Concern (TTC) is given with
1.5µg/day intake.
• EMEA: CHMP/SWP/QWP/4446/00corr.; Guideline on the Specification
Limits for Residues of Metal Catalysts; three classes of Me types and limit
values (as dose) are given.
• Solvents according to limits for residual solvents given in USP or Pharm-Eur.
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How to interpret Extractables Results?
• 25 Tablets in one bottle
• Extractables Study: Compound (X) was found with 2 µg per bottle.
• Worst case estimation: Total transfer of compound (X) to pharmaceutical formulation ⇒ 2 µg in 25 tablets.
• Maximum 3 tablets/day ⇒ (2 µg/25) x 3 = 0.24 µg
• Result: Depending on tox-profile of compound X most probably acceptable – E&L studies not necessary
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How to interpret Extractables Results?
• Infusion bag, 250 mL volume
• Results form an extractables study: Compound (X) was found with a concentration of 20 ppb in the infusion solution ⇒ 20 µg/L compound (X) in infusion solution.
• Maximum 3 bags/day ⇒ 15 µg of compound (X) is applied directly by injection.
• Result: Depending on tox-profile of compound (X) this could be an acceptable or not-acceptable dose – leachables study most probably necessary.
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Case Study: IRGANOX 1010
OH
O
O
OH
O
O
OHO
O
OH
OO
Molecular weight: 1177.7
Water solubility: <0.1 mg/l (at 20°C)
How to interpret Extractables Results?
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How to interpret Extractables Results?
Sources of toxicology data identified
• Ciba, 2000, IRGANOX 1010: Tetrakis-(Methylene-(3,5-di-tertbutyl-4-hydrocinnamate)Methane. CAS NO. 6683-19-8. Submitted by: Ciba Specialty Chemicals Corporation; New York to United States Environmental Protection Agency (EPA); Washington, DC.
• Drake, G.A.; London, J.E.; Smith, D.M.; Thomas, R.G. 1980. Preliminary Toxicological Study of Irganox 1010. Prepared by: University of California, Los Alamos Scientific Laboratory; Los Alamos, New Mexico for the US Department of Energy; Washington, DC. [LA-8037-MS].
• European Commission, 2000, IUCLID Data Set CAS No. 6683-19-8.
Case Study: IRGANOX 1010
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How to interpret Extractables Results?
Acute toxicity: oral LD50 = >10,250 mg/ kg body weight; inhalation LC50 = >1,951 mg/m3 (>2,070 mg/kg body weight)
Skin Irritation: Non-irritating (rabbits)
Sensitization: Not sensitizing (guinea pigs)
Eye Irritation: Mild, but transitory, eye irritant (rabbit)
Subchronic toxicity
• 13-week dietary study in beagles: NOAEL = 10,000 ppm (~250 mg/kg/day)
Carcinogenicity
• Dietary studies in rats and mice; no indication of tumorigenic potential in either species
Genotoxicity
• Not mutagenic in Ames assay
• Not clastogenic in in vivo bone marrow chromosomal aberration test in Chinese hamsters
Reproductive and Developmental toxicity
• Two generation reproductive dietary study in rats; no effects on reproductive capacity; no maternal toxicity; NOAEL 10,000 ppm – highest dose tested (~1,000 mg/kg/day)
• Teratology studies - oral gavage in rats; NOAEL for both maternal toxicity and teratogenicity = 1,000 mg/kg/day, the highest dose tested
Case Study: IRGANOX 1010
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How to interpret Extractables Results?
Risk Characterization
• In the absence of a regulatory agency derived acceptable
daily intake, the risk characterization was based on the
lowest NOAEL observed of 250 mg/kg/d in the 13 week dog
study
• Exposure to lrganox 1010 from use of an injectable was
estimated to be 0.4 µg/kg body weight/day
• Margin of Safety 625,000
• [250 mg/kg b.w./day / 0.0004 mg/kg b.w./day
Conclusion: no clinically relevant adverse effects expected
Case Study: IRGANOX 1010
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Step 4.) The Leachable Study is finally performed as part of the stability study for the drug product after appropriate method optimisation &
validation for the selected leachables.
Extractables versus Leachables Studies
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Extractables versus Leachables Studies
Extractables Studies are “worst case” investigations, are only partially compound-specific, the polymer chemists know-how and creativity in the lab work is valuable, a high degree of experimental freedom exists. In Extractables Studiesexperimental modifications & repetitions are possible and the ways to achieve an appropriate screening of extractables are variable.Extractables Studies should be adjusted to the drug formulation and the packaging system.
Leachables Studies simulate realistic storage conditions with the drug product (e.g. as part of the stability test protocol).Leachables Studies are compound specific, the methods have to be optimised and validated. Compounds which are monitored as leachables are potential drug impurities. Leachables Studies are performed under full QC. There is no experimental freedom & only a limited number of samples are available (e.g. out of the stability test). Qualified references are necessary. Problem: Unexpected results and/or OOS-cases.Leachables Studies are specific regarding the drug formulation and the packaging system plus the packaging size.
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Leachables Study
The method have to be validated according to ICH Q2A/Q2B:
1) Specificity - Spike experiments with authentic reference materials - GC/MS, retention time (high conc.)
2) Linearity – measurement of pure compounds and matrix spiked extracts
3) Accuracy – by spiking / comparison of linearity of pure references versus matrix spiked and extracted references
4) Precision (Reproducibility) - multiple extractions spiked and non-spiked
5) Robustness – method stability over time and extract stability
6) LOQ/LOD – determination by spiking experiments (low conc.)
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Intertek Chemicals & Pharmaceuticals
Thank you for your attention !
Questions & Discussion
Dr. Armin Hauk Tel.: +41 61 686 48 56 e-mail: [email protected]