Inorganic elemental impurity mixes according to ICH Q3D guidelines

Background

Metallic contamination in drug products, referred to as elemental impurities, may arise from several sources. They may be added intentionally in synthesis, or may be present as contaminants, (e.g., through interactions with processing equipment or by being present in components of the drug product) and are consequently detectable in the drug product. Because elemental impurities pose a risk to patient health, due to toxicological effects, their levels should be controlled within acceptable limits in the drug product.1

Potential Sources of Elemental Impurities

 

The ICH Q3D guidelines

In 2009, the International Conference on Harmonization (ICH) proposed the development of a new harmonized guideline to provide a global policy for limiting metal impurities in drug products and ingredients. This approach provides clear regulatory guidance on specification limits for elemental impurities worldwide and logically should have an impact on the work of the national regulatory bodies in having transparent and comparable results.

The ICH categorized the various elemental impurities in four different classifications to facilitate decisions during the risk assessment process.

 

Class Descriptions Elements
1
  • Significantly toxic to humans
  • Limited or no use in the manufacture of pharmaceutical
  • Require evaluation during the risk assessment across all potential sources of the production process and routes of administration
Arsenic (As)
Cadmium (Cd)
Lead (Pb)
Mercury (Hg)
2a
  • Considered as route-dependant human toxicants
  • Relatively high probability to occur in a drug product
  • Risk assessment required across all potential sources of the production process and routes of administration
Cobalt (Co)
Nickel (Ni)
Vanadium (V)
2b
  • Considered as route-dependant human toxicants
  • Reduced probability to occur in a drug product
  • Risk assessment required if they are intentionally added to a drug product, otherwise they may be excluded
Silver (Ag)
Gold (Au)
Iridium (Ir)
Osmium (Os)
Palladium (Pd)
Platinum (Pt)
Rhodium (Rh)
Ruthenium (Ru)
Selenium (Se)
Thallium (Tl)
3
  • Relatively low toxicity at oral administration
  • May require a risk assessment if applied via inhalation or parenteral routes
Barium (Ba)
Chromium (Cr)
Copper (Cu)
Lithium (Li)
Molybdenum (Mo)
Antimony (Sb)
Tin (Sn)
Other elements
  • Permitted daily exposure limits (PDEs) have not yet been established due to their low toxicity
  • If present in a drug products, regional guidelines may apply
Aluminum (Al)
Boron (B)
Calcium (Ca)
Iron (Fe)
Potassium (K)
Magnesium (Mg)
Manganese (Mn)
Sodium (Na)
Tungsten (W) Zinc (Zn)

 

The United States Pharmacopoeia (USP) and the European Pharmacopoeia (EP) Change

Starting January 1, 2018, the USP and the EP are adopting the ICH Q3D guidelines for elemental impurities limits in drug products, which results in a change of the analytical methods – from colorimetric determination of a metal sulfide precipitation (for USP) to analysis by ICP-OES or ICP-MS methods.

The revised chapters are:

  • Chapter USP <232>: Elemental impurities in Pharmaceutical Products – Limits
  • Chapter USP <233>: Elemental impurities in Pharmaceutical Products – Procedures
  • Chapter USP <2232>: Elemental contaminants in Dietary Supplements
  • European Pharmacopoeia, 9th Edition, supplement 9.3., General Chapter 5.20 and 2.4.20

 

How to accurately test for elemental impurities

We offer different element mixes as certified reference material standard mixes with element ratios corresponding to the oral and the parenteral concentrations of the ICH Q3D guideline. Their features are:

  • Produced and analyzed under ISO 17025 and ISO 17034; values traceable to at least two independent references (NIST®, BAM or SI unit kg)
  • Unique level of accuracy and lot-specific value
  • Sophisticated packaging and comprehensive documentation, including proper uncertainty calculation, expiry date and storage information. Packaged in opaque and gas-tight aluminum foil bags for extended stability. Certificates are included
  • Convenient 100 mL package size

For each classified and non-classified element, we offer single-element certified reference material solutions under the trademarks Certipur® and TraceCERT®, NIST® SRM single-element solutions as well as various multi-element mixes for ICP-OES and ICP-MS application in multiple concentrations (10g/L, 1g/L, 10mg/L, 1mg/L). Please refer to the list of products at the end of this page.

