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THOMAS DEVADDER
THOMAS DEVADDER
SGS LIFE SCIENCE SERVICES TEAM LEADER QC AAS / ICP / Particles / TGA
Laboratory Services
DETERMINATION OF ELEMENTAL IMPURITIES
– CHALLENGES OF A SCREENING METHOD
2Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
Challenges
Strategy
Potential interferences
Sample preparation / determination by ICP-MS
Validation of a screening method
Screenings on excipients, APIs and drug products
Where are the boundaries in the applicability?
AGENDA
3 Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
CHALLENGES OF A SCREENING METHOD
Method must provide
• Valid information about APIs, Excipients and Finished
Products
• Applicability for a broad variability of sample materials
• Acceptance criteria from EP 5.20 / USP <233>
• A validated basis
Challenges
• Interferences from different sample materials
4Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
STRATEGY
• Worst case limits by EP/USP/ICHOral/Parenteral/Inhalation (Late 2013)
• Daily dose of 10g/day
• Quantitative procedure
Basis
• Worst case matrix (Omega-3 fish oil)
• Closed vessle microwave digestion (nitric acid)
• Determination by ICP-MS
MethodDevelopment
• According to USP<233>/EP2.4.20 (Omega-3 fish oil)
• Simulation of potential Interferences from differentsample materials (K, Na, Ca, Mg, Cl)
MethodValidation
• Fullfilled acceptance critera (USP<233>/EP2.4.20)
• Method verification on new samples by spikingexperiment
Routine Testing
5Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
INTERFERENCES
Physical Interferences
• Viscosity
• Density
• Matrix
• Sediments on Cones
Dilution, Internal Standard, Sample Preparation
Chemical Interferences
• Absorption effects during sample introduction
• Nebulization effects
• Stability of solution
• Contaminations
• Carry over
Method-Optimization, Stabilization
6Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
Spectral Interferences
• Oxid Formation
• Double charged Ions
• Polyatomic combinations
System-Optimization
Isobare Interferences
• Elements share isotopic masses (Resolution 0.7 amu)
Choice of an appropriate isotope, Corrective equation
Polyatomic Interferences
• Combinations of Ar40, O16, Cl35, N14, H1
Dynamic Reaction Cell (NH3, CH4, H2, O2, He)
INTERFERENCES
7Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
It‘s good to know, that…
Most interferences show up in a mass range below
80 amu (atomic mass units) because of polyatomic
compounds from Ar40, O16, Cl35, N14, H1 and their
combination.
Many interferences end at a concentration of 20 µg/l
INTERFERENCES SUMMARY
IT IS GOOD TO KNOW THAT…
8Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
INTERFERENCES
To avoid Physical Interferences
Add 20 µg/l Indium / Internal Standard in all solutions
To avoid Chemical Interferences
Signal Os Standard / Os Standard after CVMD ≈ 1:10
Adding of a complexing agent
Hg Stabilization
Add 500 µg/l Gold for (preserves Hg <10µg/l)
Carry over effect
60 sec rinsing step between samples
To avoid Polyatomic Interferences
Ar40Cl35 interferes As75
O16Cl35 interferes V51
DRC using 0.6 ml/min O2
Polyatomic Combination of As75 to AsO91 and V51 to VO67
9Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
0
100
200
300
400
500
600
700
800
900
1000
0 0.5 1
[cps]
[µg/l]
As75 in Water
48000
48500
49000
49500
50000
50500
51000
51500
52000
0 0.5 1
[cps]
[µg/l]
As75 in HCl 1.5%
Ar40Cl35
Background0
100
200
300
400
500
600
700
800
900
0 0.5 1
[cps]
[µg/l]
AsO91 in HCl 1.5%(DRC O2 0.6 ml/min)
Ar40Cl 35 / As75 INTERFERENCE
10Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
MICROWAVE DIGESTION
300 mg sample material digested (6 ml HNO3/50 ml)
Max. 80 bar / max. 280°C
Sample material +6 ml HNO3 after digestion transferred filled up
11Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
# ElementLimit
[µg/g]
Range
[µg/l]
Range
[µg/g]
1 As 0.15 2.25 0.375
2 Cd 0.15 2.25 0.375
3 Hg 0.12 1.8 0.3
4 Pb 0.5 7.5 1.25
5 V 0.12 1.8 0.3
