The International Conference on Harmonization (ICH) released its Q3D Guideline for Elemental Impurities in December 2014, initiating reviews and changes in quality testing programs in bio/pharmaceutical companies around the world. In advance of the implementation dates, companies need to assess the risks of potential elemental impurities in their process and materials streams. In this presentation, experts will review the requirements of elemental impurities guidelines from ICH, the European Pharmacopeia, and United States Pharmacopeia, outline practical recommendations to address implementation challenges, and discuss key considerations for analytical testing programs.

1. 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

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Determination 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

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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

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Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
STRATEGY
• Worst case limits by EP/USP/ICH
Oral/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
Method
Development
• According to USP<233>/EP2.4.20 (Omega-3 fish oil)
• Simulation of potential Interferences from different
sample materials (K, Na, Ca, Mg, Cl)
Method
Validation
• Fullfilled acceptance critera (USP<233>/EP2.4.20)
• Method verification on new samples by spiking
experiment
Routine
Testing

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Determination 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

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Determination 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

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Determination 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…

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Determination 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

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Determination 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
Background
0
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

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Determination 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

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Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
# Element
Limit
[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

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Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
USP <233> EP 2.4.20
Quantitative
Procedure
Procedure
Acceptance
Criteria
Procedure
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

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Determination 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

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Determination 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

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Determination 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 verification
complies
Inorganic
Samples
Salts
Clear Sample
solution containing
high salt
concentration
Physical
Interferences /
False negative
results
Pigments, Ink
SiO2 , Talc, TiO2
Glue Potential for
undisolved
components
Filtration,
Potential for
physical
Interferences/
False negative
results
Finished
Products
Capsules
Tabletes
Protein
Solutions
Clear sample
solution
Method verification
complies

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Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
POTENTIAL IMPACT ON RESULTS
Salts
Potassium
Magnesium
Potential for
Physical Interferences
Sodium
Cu63 / Na23Ar40
False positive results
Calcium
Ni60 / Ca44O16
False positive results
Pigments, Ink
Silicon
components
Glue
Capsules
Tabletes
Ferric Oxide Major Physical Interferences
SiO2, Talc, TiO2 Analyte loss within filtration

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Determination of Elemental Impurities – Challenges of a Screening Method - SGS & PharmTech Webcast - 5 May 2015
USP EP ICP-MS
Excipient Procedure
Target
Elements
Procedure
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

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Determination 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)

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Determination 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

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Determination 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 : thomas.devadder@sgs.com
Web : www.sgs.com/lifescience
THANK YOU FOR YOUR ATTENTION
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