 

Elemental impurities mixes and concentrations (mg/L) according to ICH Q3D oral, parenteral, USP<232> and Ph.Eur. 9.3

    Elemental impurities mixes according to ICH Q3D oral and parenteral guidelines
    These mixes are applicable for testing according to USP<232>, Ph.Eur. Gen. Chapter 5.20.
  Cat.No. 19041 73108 69729 89118 89922 07368
    for oral application for parenteral application
  Matrix 12% HNO3 10% HCl 5% HNO3 + HF <0.5% 12% HNO3 10% HCl 5% HNO3 + HF <0.5%
Element Class            
As 1 15     15    
Cd 1 5     2    
Hg 1 30     3    
Pb 1 5     5    
Co 2a 50     5    
Ni 2a 200     20    
V 2a 100     10    
Ag 2b 150     10    
Au 2b   100     100  
Ir 2b   100     10  
Os 2b   100     10  
Pd 2b   100     10  
Pt 2b   100     10  
Rh 2b   100     10  
Ru 2b   100     10  
Se 2b 150     80    
Tl 2b 8     8    
Ba 3     140     70
Cr 3     1100     110
Cu 3     300     30
Li 3     55     25
Mo 3     300     150
Sb 3     120     9
Sn 3     600     60
Al No class            
Ca No class            
Fe No class            
K No class            
Mg No class            
Mn No class            
Na No class            
W No class            
Zn No class            

Concentration in mg/L; package size: 100 mL

Product ListingProduct Listing

Ag
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3151 HNO3 14% Ag metal 10 mg/g 5x10 mL ampoules NIST
91543 HNO3 5% Ag metal 10,000 100 mL TraceCERT®
1.70352 HNO3 2-3% AgNO3 1,000 100 mL Certipur®
12818 HNO3 2% Ag metal 1,000 100 mL TraceCERT®
69389 HNO3 2% Ag metal 1 100 mL TraceCERT®
 
Al
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3101A HNO3 10% Al metal 10 mg/g 5x10 mL ampoules NIST
1.70371 HNO3 2-3% Al(NO3)3 10,000 100 mL Certipur®
41377 HNO3 5% Al(NO3)3.9H2O 10,000 100 mL TraceCERT®
1.70301 HNO3 2-3% Al(NO3)3 1,000 100 mL Certipur®
61935 HNO3 2% Al(NO3)3.9H2O 1,000 100 mL TraceCERT®
05674 HNO3 2% Al(NO3)3.9H2O 1 100 mL TraceCERT®
 
As
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3103A HNO3 10% As2O3 10 mg/g 5x10 mL ampoules NIST
67904 HNO3 5% As2O3 10,000 100 mL TraceCERT®
1.70303 HNO3 2-3% H3AsO4 1,000 100 mL Certipur®
01969 HNO3 2% As2O3 1,000 100 mL TraceCERT®
72718 HCl 2% As2O3 1,000 100 mL TraceCERT®
76686 H2O As2O5 1,000 100 mL TraceCERT®
75016 HNO3 2% As2O3 1 100 mL TraceCERT®
 
Au
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3121 HCl 10% Au metal 10 mg/g 5x10 mL ampoules NIST
1.70321 HCl 7% H(AuCl4) 1,000 100 mL Certipur®
38168 HCl 5% + Au metal 1,000 100 mL TraceCERT®
HNO3 Traces
67363 HCl 5% + Au metal 1 100 mL TraceCERT®
HNO3 Traces
 
B
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3107 H2O H3BO3 5 mg/g 50 mL NIST
18822 H2O + H3BO3 10,000 100 mL TraceCERT®
NH4OH <0.5%
1.70307 H2O H3BO3 1,000 100 mL Certipur®
01932 H2O H3BO3 1,000 100 mL TraceCERT®
41511 H2O H3BO3 1 100 mL TraceCERT®
 
Ba
Cat. no. Matrix Starting material Concentration (mg/L) Size  
75187 HNO3 5% BaCO3 10,000 100 mL TraceCERT®
1.70304 HNO3 2-3% Ba(NO3)2 1,000 100 mL Certipur®
59943 HNO3 2% BaCO3 1,000 100 mL TraceCERT®
75017 HNO3 2% BaCO3 1 100 mL TraceCERT®
 
