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USP 232/233 Analysis for Compliance to ICH Q3D

In order to standardize the approach for compliance analyses to support the ICH Q3D Guideline for Elemental Impurities, the U.S. Pharmacopeia (USP) generated the guidance methods USP 232 and 233. The ICH guideline applies to new finished drug products (as defined in ICH Q6A and Q6B) along with new drug products containing existing drug substances. Brooks Applied Labs is a CRO specializing in elemental and metalloid speciation analyses, period. Our focus makes your decision regarding partnering on ICH Q3D compliance an easy one.

The guideline, nor the associated USP monograph, stipulates exactly how to address spectral interferences associated with mass spectrometric measurements. Elements in the mid-range mass region (30 amu -114 amu) are more prone to positive biases than heavier elements using mass spectrometry.  Brooks Applied Labs uses some of the most advanced analytical technologies, inductively coupled plasma triple quadrupole mass spectrometry (ICP-QQQ-MS), to deliver results of unparalleled quality. Research at Brooks Applied Labs has identified that operating ICP-MS instruments in KED mode, which most other laboratories are limited to, cannot properly remove all relevant spectral interferences. In addition, by using acid cleaned labware integrated into a robust quality system, biases are documented and mitigated on a continual basis reducing your risk when selecting a CRO.

Brooks Applied Labs has been audited by our pharmaceutical clients, third party accreditation services, as well as the FDA, which play an invaluable role in our desire to continue to improve our quality systems and support our clients’ needs.

The elements included in the ICH Q3D guideline are placed in three classes based on their toxicity and likelihood of occurrence in the drug product. The table below delineates the classifications:

Classification Elemental Impurities
Class 1 As, Cd, Hg, and Pb
Class 2A Co, Ni, and V
Class 2B Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se, and Tl
Class 3 Ba, Cr, Cu, Li, Mo, Sb, and Sn
Other Elements
Al, B, Ca, Fe, K, Mg, Mn, Na, W, and Zn

 

The ICH Q3D guideline should be consulted with regards to performing a risk assessment for the listed elemental impurities. Tables presenting the permitted daily exposures and extrapolated permitted concentrations are listed in the tables below. The tables are for reference purposes only and reflect the ICH Q3D Guideline as of January 1, 2019.

Permitted Daily Exposures for Elemental Impurities1

Element Class Oral PDE (μg/day) Parenteral PDE (μg/day) Inhalation PDE (μg/day)
Cd 1 5 2 2
Pb 1 5 5 5
As 1 15 15 2
Hg 1 30 3 1
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
Rh 2B 100 10 1
Ru 2B 100 10 1
Se 2B 150 80 130
Ag 2B 150 10 7
Pt 2B 100 10 1
Ll 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

1Values in this table have beeb taken from Table A.2.1 from ICH Q3D. Please see the respective ICH guidelines for additional information.

Permitted Concentrations of Elemental Impurities2

Element Class Oral PDE (μg/day) Parenteral PDE (μg/day) Inhalation PDE (μg/day)
Cd 1 0.5 0.2 0.2
Pb 1 0.5 0.5 0.5
As 1 1.5 1.5 0.2
Hg 1 3 0.3 0.1
Co 2A 5 0.5 0.3
V 2A 10 1 0.1
Ni 2A 20 2 0.5
Tl 2B 0.8 0.8 0.8
Au 2B 10 10 0.1
Pd 2B 10 1 0.1
Ir 2B 10 1 0.1
Os 2B 10 1 0.1
Rh 2B 10 1 0.1
Ru 2B 10 1 0.1
Se 2B 15 8 13
Ag 2B 15 1 0.7
Pt 2B 10 1 0.1
Ll 3 55 25 2.5
Sb 3 120 9 2
Ba 3 140 70 30
Mo 3 300 150 1
Cu 3 300 30 3
Sn 3 600 60 6
Cr 3 1100 110 0.3

2Values in this table have been taken from Table A.2.2 from ICH Q3D. Please see the respective ICH guideline for additional information.

Brooks Applied Labs has been audited by our pharmaceutical clients, third party accreditation services, as well as the FDA, which play an invaluable role in our desire to continue to improve our quality systems and support our clients’ needs. Our approach to quality is dynamic with the understanding that the regulatory environment can, and will, change necessitating a proactive approach by both our clients and Books Applied Labs.

Contact us to find out how your quality and process objectives can be met more efficiently than ever.