6 Cr 0.29 4.35 0.725
7 Ni 0.15 2.25 0.375
8 Cu 1.3 19.5 3.25
9 Mo 0.76 11.4 1.9
10 Ru 0.14 2.1 0.35
11 Rh 0.14 2.1 0.35
12 Pd 0.1 1.5 0.25
13 Ir 0.14 2.1 0.35
14 Pt 0.14 2.1 0.35
15 Os 0.14 2.1 0.35
16 Fe 130 1950 325
17 Zn 130 1950 325
18 Mn 25 375 62.5
19 Co 0.29 4.35 0.725
20 Se 8.5 127.5 21.25
21 Ag 0.69 10.35 1.725
22 Sb 2.2 33 5.5
23 Tl 0.8 12 2
24 Ba 34 510 85
25 Li 2.5 37.5 6.25
26 Sn 6.4 96 16
CALIBRATION
Calibration up to 250% of target limit
Correlation coefficient r ≥ 0,998
Recovery QC Standard 80-120%
Sample: 300 mg in 50 ml final
solution via microwave digestion
12Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
USP <233> EP 2.4.20Quantitative
ProcedureProcedure
Acceptance
CriteriaProcedure
Acceptance
Criteria
Specificity Method must show reliable
measurements for target
elements in the matrix and
components including other
target elements
- Method must show reliable
measurements for target
elements in the matrix
Demonstrating compliance
with Acceptance Criteria
from Accuracy
Linearity, Range - Demonstrating by
meeting the Accuracy
requirement
- Demonstrating compliance
with Acceptance Criteria
from Recovery
Accuracy Standard solutions within a
range of 50% – 150% of the
specification limit in triplicate
and Spiking Experiment within
a range of 50% – 150% of the
specification limit in triplicate
(+ e.g. spiking Experiment at
10% Specification limit for
LOQ)
Mean recovery of 3
individual replicates must
be within
70% - 150% for each level
Spiking Experiment in 3
Levels within a range of 50%
– 150%
of the specification limit in
triplicate
(+ e.g. spiking Experiment at
10% Specification limit for
LOQ)
Mean recovery of 3 individual
replicates must be within
70% - 150% for each level
Repeatability 6 spiking experiments at
specification limit
RSD <= 20% 6 spiking experiments at
specification limit or
procedure of Accuracy
RSD <= 20%
Ruggedness Experiments of Repeatability
on a different day, or with a
different instrument or by
different analyst. Minimum 1
of these 3 choices.
RSD <= 25% Experiments of Repeatability
on a different day, or with a
different instrument or by
different analyst. Minimum 1
of these 3 choices.
RSD <= 25%
Quantification Limit
(LOQ)
- Demonstrating by meeting
the Accuracy requirement
Determine the lowest
concentration meeting the
Acceptance Criteria from
Accuracy
LOQ < Specification limit
VALIDATION REQUIREMENTS
13Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
# Element Limit Selectivity Linearity Method precision Intermediate precision
[µg/g] Isotope Ratio: 0,8-1,2 Criteria: r≥0,998 RSD n=6 (100%): ≤20% RSD n=12 (100%): ≤25%
1 As 0.15 Reaction cell 0.99976 10.0% 7.1%
2 Cd 0.15 complies 0.99910 2.4% 2.2%
3 Hg 0.12 complies 0.99972 15.3% 16.6%
4 Pb 0.5 complies 0.99983 11.3% 12.6%
5 V 0.12 Reaction cell 0.99996 7.3% 5.5%
6 Cr 0.29 Reaction cell 0.99983 1.9% 2.6%
7 Ni 0.15 complies 0.99994 8.6% 6.5%
8 Cu 1.3 complies 0.99964 2.4% 1.7%
9 Mo 0.76 complies 0.99950 4.8% 3.4%
10 Ru 0.14 complies 0.99972 3.2% 3.5%
11 Rh 0.14 Mono Isotope 0.99993 2.1% 3.3%
12 Pd 0.1 complies 0.99976 2.3% 3.0%
13 Ir 0.14 complies 0.99994 9.8% 10.9%
14 Pt 0.14 complies 0.99807 12.3% 13.5%
15 Os 0.14 complies 0.99993 10.2% 9.5%
16 Fe 130 complies 1.00000 1.5% 1.3%
17 Zn 130 complies 0.99976 7.6% 5.7%
18 Mn 25 Mono Isotope 0.99986 1.0% 1.0%
19 Co 0.29 Mono Isotope 0.99991 1.3% 1.5%
20 Se 8.5 complies 0.99837 11.6% 9.4%
21 Ag 0.69 complies 0.99839 1.9% 12.5%
22 Sb 2.2 complies 0.99998 8.9% 8.6%
23 Tl 0.8 complies 0.99996 12.3% 11.1%
24 Ba 34 complies 0.99993 3.6% 2.5%
25 Li 2.5 complies 0.99996 2.9% 3.3%
26 Sn 6.4 complies 1.00000 3.1% 3.2%
VALIDATION RESULTS 1/2
14Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
# Element Limit Accuracy / Mean Recovery 70-150% for each spiking level LOQ [Level]
[µg/g] 10% Level 20% Level 50% Level 100% Level 200% Level Target: ≤50%
1 As 0.15 104.2% 98.8% 101.1% 98.5% 100.5% 10%
2 Cd 0.15 93.1% 97.1% 97.4% 99.4% 100.3% 10%