Ca
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3109A HNO3 10% CaCO3 10mg/g 5x10 mL ampoules NIST
1.70373 HNO3 2-3% Ca(NO3)2 10,000 100 mL Certipur®
94458 HNO3 5% CaCO3 10,000 100 mL TraceCERT®
1.70308 HNO3 2-3% Ca(NO3)2 1,000 100 mL Certipur®
19051 HNO3 2% CaCO3 1,000 100 mL TraceCERT®
41559 HNO3 2% CaCO3 1 100 mL TraceCERT®
 
Cd
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3108 HNO3 8% Cd metal 10 mg/g 5x10 mL ampoules NIST
90006 HNO3 5% Cd metal 10,000 100 mL TraceCERT®
1.70309 HNO3 2-3% Cd(NO3)2 1,000 100 mL Certipur®
36379 HNO3 2% Cd metal 1,000 100 mL TraceCERT®
12313 HNO3 2% Cd metal 1 100 mL TraceCERT®
 
Co
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3113 HNO3 10% Co metal 10 mg/g 5x10 mL ampoules NIST
01488 HNO3 5% Co metal 10,000 100 mL TraceCERT®
1.70313 HNO3 2-3% Co(NO3)2 1,000 100 mL Certipur®
30329 HNO3 2% Co metal 1,000 100 mL TraceCERT®
41798 HNO3 2% Co metal 1 100 mL TraceCERT®
 
Cr
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3112A HNO3 10% N.N. 10 mg/g 5x10 mL ampoules NIST
1.70374 HNO3 2-3% Cr(NO3)3.9H2O 10,000 100 mL Certipur®
93104 HNO3 5% Cr(NO3)3.9H2O 10,000 100 mL TraceCERT®
1.70312 HNO3 2-3% Cr(NO3)3.9H2O 1,000 100 mL Certipur®
74582 HNO3 2% Cr(NO3)3.9H2O 1,000 100 mL TraceCERT®
68131 HNO3 2% (NH4)2Cr2O7 1,000 100 mL TraceCERT®
92966 HNO3 2% Cr(NO3)3.9H2O 1,000 100 mL TraceCERT®
19036 H2O (NH4)2Cr2O7 1,000 100 mL TraceCERT®
72995 HNO3 2% Cr(NO3)3.9H2O 1 100 mL TraceCERT®
 
Cu
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3114 HNO3 10% Co metal 10 mg/g 50 mL NIST
1.70378 HNO3 2-3% Cu(NO3)2 10,000 100 mL Certipur®
94459 HNO3 5% Cu metal 10,000 100 mL TraceCERT®
1.70314 HNO3 2-3% Cu(NO3)2 1,000 100 mL Certipur®
68921 HNO3 2% Cu metal 1,000 100 mL TraceCERT®
41621 HNO3 2% Cu metal 1 100 mL TraceCERT®
 
Hg
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3133 HNO3 10% Hg metal 10 mg/g 5x10 mL ampoules NIST
1.70384 HNO3 10% Hg(NO3)2 10,000 100 mL Certipur®
75111 HNO3 12% Hg metal 10,000 100 mL TraceCERT®
1.70333 HNO3 10% Hg(NO3)2 1,000 100 mL Certipur®
28941 HNO3 12% Hg metal 1,000 100 mL TraceCERT®
1.08623 HNO3 2-3% Hg(NO3)2 10 100 mL Certipur®
 
Ir
Cat. no. Matrix Starting material Concentration (mg/L) Size  
1.70325 HCl 7% IrCl3 1,000 100 mL Certipur®
 
K
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3141A HNO3 1% KCl 10 mg/g 5x10 mL ampoules NIST
1.70377 HNO3 2-3% KNO3 10,000 100 mL Certipur®
68371 HNO3 5% KNO3 10,000 100 mL TraceCERT®
1.70342 HNO3 2-3% KNO3 1,000 100 mL Certipur®
06335 HNO3 2% KNO3 1,000 100 mL TraceCERT®
30937 HNO3 2% KNO3 1 100 mL TraceCERT®
 
