Elemental Impurities - Certified Reference Materials for ICH Q3D, USP 232, USP 2232, and Ph.Eur. 5.20

By: Ingrid Hayenga, Product Manager Reference Materials,

About Elemental Impurities

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 presence in components of the drug product) and are consequently detectable in the drug product. Since elemental impurities pose a risk to patient health due to toxicological effects, element impurity levels should be controlled within acceptable limits in the drug product.1

Evolution of ICH Q3D Guidelines for Elemental Impurities

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 should provide 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. 

In a step 4 version of its “Guidelines for Element Impurities” document, the ICH categorized the various elemental impurities in four different classifications which were intended to facilitate decisions during the risk assessment process: 

Class 1 Impurities

These impurities are significantly toxic to humans and have limited or no use in the manufacture of pharmaceuticals. They can be found as impurities from commonly used materials (e.g., mined excipients). All four elements require evaluation during the risk assessment across all potential sources of elemental impurities and routes of administration. The class 1 elements are: As, Cd, Hg, Pb.

Class 2 Impurities

These impurities are generally considered routedependent human toxicants. These impurities are further divided into two sub-classes, 2A and 2B, based on their relative likelihood of occurrence in the drug product.

  • Class 2A elements have relatively high probability of occurrence in the drug product and thus require risk assessment across all potential sources of elemental impurities and routes of administration (as indicated).
    The class 2A elements are: Co, Ni and V.
  • Class 2B elements have a reduced probability of occurrence in the drug product related to their low abundance and low potential to be co-isolated with other materials. As a result, they may be excluded from the risk assessment unless they are intentionally added during the manufacture of drug substances, excipients or other components of the drug product.  Class 2B elements are: Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se and Tl.  

Class 3 Impurities

These elements have relatively low toxicity at oral administration but may require a risk assessment if applied via inhalation or parenteral routes. Class 3 elements are: Ba, Cr, Cu, Li, Mo, Sb and Sn. 

Other Elements

There are some elemental impurities for which Permitted Daily Exposures (PDEs) have not been established due to their low toxicities and/or differences in regional regulations. If they are present in a drug product, they are addressed by other guidelines and/or regional regulations. These elements are: Al, B, Ca, Fe, K, Mg, Mn, Na, W and Zn.

Evaluation per USP and EP

Up to 2010, the USP and EP proof of heavy metal contamination in drugs was obtained via a colorimetric analytical method based on the precipitation of a metal sulfide in a sample and comparing it to a lead standard (USP <231> and Ph.Eur. 2.4.8).

Based on the Guideline for Elemental Impurities (Q3D) which was published by the International Conference on Harmonization (ICH) in 2010, the USP proposed three new General Chapters covering impurity limits, analytical procedures in pharmaceutical products and raw materials, and elemental contaminants in dietary supplements.

  • Chapter USP <232>, Ph.Eur. 5.20: Elemental Impurities in Pharmaceutical Products – Limits
  • Chapter USP <233>: Elemental Impurities in Pharmaceutical Products – Procedures
  • Chapter USP<2232>: Elemental Contaminants in Dietary Supplements

In January 2015, the USP established January 1, 2018 as the new date of applicability for General Chapters <232>, <233> and <2232>. The implementation should align with limits and timelines set down by other pharmaceutical and medical agencies such as the ICH Q3D Step 4 Guidelines for Elemental Impurities announced on December 16, 2014.

The Pharmacopoeia Europe announced in July 2014 their strategy regarding elemental impurities and the implementation of the ICH Q3D. Nearly one year later, in April 2015, they published their policy on elemental impurities and timelines for revision of general and individual texts. In August of the same year, clarification was given for products outside the scope of ICH Q3D.

The implementation of the guideline compliances should start in June 2016 for products with new marketing authorization, either containing new active substances or already approved substances. Marketed products, including new mutual recognition applications of already approved substances, should comply with the Guideline from December 2017.

The implementation of the General Test 5.20 and the General Method 2.4.20 replaced the EMA guideline on metal catalysts and metal reagents by the principles of the ICH. The publication was done in the Ph.Eur. Suppl. 9.3 (implementation date January 1, 2018), having no test for elemental impurities in the individual monographs except for substances of natural origin. Given the intrinsic nature of elemental impurities in these substances, they are among the major potential sources of elemental contamination in medicinal products. The Ph.Eur. Commission has also specifically recommended keeping the different tests for elements for which no PDE limits have been established, i.e., those identified as “other elements” in the ICH Q3D guideline in individual monographs.2  

 

Analytical methods

Concerning new analytical methods, ICH Q3D does not include any recommendation on instrumental methods but the following analytical procedures are suggested in USP<233> dependent on the expected concentration of the elemental impurity in the product or component:

  • Parts-per-million (ppm) concentrations ICP-OES or atomic absorption
  • Parts-per-billion (ppb) concentrations ICP-MS

ICH Q3D limits for elemental impurities

For a total of 24 elements, toxicity limits are specified and defined as maximum PDE levels in mg/day for the four major drug delivery categories. Table 1 lists the PDE values in μg/day, valid for drug products with an intake of ≤10 g/day.

