The document discusses the importance of monitoring elemental impurities in pharmaceuticals, detailing regulatory compliance and specific guidelines for acceptable limits of various trace metals using ICP-MS (Inductively Coupled Plasma Mass Spectrometry). It outlines the principles of ICP-MS, including sample preparation and ionization techniques, and compares different analytical methods, highlighting advantages and limitations. The conclusion emphasizes ICP-MS as a highly effective technique for achieving low detection limits and high productivity in elemental analysis.

1. ELEMENTAL ANALYSIS AND
TRACE METALS BY ICP-MS
K.LOHITHA
PA2016106 (Department of Pharmaceutical Analysis)
1/3/2017
1

2. INTRODUCTION
REGULATORY COMPLIANCE
ICP-MS
INSTRUMENTATION &WORKING
ASSETS & LIMITATIONS
APPLICATIONS & REFERENCES
1/3/2017
2

3. Elemental impurities are
 Elements found in environment
 Introduced in manufacturing of drug and excipients
 They have to be monitored for two reasons
 Enter the human body via food chain including medicines, ambient
air and drinking water leading to health problems
 Affect the stability of formulation and catalyze degradation of drug
substance
1/3/2017
3

4. POTENTIAL SOURCES OF ELEMENTAL
IMPURITIES
(As,Cd,Cu,Sn,Sb,Pb,Bi,Ag,Hg,Mo,In,Os,Pd,Pt,Rh,Ru,Cr,Ni,V,etc.)
1/3/2017
4

5. REGULATORY COMPLIANCE
1/3/2017
5
ICH Q3D-Guideline for elemental impurity
Development of
design for control
Establishment of
permitted daily exposure
(PDE)
Evaluation of toxicity
data for potential source
Safety Toxicity
Acceptance
level
International Council for Harmonisation

6. CLASSIFICATIONOF ELEMENTAL IMPURITIES
1/3/2017
6

7. 1/3/20177
ICH Classl Element ICH Q3D**
(µg/day)
USP<232>**
(µg/day)
EMA/CHMP
(µg/day)
Class 1 As 1.5 1.5 na
Cd 0.5 0.5 na
Hg 4 1.5 na
Pb 0.5 0.5 na
Class 2A Co 5
Mo 18 18 25
Se 17 - -
V 12 12 25
Class 2B Ag 17 - -
Au 13 - -
Ir 100* 10 10***
Os 100* 10 10***
Pd 10 10 10
Pt 100 10 10
Rh 100* 10 10***
Ru 100* 10 10***
Tl 0.8 - -
Class 3 Ba 1300 - -
Cr 1100 nc 25
Cu 130 130 250
Li 78 - -
Ni 60 60 25
Sb 120 - -
Su 640 - -
Class 4 Mn - - 250
Zn - - 1300
* PDE is based on Pt, due to
insufficient data
** Subclass limit - PDE is based
on the
sum of these elements
na: Not included in EMA guidance
nc: Not considered a safety
concern except for drugs
administered by inhalation
Fe - - 1300

8. DIFFERENT ANALYTICAL TECHNIQUES FOR
ELEMENTAL ANALYSIS
1/3/2017
8
ELEMENT
AL
TECHNIQ
UES
ATOMIC
ABSORPTION
SPECTROSCO
PY
INSTRUMENTAL
NEUTRON
ACTIVATION
ANALYSIS
ICP-MS
ICP-AES/
ICP-
OES/GFAAS
X-RAY
FLUORESCENCE
SPECTROMETRY

9. WHAT IS ICP-MS ???
1/3/2017
9
 Inductively coupled plasma mass spectrometry (ICP-MS) is a type
of mass spectrometry which is capable of detecting metals and non-
metals at concentrations as low as one part in 1015 (ppq).
 This is achieved by ionizing the sample with ICP and then using a
MS to separate and quantify those ions.

10. PRINCIPLE
1/3/2017
10
 Liquid sample is introduced into an argon plasma as aerosol
droplets.
 The plasma dries the aerosol, dissociates the molecules, and then
removes an electron from the components, forming singly-charged
ions, which are directed into a mass filtering device known as mass
spectrometer.
 Once the ions enter MS (mostly quadrupole), they are separated by
their mass-to-charge ratio and gets detected.

11. ICP-MS INSTRUMENTATION AND
WORKING
1/3/2017
11

12. SAMPLE PREPARATION TECHNIQUES
1/3/2017
12
• By HNO3, HF, HCl, HClO4
ACID DIGESTION
• Rare earth elements are made soluble in the sample
material by sintering with Sod.peroxide, leaching with
water and acidifying with HNO3
SODIUM PEROXIDE SINTERED
DIGESTION
• For biological or organic samples.
• Sample is digested with small amount of high purity acid
or peroxide in closed teflon vessel.
MICROWAVE DIGESTION
LASER ABLATION

13. Laser ablation
1/3/2017
13
 Useful for surface analysis of solid
samples

14. ICP TORCH – making ions
1/3/2017
14
 Argon gas flows through a series of concentric quartz tubes (ICP
torch) that are wrapped at one end by a radio frequency (RF) coil.
 Energy supplied to the coil by the RF generator couples with the
argon to produce plasma.
 As the sample travels through the different heating
zones of plasma torch (6000-7000K)it is dried,
vaporized, atomized, and ionized.
 The singly charged ions exit the plasma and enter
the interface region.

