Understanding Elemental Impurities USP <232> and <233>

Dr. Brian Alexander, Vice President and Technical Operations at Inorganic Ventures talks to AZoM about trace metal analyses and understanding USP <232> and <233>

Please describe USP <232> and USP <233> and what they are used for?

USP<232> and USP<233> describe acceptable limits and analytical methods for measurements of elemental impurities in drug products. The United States Pharmacopeia (USP) developed General Chapters <232> and <233> with the goal of better protecting public health.

What are the differences between General Chapter <231> Heavy Metals and USP <232> and <233>?

General Chapter <231> describes the measurement of heavy metals (e.g., mercury, cadmium, lead) in various substances, and is based upon analytical methods developed over 100 years ago. USP<231> can be difficult to conduct and is not specific for elemental impurities. In contrast, USP<232> and <233> are based upon modern technologies and a better understanding of the impacts elemental impurities may have upon human health.

USP <232> includes the four metals considered as most likely to contaminate drug products. What are those?

They are arsenic, cadmium, lead, and mercury. These four metals have little or no use in the manufacturing of drugs, and they typically originate from materials commonly added to the active ingredient as a filler or to enhance stability, absorption, etc.

Following the introduction of the proposed <232> in 2010, and subsequent commentary period and review, the initial version of USP <232> was introduced in May, 2011. This version of USP <232> included detailed elemental impurities for both drug products and drug substances/excipients. What products did Inorganic Ventures originally create to conform to these recommendations and why?

Inorganic Ventures originally created two stock products to meet the USP <232> specifications: IV-STOCK-37 and IV-STOCK-38.  These products were designed to match the element concentrations and ratios stipulated in the initial version of USP<232> while addressing safety and compatibility concerns, such as avoiding nitric acid for osmium when creating IV-STOCK-38.

In April, 2012, USP posted the Second Supplement to USP 35–NF 30, which included an update to USP<232>. The second supplement had three major changes regarding elemental impurities. What were they?

One significant change was that the elemental impurity limits were updated, with limits being reduced, or increased, for some elements in some drug product categories. Most of the changes reflected decreases in the permissible exposure limits, whether in drug products or non-active ingredients, or, for example, within categories such as oral versus inhaled administration routes.

Why are experts revisiting general chapter <232> relating to step 4 outcome of ICH Q3D? What will this mean for Inorganic Ventures?

While USP sets standards and quality measures for medicinal products in the United States, much of the world relies upon ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) for these purposes. The Q3D Guideline on Elemental Impurities is the ICH equivalent of USP<232>, and Step 4 concerns the adoption of Q3D, which occurred in December 2014.

Though USP<232> and ICH Q3D differ somewhat, USP intended to revisit <232> upon the ICH adoption of Q3D to facilitate harmonization between the two approaches.  For Inorganic Ventures, the general alignment of <232> and Q3D has resulted in updating our product list in an effort to best meet the needs of our customers.

Currently how many products does Inorganic Ventures currently carry to meet the USP 232 needs?

Inorganic Ventures currently has four stock products, and several custom formulations, designed to meet the elemental impurity limits stipulated in USP<232>. The stock products are IV-STOCK-38, IV-STOCK-40, IV-STOCK-41, and IV-STOCK-60, and these are suitable for the majority of customer requests.

However, we frequently receive inquiries for modified versions of these stock products, as individual customers are often better served by comparable, but slightly different certified reference materials.

In these cases we offer pricing that is similar to our stock products in an effort to provide the most appropriate product in a cost-effective manner.

Where can our readers go to find out more?

We would recommend visiting the Tech Center located on the Inorganic Ventures website, which includes not only observations and details about USP<232>, but additional technical and consumer guides for certified reference materials (https://www.inorganicventures.com/guides-and-papers).

About Dr. Brian Alexander

Dr. Brian Alexander is an earth scientist specializing in geochemistry. His research has focused on trace metal analyses using ICP techniques and rare earth element studies of natural waters and chemical sediments. Today, Dr. Alexander is the Vice President, Technical Operations at Inorganic Ventures.