On January 1, 2018, USP/NF Chapter 231 on Heavy Metals will be shuttled and new chapters 232, 233 and 2232 on Elemental Impurities will be implemented.
What does this mean?
It means that the century-old qualitative colorimetric test for the presence of Heavy Metals has been replaced by considerably more sophisticated methods (ICP-OES and ICP-MS) that can quantify very low levels of metals, in many cases down to parts per billion (ppb), in drug products, drug substances and excipients. While this will provide a higher level of product safety assurance for consumers, it requires manufacturers and raw material suppliers to make changes to how they perform risk assessments and how they control the quality of their products.
How to Meet Compliance
The new USP/NF chapters provide detection limits, guidance on performing a risk assessment and procedures for performing analyses. Chapter 232 targets 24 elements and places them in 3 classes according to toxicity and prevalence of the element. Four elements are designated as class 1 elements, Cadmium, Lead, Arsenic and Mercury. Thirteen elements are given Class 2 designation (3 listed as 2A and ten as 2B), with the remaining seven identified as Class 3 elements. A risk assessment should be performed to determine the likelihood of these elements ending up in products at limits higher than those indicated as safe for Permitted Daily Exposure (PDE), taking into account the multiple ways elements can enter the product such as: adding elements during production, plant or marine based raw materials, mined raw materials, inorganic substances in excipients, and leaching/extracting from containers or closures.
Part of the risk assessment may include Certificates of Analysis (CofA) from API, excipient or drug substance providers, however, the manufacturer is ultimately responsible for assuring each CofA is accurate and up-to-date.
There may also be some up-front work required to establish the effectiveness of the procedures for each material, as stated in USP Chapter 233, “by means of validation studies, analysts will confirm that analytical procedures described herein are suitable for use on specified material.” A qualified lab, such as Q Laboratories, can perform a validation/verification study to confirm suitability of the procedure.
For most firms, the process for complying with the new guidelines will be: performing a risk assessment, contracting with a qualified laboratory to perform a validation study and subsequent testing for the Class I elements and any others that are likely to appear in their product(s), and gathering information from suppliers or requiring suppliers to test their materials, utilizing validated methods.
The new USP/NF chapters have endured multiple implementation delays, due in part to the desire to harmonize the limits and procedures as closely as possible with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Q3D Guideline for Elemental Impurities, which has been in development for several years. Manufacturers who want to market their products in Europe, Japan and certain other International locations, must assure their existing products meet the ICH guideline by December 2017.
USP/NF Chapter 2232 addresses Elemental Impurities in Dietary Supplements and recommends using the procedures outlined in Chapter 233 to validate and quantify the elemental impurities in dietary supplement products and/or ingredients.