Li
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3129A HNO3 1% Li2CO3 10 mg/g 5x10 mL ampoules NIST
90766 HNO3 5% Li2CO3 10,000 100 mL TraceCERT®
1.70329 HNO3 2-3% LiNO3 1,000 100 mL Certipur®
12292 HNO3 2% Li2CO3 1,000 100 mL TraceCERT®
39185 HNO3 2% Li2CO3 1 100 mL TraceCERT®
 
Mg
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3131a HNO3 10% Mg metal 10mg/g 5x10 mL ampoules NIST
1.70379 HNO3 2-3% Mg(NO3)2 10,000 100 mL Certipur®
80759 HNO3 5% Mg(NO3)2 10,000 100 mL TraceCERT®
1.70331 HNO3 2-3% Mg(NO3)2 1,000 100 mL Certipur®
30083 HNO3 2% Mg(NO3)2 1,000 100 mL TraceCERT®
53906 HNO3 2% Mg(NO3)2 1 100 mL TraceCERT®
 
Mn
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3132 HNO3 10% N.N. 10 mg/g 5x10 mL ampoules NIST
1.7038 HNO3 2-3% Mn(NO3)2 10,000 100 mL Certipur®
42071 HNO3 5% Mn(NO3)2x4H2O 10,000 100 mL TraceCERT®
1.70332 HNO3 2-3% Mn(NO3)2 1,000 100 mL Certipur®
74128 HNO3 2% Mn metal 1,000 100 mL TraceCERT®
42058 HNO3 2% Mn metal 1 100 mL TraceCERT®
 
Mo
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3134 HCl 10% Mo metal 10 mg/g 5x10 mL ampoules NIST
39891 HNO3 5% + <0.5% HF Mo metal 10,000 100 mL TraceCERT®
1.70334 H2O (NH4)6Mo7O24 1,000 100 mL Certipur®
68780 HCl 10% + Mo metal 1,000 100 mL TraceCERT®
HNO3 Traces
04488 NH4OH + H2O (NH4)6Mo7O24 1 100 mL TraceCERT®
 
Na
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3152A HNO3 1% NaCl 10mg/g 50 mL NIST
1.70381 HNO3 2-3% NaNO3 10,000 100 mL Certipur®
39924 HNO3 5% NaNO3 10,000 100 mL TraceCERT®
1.70353 HNO3 2-3% NaNO3 1,000 100 mL Certipur®
00462 HNO3 2% NaNO3 1,000 100 mL TraceCERT®
80831 HNO3 2% NaNO3 1 100 mL TraceCERT®
 
Ni
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST986 HNO3 8% Ni metal 10 mg/g 5x10 mL ampoules NIST
1.70382 HNO3 2-3% Ni(NO3)2 10,000 100 mL Certipur®
19013 HNO3 5% Ni metal 10,000 100 mL TraceCERT®
1.70336 HNO3 2-3% Ni(NO3)2 1,000 100 mL Certipur®
28944 HNO3 2% Ni metal 1,000 100 mL TraceCERT®
72631 HNO3 2% Ni metal 1 100 mL TraceCERT®
 
Os
Cat. no. Matrix Starting material Concentration (mg/L) Size  
1.70338 HCl 7% (NH4)2OsCl6 1,000 100 mL Certipur®
 
Pb
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3128 HNO3 10% Pb metal 10 mg/g 5x10 mL ampoules NIST
1.70372 HNO3 2-3% Pb(NO3)2 10,000 100 mL Certipur®
39082 HNO3 5% Pb(NO3)2 10,000 100 mL TraceCERT®
1.70328 HNO3 2-3% Pb(NO3)2 1,000 100 mL Certipur®
41318 HNO3 2% Pb(NO3)2 1,000 100 mL TraceCERT®
75015 HNO3 2% Pb(NO3)2 1 100 mL TraceCERT®
 
Pd
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3138 HCl 10% Pd metal 10 mg/g 5x10 mL ampoules NIST
50719 HCl 10% + Pd metal 10,000 100 mL TraceCERT®
HNO3 Traces
1.70339 HNO3 2-3% Pd(NO3)2 1,000 100 mL Certipur®
77091 HCl 5% + Pd metal 1,000 100 mL TraceCERT®
HNO3 Traces
42396 HNO3 2% + Pd metal 1 100 mL TraceCERT®
HCl Traces
 
