The Process for Change

Given all these issues, the test remained as an official test in the USP until January, 2018, approximately 110 years after its introduction; the primary reason being that there was no industry-wide, globally accepted test to replace it. For all its faults, the methodology of general Chapter <231> was well understood, routinely used by the industry, and was harmonized with the European and Japanese Pharmacopoeias. The winds of change began with the publication in 1995 of Stimuli to the Revision Process article in the USP Pharmacopeial Forum.² In this article, it was well understood that almost half the metals of interest were lost in the ashing process, and that there was essentially zero recovery for mercury, one of the more toxic and common elements of interest. In 2000, Wang made similar observations in an article in the Journal of Pharmaceutical and Biomedical Analysis, where he noted “Although still widely accepted and used in the pharmaceutical industry, these methods based on the intensity of color of sulfide precipitation are non-specific, labor intensive, and more often than not, yield low recoveries or no recoveries at all.”³ Then in 2004, Lewen and coworkers directly compared the recoveries of 14 different elements using the USP <231> Method with inductively coupled plasma mass spectrometry (ICP-MS). Consistent with the other two articles, this study showed a number of recoveries around 50%, with recoveries of 5% or less for Se, Sn, Sb, and Ru, with, as anticipated, no recovery at all for Hg, as exemplified in Figure 3.2.-¹

FIGURE 3.1 A group of common elements that produce insoluble sulfides, exemplifying how difficult it is for an operator to compare a sample containing many elements with slightly different colored precipitates against a lead reference standard. (Used with permission from PerkinElmer Inc., All Rights Reserved.)

FIGURE 3.2 Comparisons between ICP-MS and the method described in USP Chapter.

USP Implementation Process

This work set the stage for the establishment at USP of a series of committees, beginning in 2005 to update the concept of heavy metals testing. The process built on an Institute of Medicine meeting commissioned by USP in 2008 and on a document issued by the European Medicines Agency (EMA) which developed a guideline on the control of residual catalysts in pharmaceuticals with the goal of establishing limits based on toxicological safety assessments of common catalytic elements. This work began in 1998 and resulted in a guideline that was officially implemented in 2008.⁵

Building on this, USP published two draft chapters in 2008. These were general Chapter <232>—Elemental Impurities—Limits,⁶ and Chapter <233>—Elemental Impurities—Procedures.⁷ This effort led to the desire by the pharmaceutical industry to have a chapter that was harmonized across the pharmacopeias in the ICH (The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) regions of the world (United States, Europe, and Japan). The result was the ICH Q3D expert working group, and the final output was the ICH Q3D guideline on elemental impurities, with the step 4 document published on the ICH website in 2014.⁸ The guideline was implemented by the FDA for new drug products in July, 2017, and for all existing drug products in January, 2018, concurrent with the removal of USP general Chapter <231 >. (Note: The final version of ICH Q3D (Rl) was adopted by the EMA’s Committee for Human Medicinal Products (CHMP) on March 28, 2019.)

ICH Q3D focused strictly on the establishment of a list of elements of toxicological concern, and their limits in oral, parenteral, and inhalational dosage forms. An extensive body of information is also available to help practitioners understand the scope of the guideline and how to think about issues such as the calculations of concentrations in the drug product and extension to other dosage form.⁸ The entire process is risk based, and testing is only one of many ways by which compliance with the standard can be demonstrated. The full list of Permitted Daily Exposure (PDE) elemental impurity limits defined in USP Chapter <232> and ICH Q3D (Rl) guidelines are shown in Table 3.1. Note: The USP Group responsible for dietary and herbal supplements generated its own limits for elemental contaminants which were described in USP Chapter <2232>.⁹

Note: The new' methodology no longer referred to heavy metals but as elemental impurities or contaminants. The reason being that heavy metal is a loose term that typically indicates “environmentally harmful” but is scientifically meaningless as defined by IUPAC (International Union of Pure and Applied Chemistry), the world authority on chemical nomenclature,¹⁰ which stated ... You may know what you mean when you talk about a heavy metal but someone else may mean something entirely different. However, in order to use terminology understood by the cannabis industry, we will continue to use the term heavy metals which refers to elemental impurities or elemental contaminants, for the purpose of clarity.

It should also be emphasized that PDE limits are defined as the maximum acceptable intake of elemental impurity in pharmaceutical products per day. So if the suggested daily dosage of a drug is 10 g, these PDE levels must be divided by 10 to determine the allowable elemental concentration in the drug compound per day. It’s also important to emphasize that classification of each elemental impurity showm in Table 3.1 is based on the toxicological impact of each element, with Class 1 and 2A elements considered the most toxic, followed by Class 2B and finally Class 3 being the least toxic. However, it is very important to mention that Chapter <232> clearly states that it’s critical to monitor Class 3 element impurities in drugs that are delivered via inhalation, because the impact of these heavy metals on the lungs and repertory system is more serious.

It’s also important to point out that neither USP nor the ICH specifically addresses PDE levels for transdermal (via the skin) applications in their guidelines, mainly because elemental impurities are omnipresent throughout life and the skin, as the outer barrier of the body is in direct contact with these metals on a regular basis particularly from metal-containing particles that might be in the surrounding environment. For that reason, the dermal uptake of elemental impurities in the human body via the skin from topically applied drug product is expected to be low' or even negligible due to the excellent barrier properties of the skin itself.

Ultimately, all available evidence and data to date support the view that dermal exposure to most elemental impurities is unlikely to represent a substantive toxicological concern. Currently, the establishment of limits for elemental impurities in cutaneous and transdermal drug products is under examination and is expected to be announced in mid-2020. In the meantime, oral PDEs given in ICH guidelines may be considered a suitable point of reference as the intestine may be regarded as a comparable absorption mechanism to the skin.

TABLE 3.1

Permitted Daily Exposure (PDE) Limits as Defined in USP Chapter <232> and ICH Q3D Step 4 Guidelines⁶-⁸

^a The inhalation PDE for Cd was initially set at 2 ng/day in January, 2018, but was reassessed in March, 2019 to 3 pg/day, because of an error in the original calculation.¹¹

Testing procedures of drug products and excipients were not discussed in detail by the ICH Q3D working group. Rather, it was left to the individual pharmacopeias to work out their own procedures, with the goal of long-term harmonization of the final results. However, the USP wrote general Chapter <233>, which describes two procedures, ICP-OES and ICP-MS, along with system suitability and validation requirements for these tests. Let’s take a closer look at the validation protocols, which are described in Chapter <233>.