15. 1/3/2017
15
+
++
N
Vaporized
sample
Ionization chamber Sample cone
M
+
Ar
+
M
Ar

16. THE INTERFACE – sampling ions
16
 The interface region in the ICP-MS transmits the ions travelling in
the argon sample stream at atmospheric pressure(1-2torr) into the
low pressure region of the mass spectrophotometer(<1× 10-5 torr)
 It consists of 2-3 inverted funnel-like devices called cones.
Two-cone design Three-cone design
Large pressure reduction-wide ion
beam divergence
Small pressure reduction- small ion
beam divergence
PURPOSE – to sample the center portion of the ion beam coming from
ICP torch

17. TWO-CONE DESIGN
1/3/2017
17
The ions from the ICP source are then focussed by the electrostatic lenses in the
system.
The ions coming from the system are positively charged, so the electrostatic lens
which also has a positive charge serves to collimate the ion beam and focus into
the entrance aperture or slit of MS.

18. MASS ANALYZER
1/3/2017
18
 Heart of MS
 Mass analyzers separate the ions according to their mass-to-charge
ratio.
 The most commonly used type of mass analyzer is Quadrupole
mass filter.
 It consists of 4 cylindrical rods, set parallel to eachother.
 Alternating AC and DC voltages are applied to opposite pairs of
rods.
 The result is that an electrostatic filter is established that only allows
ions of a single mass-to-charge ratio (m/z) pass through the rods to
the detector at a given instant in time.
 So, quadrupole mass filter is really a sequential filter, with the
settings being change for each specific m/z at a time.

19. QUADRUPOLE ANALYZER
1/3/2017
19
+
+ ++ m/z
RA

20. OTHER MASS ANALYZERS
1/3/2017
20
 Time-of-flight ( rare)
 High resolution (HR) – Uses magnetic sector analyzer
High sensitivity and resolution
but slow, and requires stable working
environment
Quite expensive
 Multi-collector (MD) – Also with magnetic sector, but with detector
array
Good for accurate and precise isotope ratios
Isotope dilution measurements – eg., for
accurate
elemental ratios.

21. INTERFERENCES
 Polyatomic interference
40 Ar & 35 Cl for 75As
 Isobaric interference
Fe and Ni
 Matrix interference
 Optimization of nebulizer gas
flow (1.5-1.8ml/min)
 RF Power adjustment (500-
800watt)
 Sampling position within
plasma
 Cold plasma technique
 Collision or reaction cell
 HR-mass analyzer as double
focusing magnetic field sector
 Internal standard
1/3/2017
21
TYPES MINIMIZED BY

22. DETECTOR
1/3/2017
22
 Fundamental purpose of the detector is to translate the number of
ions striking the detector into an electrical signal that can be
measured and related to the number of atoms of that element in the
sample via the use of calibration standards.
 Uses a high negative voltage to attract positively charged ions
 Most commonly used are discrete dynode detectors
Ion striking
active surface
of detector
Electrons
release
Striking next
surface of
detector
Amplification of
signal

23. ICP-MS AND HYPHENATION
1/3/2017
23
 ICP-MS can be coupled with various separation techniques :
Liquid chromatography HPLC-ICP-MS
Capillary electrophoresis CE-ICP-MS
Laser ablation LA-ICP-MS
 For surface analysis
 For materials that are difficult to
digest (eg., Alloys)
ADVANTAGES OF HYPHENATED TECHNIQUES :
 Better control over matrix
 Allows separation of different components : direct access
to speciation

24. ELEMENTAL COVERAGE OF ICP-MS
1/3/2017
24

25. TECHNIQUE DECISION MATRIX
1/3/2017
25

26. DETECTION LIMIT RANGES & WORKING
RANGES
1/3/2017
26

27. COST
1/3/2017
27

28. COMPARISON BETWEEN DIFFERENT
INORGANIC TECHNIQUES
1/3/2017
28

29. ADVANTAGES
1/3/2017
29
 Multi Element Analysis (consistent conditions for most/all
elements)
 Wide elemental coverage (almost all except H, noble gases and F)
 Low detection limits for most elements (ppt or sub ppt in most
cases)
 Wide dynamic range (10-9 – 0.5 ppt-500 ppm)
 Short acquisition times (full mass acquisition in less than 5 mins)
 Good matrix tolerance (will handle acids, solvents, matrix up to
0.5%)

30. LIMITATIONS
1/3/2017
30
 Difficult to determine negative species (Cl,Br)
 Dissolved solids/matrix effects –need to dilute samples more than
other techniques
 High capital cost
 Require skilled personnel

31. APPLICATIONS
1/3/2017
31
PHARMACEUTICAL
FOOD ANALYSIS
ENVIRONMENTAL
GEOLOGICAL
ARCHAELOGICAL
FORENSIC

32. CASE STUDY
1/3/2017
32

33. RESULT AND DISCUSSION
1/3/2017
33
Comparison of analytical values is done for discrimination of pellets with
possession of a suspect in order to determine whether they are of common
origin or not.

34. 1/3/2017
34

35. ICP-MS is an ideal choice for the laboratory that is
seeking the lowest possible detection limits and the
highest level of productivity.
Conclusion
1/3/2017
35

36. REFERENCES
1/3/2017
36
[1] V. Balaram ; Recent advances in the determination of elemental
impurities in pharmaceuticals – Status, challenges and moving
frontiers ; Trends in Analytical Chemistry.
[2] R.N. Rao, M.K. Talluri, An overview of recent applications of
inductively coupled plasma-mass spectrometry (ICP-MS) in
determination of inorganic impurities in drugs and pharmaceuticals,
J. Pharm. Biomed. Anal. 43 (2007) 1-13.
[3] ICH, Guideline for Elemental Impurities Q3D, in: International
Council for Harmonisation, IFPMA, Geneva, Switzerland, 2014.
[4] Skoog, D. A., Holler, F. J., & Crouch, S. R.(2007).Principles of
Instrumental Analysis.
[5] Available from:
http://www.perkinelmer.com/icpmsthirtminuteguide.pdf

37. 1/3/201737

38. 1/3/2017
T
H
N
K
Y
O
UA