Transcription
Regulating Heavy Metals in Cannabis Products
Okay just as an introduction my name is Robert Thomas and I run my own consulting company which focuses on the educational needs of the cannabis testing industry and in particular the measurement of heavy metals. First of all, I want to thank Patti Atkins, and the Spex team for inviting me to contribute to this podcast, it's very much appreciated.
My talk today is focused on regulating elemental contaminants in cannabis and hemp consumer products, and in particular how the cannabis injury industry can learn from the almost 20 years it took
to regulate elemental impurities in pharmaceutical materials. So, let me dive straight in by giving you
an overview of my talk.
I'll kick off with the current status of heavy metal regulations for cannabis and hemp, particularly the limitations of a fractured state-based system. I'll then focus on how the pharmaceutical and dietary supplement industries approached regulating elemental impurities and how they abandoned the 100-year-old semi-quantitative calorimetric method for lead and replaced it with plasma spectrochemistry.
I'll also offer my perspective on what the cannabis and hemp industry can learn from this process and give my thoughts on how the industry should move forward with federal oversight around the corner.
So, where is cannabis legal in the us today? Here's a map of the US with light green representing states where medicinal cannabis is legal, and dark green where both recreational and medicinal is legal. It is legal for both medicinal and recreational use in 37 states, with 19 of them allowing for medical use. Most of these 37 states have heavy metal limits. The majority just specify four heavy metals known as the big four; lead, cadmium, arsenic, and mercury. While New York adds nickel, chromium, antimony, zinc, and copper. Maryland and a few other states add chromium, however, Michigan also includes inorganic arsenic and now total arsenic as well as chromium, copper, and nickel. Some states have no heavy metal limits at all. Let's take a more detailed look at some of the individual states.
This is a summary of seven different US states. The heavy metal limits are for California, Colorado, Oregon, Maryland, New York, Connecticut, and Massachusetts, compared to United States Pharmacopoeia (USP) Chapter 232 (permitted daily exposure limits for elemental impurities in drug products), together with USP Chapter 2232 limits for dietary supplements, and the American Herbal Pharmacopoeia limits for heavy metals in botanicals and herbal products.
A couple of points to emphasize, USP Chapter 232 defines a total of 24 elemental impurities based on the drug delivery method, which is oral, parenteral, inhalation, or transdermal. Well chapter 2232 only defines the big four in dietary supplements. So, nine of these elements have been included to reflect the big four plus additional elements regulated in New York, Maryland, and Michigan. It's also important to emphasize the chapter 232 limits are based on microgram per gram. So, to know what's allowable in the
actual drug or supplement, these limits must be recalculated based on the suggested daily dosage for the drug or supplement. For example, if the maximum dosage is 10 grams per day, these limits must be divided by 10 to convert to microgram per gram in the drug. To make these state-based limits a little easier to understand the botanical review team in the office of the new drug products at the US FDA
recently published a study entitled Quality Standards in State Programs Permitting Cannabis for Medical Uses which compared the maximum allowed limits of the big four heavy metals for states that had medical cannabis programs with USP chapter 232 permitted concentrations. Although the actual states are not mentioned here, it can be seen from the eight medical programs reported that the limits shown in red are very different for the USP limits. In fact, the overall conclusion of this study was threefold. First the testing for the four heavy metals in inhalation on all products was lacking in the majority of
the state medical programs. Two it was inconsistent across programs when present. And three it did not always align with USP recommendations. So, let's take a closer look at three of those states which emphasizes the inconsistencies and fractured nature of these regulations.
Let's begin with California. California was the very first state to regulate cannabis in 1996 and as a result it is considered the gold standard with regard to cannabis regulations. California limits are defined in
microgram per gram in two different categories, inhalation cannabis products and all other cannabis products. So, these are the same as USP chapter 232 limits for inhaled and oral drugs respectively based on 10 grams of consumption per day. However, it's also worth pointing out that even though typical pharmaceutical PDEs are based on 10-gram maximum doses per day, we really have no way of knowing
in what quantities people consume cannabis products. Another point to emphasize is that California requires a minimum of half a gram for carrying out heavy metal determinations, while most of the states do not have this stipulation and lower weights are allowed.