Table 1. Permitted daily exposure (PDE) for elemental impurities

 

Element Class Oral PDE
(μg/day)
Parenteral PDE
(μg/day)
Inhalation PDE
(μg/day)
As 1 15 15 2
Cd 1 5 2 2
Hg 1 30 3 1
Pb 1 5 5 5
Co 2A 50 5 3
V 2A 100 10 1
Ni 2A 200 20 5
Tl 2B 8 8 8
Au 2B 100 100 1
Pd 2B 100 10 1
Ir 2B 100 10 1
Os 2B 100 10 1
Rb 2B 100 10 1
Ru 2B 100 10 1
Se 2B 150 80 130
Ag 2B 150 10 7
Pt 2B 100 10 1
Li 3 550 250 25
Sb 3 1200 90 20
Ba 3 1400 700 300
Mo 3 3000 1500 10
Cu 3 3000 300 30
Sn 3 6000 600 60
Cr 3 11000 1100 3

Table 2 lists the elements to be considered in the risk assessment.

For the new adapted USP <232> and Ph.Eur.Suppl. 9.3 chapters, we offer three TraceCERT® element mixes with element ratio corresponding to the oral concentrations of the ICH Q3D guideline, mix I covers class 1, 2A and some of 2B elements; mix II covers the remaining 2B class elements; mix III covers all class 3 elements.

A second series of three mixes covers the parenteral concentration ratios. All products with their element respective concentrations (mg/L) are listed in Table 3.

Table 4 lists the features of the TraceCERT® Certified Reference Material (CRM) solutions.

Table 2. Elements to be considered in the risk assessment

 

Element Class If Intentionally Added
(all routes)
If not intentionally added
Oral Parenteral Inhalation
As 1 Yes Yes Yes Yes
Cd 1 Yes Yes Yes Yes
Hg 1 Yes Yes Yes Yes
Pb 1 Yes Yes Yes Yes
Co 2A Yes Yes Yes Yes
V 2A Yes Yes Yes Yes
Ni 2A Yes Yes Yes Yes
Tl 2B Yes No No No
Au 2B Yes No No No
Pd 2B Yes No No No
Ir 2B Yes No No No
Os 2B Yes No No No
Rb 2B Yes No No No
Ru 2B Yes No No No
Se 2B Yes No No No
Ag 2B Yes No No No
Pt 2B Yes No No No
Li 3 Yes No No No
Sb 3 Yes No No No
Ba 3 Yes No No No
Mo 3 Yes No No No
Cu 3 Yes No No No
Sn 3 Yes No No No
Cr 3 Yes No No No

 

Table 3. Suitable Multi-Element CRM Solutions according to ICH Q3D TraceCERT®

 

    TraceCERT® TraceCERT®
Element Class Elemental Impurities
Mix according to
ICH Q3D oral
Elemental Impurities
Mix according to
ICH Q3D parenteral
    Standard
1
Standard 2 Standard
3
Standard 1 Standard 2 Standard 3
    Cat.
No.
Cat.
No.
Cat.
No.
Cat.
No.
Cat.
No.
Cat.
No.
    19041 73108 69729 89118 89922 07368
    In 12% HNO3 In 10% HCl In 5% HNO3 & HF<0.5% In 12%
HNO3
In 10%
HCl
In 5%
HNO3 &
<0.5% HF
_____________________________________________________________________________________________________________
Ag
2B 150 mg/L     10 mg/L    
As
1 15 mg/L     15 mg/L    
Au
2B 100 mg/L 100 mg/L
Ba
3     140 mg/L     70 mg/L
Cd
1
5 mg/L     2 mg/L    
Co
2A 50 mg/L     5 mg/L    
Cr
3     1100 mg/L     110 mg/L
Cu
3     300 mg/L     30 mg/L
Hg
1
30 mg/L     3 mg/L    
Ir
2B   100 mg/L     10 mg/L  
Li
3     55 mg/L     25 mg/L
Mo
3     300 mg/L     150 mg/L
Ni
2A 200 mg/L     20 mg/L    
Os
2B   100 mg/L     10 mg/L  
Pb
1
5 mg/L     5 mg/L    
Pd
2B   100 mg/L     10 mg/L  
Pt
2B   100 mg/L     10 mg/L  
Rh
2B   100 mg/L     10 mg/L  
Ru 2B   100 mg/L     10 mg/L  
Sb 3     120 mg/l      
Se 2B 150 mg/l     80 mg/l    
Sn 3     600 mg/l      
Tl 2B 8 mg/l     8 mg/l    
V 2A 100 mg/l     10 mg/l    

 

Table 4. Features of the TraceCERT® CRMs

 

TraceCERT® Solution
Unique level of accuracy and lot-specific value
Produced according to ISO Guide 34 and analyzed in our ISO/IEC 17025 accredited lab; traceable to at least two independent references (NIST, BAM or SI unit kg)
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 and list up to 70 trace impurities for the TraceCERT® products.
250 mL package size

 

Materials

     

References

  1. ICH Q3D limits from Step 4 version, December 16, 2014 Option 1
  2. Thermo Fischer, the Medicine Maker, Edition 4 – August 2016100