3 Hg 0.12 69.7% 78.5% 74.6% 84.3% 88.5% 10%
4 Pb 0.5 89.7% 95.7% 92.1% 76.8% 82.8% 10%
5 V 0.12 92.5% 93.3% 92.3% 93.7% 95.3% 10%
6 Cr 0.29 98.3% 92.7% 104.3% 102.6% 100.8% 10%
7 Ni 0.15 66.4% 110.3% 93.0% 95.0% 100.8% 20%
8 Cu 1.3 100.3% (RSD:32.7%) 92.5% 102.8% 102.4% 106.3% 20%
9 Mo 0.76 118.1% 113.5% 120.1% 111.2% 104.9% 10%
10 Ru 0.14 109.5% 110.7% 117.5% 110.0% 109.3% 10%
11 Rh 0.14 106.4% 106.8% 114.0% 107.5% 106.7% 10%
12 Pd 0.1 75.0% 88.0% 103.7% 102.6% 103.7% 10%
13 Ir 0.14 76.2% 78.5% 74.6% 84.3% 88.5% 10%
14 Pt 0.14 79.8% 72.3% 78.5% 79.4% 84.4% 10%
15 Os 0.14 84.5% 82.5% 74.9% 84.4% 80.0% 10%
16 Fe 130 97.2% 98.6% 102.0% 99.8% 100.4% 10%
17 Zn 130 91.4% 93.2% 94.6% 98.0% 103.0% 10%
18 Mn 25 107.6% 108.8% 113.8% 109.9% 110.8% 10%
19 Co 0.29 106.2% 107.6% 114.2% 110.4% 111.1% 10%
20 Se 8.5 92.5% 93.1% 98.8% 97.3% 104.5% 10%
21 Ag 0.69 72.7% 86.2% 101.4% 106.0% 106.7% 10%
22 Sb 2.2 92.4% 90.0% 90.5% 92.3% 79.6% 10%
23 Tl 0.8 74.8% 76.3% 73.8% 81.7% 86.2% 10%
24 Ba 34 93.7% 95.7% 93.6% 98.8% 101.6% 10%
25 Li 2.5 106.8% 108.8% 113.9% 115.6% 116.7% 10%
26 Sn 6.4 95.3% 92.9% 97.4% 95.0% 81.4% 10%
VALIDATION RESULTS 2/2
15Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
ROUTINE SCREENING
Organic
Samples
APIs
Solvents, Polyol
Artificial flavours
Cellulose
Fatty oils
Clear sample solution
Method verificationcomplies
Inorganic
Samples
Salts
Clear Sample solution containing
high saltconcentration
PhysicalInterferences /
False negative results
Pigments, InkSiO2 , Talc, TiO2
Glue Potential forundisolved
components
Filtration,
Potential forphysical
Interferences/
False negative results
Finished
Products
Capsules
Tabletes
Protein
Solutions
Clear sample solution
Method verificationcomplies
16Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
POTENTIAL IMPACT ON RESULTS
Salts
PotassiumMagnesium
Potential forPhysical Interferences
SodiumCu63 / Na23Ar40
False positive results
CalciumNi60 / Ca44O16
False positive results
Pigments, InkSilicon
componentsGlue
CapsulesTabletes
Ferric Oxide Major Physical Interferences
SiO2, Talc, TiO2 Analyte loss within filtration
17Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
USP EP ICP-MS
Excipient ProcedureTarget
ElementsProcedure
Target
Elements
Method
Improvement
Ferric Oxide AAS
Colorimetric
Limit Test
Hg, Pb
As
- - Reduced sample
concentration,
Improved Digestion
Talc Flame AAS Al, Ca, Fe, Pb
(Impurity)
Mg (Assay)
Flame AAS Al, Ca, Fe, Pb
(Impurity)
Mg (Assay)
Digestion with
nitric acid + hydrofluoric acid
Titanium
Dioxide
Colorimetric
Limit Test
As <211> Colorimetric
Limit Test
Sb, As, Ba, Fe
Heavy metals
(2.4.8)
Digestion with
nitric acid + hydrofluoric acid
Silicon Dioxide Colorimetric
Limit Test
As <211>
Heavy metals
<231>
- - Digestion with
nitric acid + hydrofluoric acid
Salts Reduced sample
concentration,
Improved Interference control
WAYS TO CONTROL CRITICAL EXCIPIENTS
18Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
SGS SOLUTIONS 1/2
Latest equipment and techniques
ICP-MS
ICP-OES
Flame / Graphite Furnace-AAS
FIMS (Hydrid System) and combination to AAS
Large geographic coverage and sites with ICP-MS
Europe Berlin (Germany), Clichy (France)
Asia Chennai (India), Taipei (China)
North America Fairfield (USA), Lincolnshire (USA)
19Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
Wide experiences in:
Method Development and Validation
Verification of pharmacopeia methods
ICH Q3D, USP <232> / <233> and EP 5.20 / 2.4.20
Extractable / Leachable Studies
Determination of Silicon Oil traces
SGS SOLUTIONS 2/2
20Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
Life Science Services Thomas Devadder
Team Leader QC AAS/ICP/Particles/TGA
Laboratory Services
SGS Institut Fresenius GmbH t: + 49 30 34607 659
Tegeler Weg 33, f: + 49 30 34607 600
D-10589 Berlin
Germany E-mail : [email protected]
Web : www.sgs.com/lifescience
THANK YOU FOR YOUR ATTENTION
+ 41 22 739 9548
+ 1 866 SGS 5003
+ 65 637 90 111
+ 33 1 41 24 87 87
+ 1 877 677 2667