Here are the limits for Colorado which are a little more complicated to explain. Colorado limits are categorized first by heavy metals of interest, then by acceptable limits, and finally products to be tested. These acceptable limits are defined in part per million, are not microgram per gram in the product as in California. So, besides inhaled, and oral they also include limits for transdermal
products via the skin. The limits for inhaled products are based on USP chapter 232 for inhalation drugs, while limits for the oral drugs are based on USP chapter 2232 for dietary supplements. However, the topical values are based on FDA limits for heavy metals in cosmetics. So, in reality the, difference makes no logical sense at all.
Here are the limits for Connecticut. They're defined a little differently because they are based on microgram of heavy metal contaminant per kilogram of user body weight per day. So, it's very difficult to get a good understanding what this means with regard to maximum daily consumption because it's only based on the body weight of the consumer. However, in toxicology studies very often a typical body weight of 60 to 70 kilogram is used but you still need to know what the recommended consumption per day of cannabis product is to make the calculation of the heavy metal maximum allowable limit per day. So, i'm not too sure that Connecticut is insisting that you have to weigh before you consume cannabis but that's what it appears to be like.
Okay so let's talk more about the PDEs defined in USP chapter 232. The full panel of USP chapter 232 limits are based on maximum limits in microgram per day for 24 elemental impurities in the drug compound per delivery method. So, for a suggested dosage of 10 grams, these limits should be divided by 10. Note, chapter 232 limits are the same as the ones defined in ICH Q3D guidelines for elemental impurities. For those of you who are not familiar with the ICH, it is a consortium representing the global pharmaceutical industry including the United States, European and Japanese pharmacopoeias. A few points to make, these PDEs have all been determined using toxicology studies based on well-established animal models which are fully explained in the ICH guidelines. They made recent changes to a few of these elements recently which are shown in red. Each elemental impurity is characterized by its likelihood of being found in the drug manufacturing process, which is shown here in the second column.
At this point of the presentation I'd like to give you a little background to the United States Pharmacopoeia, or USP as it's known for short. USP is an independent nonprofit organization which is not part of the US government, however, it works very closely with government agencies and ministries and authorities around the world. The mission of the USP is to improve the health of people through public standards to ensure the quality, safety, and purity of medicines, dietary supplements, and foods. USP standards have ensured consistency for drug products throughout the world for close to 200 years and are recognized in more than 130 countries. These standards known as the USP NF is a book of public standards for drug substances and products. The FDA designates the USP NF as the official compendium for drugs sold in market in the US which must conform to these standards to avoid possible charges of
adulteration and misbranding.
So, what is the USP process to change a standard method? USP continually revises standards through a unique public-private collaborative process which involves scientists in industry, academia, government,
and other interested parties. The American Chemical Society, or ACS, was one of these interested parties that worked very closely with USP to update the test for heavy metals. I lead the heavy metals plasma spectrochemistry task force on the ACS reagent chemicals committee. The USP test for heavy metals, described in USP chapter 231, was first introduced in 1908 and is very similar to the test described in specifications and procedures for ACS reagent chemicals. When we updated our ACS heavy metals test, we wanted to make sure we aligned it with USP test. The test relies on precipitation of the
metal sulfide in a sample and compares the color intensity to a lead standard. USP felt that it was time to replace chapter 231 with methodology that reflected modern test methods and updated toxicology data.
To put this in perspective allow me to explain USP chapter 231 in greater detail. It is based on a sulfide precipitation of the analyte elements using an organo sulfur compound and assumes that all analyte heavy metals behave in a similar manner to alleged standard which samples are compared to. Tt is semi-quantitative at best, and was initially intended to detect a small group of heavy metals but there was no
clear definition of which individual elements were being detected. It is well recognized to have many
limitations so it's pretty amazing that it survived over 100 years.
