determination of elemental impurities – challenges of a screening method

DETERMINATION OF ELEMENTAL IMPURITIES

– CHALLENGES OF A SCREENING METHOD

THOMAS DEVADDERTHOMAS DEVADDERSGS LIFE SCIENCE SERVICES TEAM LEADER QC AAS / ICP / Particles / TGALaboratory Services

� Challenges

� Strategy

� Potential interferences

� Sample preparation / determination by ICP-MS

� Validation of a screening method

AGENDA

2SGS LIFE SCIENCE SERVICES – CPHI/ICSE Madrid October 2015

� Validation of a screening method

� Screenings on excipients, APIs and drug products

� Where are the boundaries in the applicability?

CHALLENGES OF A SCREENING METHOD

� Method must provide

• Valid information about APIs, Excipients and FinishedProducts

• Applicability for a broad variability of sample materials

• Acceptance criteria from EP 5.20 / USP <233>

• A validated basis


• A validated basis

� Challenges

• Interferences from different sample materials

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)Method

Development


• Closed vessle microwave digestion (nitric acid)

• Determination by ICP-MSDevelopment

• According to USP<233>/EP2.4.20 (Omega-3 fish oil)

• Simulation of potential Interferences from different sample materials (K, Na, Ca, Mg, Cl)

MethodValidation

• Fullfilled acceptance critera (USP<233>/EP2.4.20)

• Method verification on new samples by spikingexperiment

Routine Testing

INTERFERENCES

� Physical Interferences

• Viscosity

• Density

• Matrix

• Sediments on Cones

� Dilution, Internal Standard, Sample Preparation


� Dilution, Internal Standard, Sample Preparation

� Chemical Interferences

• Absorption effects during sample introduction

• Nebulization effects

• Stability of solution

• Contaminations

• Carry over

� Method-Optimization, Stabilization

� Spectral Interferences

• Oxid Formation

• Double charged Ions

• Polyatomic combinations

� System-Optimization

INTERFERENCES


� 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)

It‘s good to know, that…

� Most interferences show up in a mass range below 80 amu (atomic mass units) because of polyatomic

INTERFERENCES SUMMARY

IT IS GOOD TO KNOW THAT…


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

� 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


� 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

600

700

800

900

1000

[cps] As75 in Water

50500

51000

51500

52000

[cps] As75 in HCl 1.5%

500

600

700

800

900

[cps] AsO91 in HCl 1.5%(DRC O2 0.6 ml/min)

Ar40Cl 35 / As75 INTERFERENCE


0

100

200

300

400

500

0 0.5 1

[µg/l]

48000

48500

49000

49500

50000

0 0.5 1

[µg/l]

Ar40Cl35 Background

0

100

200

300

400

500

0 0.5 1

[µg/l]

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


Sample material +6 ml HNO3 after digestion transferred filled up

# 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

CALIBRATION


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 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

USP <233> EP 2.4.20Quantitative Procedure

ProcedureAcceptanceCriteria

ProcedureAcceptanceCriteria

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

Mean recovery of 3 individual replicates must be within

Spiking Experiment in 3 Levels within a range of 50% – 150%

Mean recovery of 3 individual replicates must be within 70% - 150% for each level

VALIDATION REQUIREMENTS


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)

be within 70% - 150% for each level

– 150% of the specification limit in triplicate (+ e.g. spiking Experiment at

10% Specification limit for

LOQ)

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

# 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%

VALIDATION RESULTS 1/2


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%

# 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%

VALIDATION RESULTS 2/2


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%

ROUTINE SCREENING

Organic

Samples

APIs

Solvents, Polyol

Artificial flavours

Cellulose

Fatty oils

Clear sample solution

Method verificationcomplies

Salts

Clear Sample solution containing

high saltconcentration

PhysicalInterferences /

False negative


Inorganic

Samples

high saltconcentration

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

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

USP EP ICP-MS

Excipient ProcedureTarget Elements

ProcedureTarget Elements

MethodImprovement

Ferric Oxide AAS

ColorimetricLimit Test

Hg, Pb

As

- - Reduced sample concentration,Improved Digestion

Talc Flame AAS Al, Ca, Fe, Pb(Impurity)

Flame AAS Al, Ca, Fe, Pb(Impurity)

Digestion with nitric acid + hydrofluoric acid

WAYS TO CONTROL CRITICAL EXCIPIENTS


Mg (Assay) Mg (Assay)

TitaniumDioxide

ColorimetricLimit Test

As <211> ColorimetricLimit Test

Sb, As, Ba, Fe

Heavy metals (2.4.8)

Digestion with nitric acid + hydrofluoric acid

Silicon Dioxide ColorimetricLimit Test

As <211>

Heavy metals<231>

- - Digestion with nitric acid + hydrofluoric acid

Salts Reduced sample concentration, Improved Interference control

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)

� Wide experiences in:

� Method Development and Validation

� Verification of pharmacopeia methods

� ICH Q3D, USP <232> / <233> and EP 5.20 / 2.4.20

SGS SOLUTIONS 2/2


� Extractable / Leachable Studies

� Determination of Silicon Oil traces

Life Science Services Thomas Devadder

Team Leader QC AAS/ICP/Particles/TGA

Laboratory Services

THANK YOU FOR YOUR ATTENTION

+ 41 22 739 9548

+ 1 866 SGS 5003


SGS Institut Fresenius GmbH t: + 49 30 34607 659Tegeler Weg 33, f: + 49 30 34607 600D-10589 Berlin Germany E-mail : [email protected]

Web : www.sgs.com/lifescience

+ 1 866 SGS 5003

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determination of elemental impurities – challenges of a screening method

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