Pt
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3140 HCl 10% Pt metal 10 mg/g 5x10 mL ampoules NIST
74554 HCl 10% Pt metal 10,000 100 mL TraceCERT®
1.70341 HCl 7% H2PtCl6 1,000 100 mL Certipur®
19078 HCl 5% + Pt metal 1,000 100 mL TraceCERT®
HNO3 Traces
49763 HCl 5% + Pt metal 1 100 mL TraceCERT®
HNO3 Traces
 
Rh
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3144 HCl 10% (NH4)3RhCl6 1 mg/g 5x10 mL ampoules NIST
1.70345 HNO3 2-3% Rh(NO3)3 1,000 100 mL Certipur®
04736 HCl 5% RhCl3 1,000 100 mL TraceCERT®
1.08525 HNO3 0.5 mol/l Rh(NO3)3 10 100 mL Certipur®
04026 HNO3 0.5 mol/l Rh(NO3)3 10 100 mL TraceCERT®
 
Ru
Cat. no. Matrix Starting material Concentration (mg/L) Size  
1.70347 HCl 7% RuCl3 1,000 100 mL Certipur®
 
Sb
Cat. no. Matrix Starting material Concentration (mg/L) Size  
91482 HNO3 5% + Sb metal 10,000 100 mL TraceCERT®
HF <0.5%
1.70302 HCl 7% Sb2O3 1,000 100 mL Certipur®
73495 HNO3 2% + Sb metal 1,000 100 mL TraceCERT®
HF Traces
89519 HNO3 2% + Sb metal 1 100 mL TraceCERT®
HF <0.1%
 
Se
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3149 HNO3 10% Se semi metal 10 mg/g 5x10 mL ampoules NIST
98838 HNO3 5% Se semi metal 10,000 100 mL TraceCERT®
1.7035 HNO3 2-3% SeO2 1,000 100 mL Certipur®
50002 HNO3 2% Se semi metal 1,000 100 mL TraceCERT®
56544 HNO3 2% Se semi metal 1 100 mL TraceCERT®
 
Sn
Cat. no. Matrix Starting material Concentration (mg/L) Size  
42991 HNO3 5% + Sn metal 10,000 100 mL TraceCERT®
HF <0.5%
1.70362 HCl 7% SnCl4 1,000 100 mL TraceCERT®
92615 HCl 10% Sn metal 1,000 100 mL TraceCERT®
63564 HNO3 2% + Sn metal 1 100 mL TraceCERT®
HF <0.1%
 
Tl
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3158 HNO3 10% Tl metal 10 mg/g 5x10 mL ampoules NIST
5295 HNO3 5% TlNO3 10,000 100 mL TraceCERT®
1.70359 HNO3 2-3% TlNO3 1,000 100 mL Certipur®
51873 HNO3 2% TlNO3 1,000 100 mL TraceCERT®
 
V
Cat. no. Matrix Starting material Concentration (mg/L) Size  
1.70388 HNO3 15% NH4VO3 10,000 100 mL Certipur®
44712 HNO3 5% V metal 10,000 100 mL TraceCERT®
1.70366 HNO3 2-3% NH4VO3 1,000 100 mL Certipur®
18399 HNO3 2% V metal 1,000 100 mL TraceCERT®
75593 HNO3 2% V metal 1 100 mL TraceCERT®
 
W
Cat. no. Matrix Starting material Concentration (mg/L) Size  
50938 HNO3 5% + W metal 10,000 100 mL TraceCERT®
HF 2%
1.70364 H2O (NH4)2WO4 1,000 100 mL Certipur®
50334 HNO3 5% + W metal 1,000 100 mL TraceCERT®
HF 2%
 
Zn
Cat. no. Matrix Starting material Concentration (mg/L) Size  
NIST3168A HNO3 10% Zn metal 10 mg/g 5x10 mL ampoules NIST
1.70389 HNO3 2-3% Zn(NO3)2 10,000 100 mL Certipur®
68961 HNO3 5% Zn metal 10,000 100 mL TraceCERT®
1.70369 HNO3 2-3% Zn(NO3)2 1,000 100 mL Certipur®
18562 HNO3 2% Zn metal 1,000 100 mL TraceCERT®
75594 HNO3 2% Zn metal 1 100 mL TraceCERT®

 

Materials