So, what are these limitations? Here are colored sulfide precipitates of 12 different heavy metals. Imagine if all 12 elements are present in a sample, how difficult it would be to compare the color to the lead standard which is circled in red. Some of its limitations include it cannot detect individual heavy metals typically 5 ppm is the limit of detection, it's very labor intensive, and the interpretation of the color varies with the experience of the analyst. And it also needs a large sample weight of approximately five grams to work correctly.
So. let's take a look at the timeline to change this method. It first began in 1995 where a USP pharmacopoeia forum report identified issues with the chapter 231 method. Then in 2000 an article in the journal of pharma pharmaceutical and biomedical analysis proposed ICP-MS as an instrumental
Alternative. And in 2004 a publication by Nancy Lewin and co-workers at Bristol Myers Squibb in the same journal showed major recovery issues with USP chapter 231 compared to ICP-MS. However, it took approximately another 14 years for various expert committees, expert panels, working groups, and
stakeholder meetings to implement these proposed changes. In January 2018, USP chapters 232 for elemental impurity PDE limits and chapter 233 covering the analytical procedure were approved and
aligned with ICH’ Q3D guidelines for measuring elemental impurities in drug compounds and substances.
So, how did the USP and ICH propose the design and scope of these new PDE limits? They decided it was important to have a chapter specifically for pharmaceuticals only, they call this chapter 232. They wanted to separate dietary supplements from pharmaceuticals, so they call this chapter 2232. They also wanted to simplify the harmonization process between USP and ich by separating the limits from the
analytical procedure to measure them. They covered this in chapter 233 which focuses on the use of ICP-OES or ICP-MS, the microwave digestion procedure, and a full set of validation protocols.
So, what elemental impurities could end up in the drug products? They identified four potential sources,
the first one was elements intentionally added in the formulation of the drug substance. Examples of this might include platinum group metal catalysts which are often used in the organic synthesis of drugs. Second category elements that are not intentionally added but could be present in the preparation of the drug product. Examples of this might include talcum powder, which is used primarily used for tablet compression. Talc is basically magnesium silicate that is mined from the earth, so it can potentially contain high levels of certain heavy metals. Third category elements that are introduced into the drug substance from the manufacturing equipment itself. Examples of this might include the leaching out of chromium, nickel, and iron from the stainless steel mixing or storage vessels. The fourth category elements that have the potential to be leached into the drug product from the storage containers
or the closure systems. Examples of this might include transition metals in some plastic and glass materials. The bottom line was that regulators required the pharmaceutical industry to have a comprehensive understanding of elemental impurities in the drug products by categorizing them by the toxicity and the likelihood of finding them in the entire manufacturing process. Since 2018 all manufacturers of pharmaceuticals are liable to be inspected by the FDA at any time and be expected to show data that elemental impurities are below PDE limits.
So, let's talk more about the classification of these elemental impurities because it's important when we when we're going to be talking about cannabis regulations. Here are the PDEs defined in chapter 231
in microgram per day for three different drug delivery systems. But this time I'd like to emphasize the classification of the elemental impurity. Class 1 includes the classic heavy metals lead, arsenic, cadmium,
mercury, which are human toxicants that have no use in the manufacture of pharmaceuticals. These should be evaluated at all times. Class 2A elements have a high probability of occurrence in the drug
product and also should be evaluated at all times. Class 2B elements have a reduced probability of occurrence related to the low abundance and as a result can be excluded unless they're intentionally added during the manufacture of the drug product. Class 3 elements have relatively low toxicity by the oral route of administration but could definitely warrant consideration for inhalation or intravenous routes.
So, with this as background information let's now take a closer look or a big picture look at the potential sources of elemental contaminants in cannabis consumer products. We can break these sources down into three main categories. The first one is cultivation and growing, the second one is extraction and processing, and the third one is packaging and delivery. Let's take a closer look at those three different categories. Cultivation and growing sources first point to emphasize is that cannabis and hemp are considered hyper accumulators of contaminants in the soil and have been used for phytoremediation
purposes to clean up heavy metals from toxic waste sites. So, if plants are grown outdoors and there are high levels of heavy metals in the soil, they will likely end up in the plant. On the other hand, if the
cannabis plant is cultivated indoors in greenhouses where the growing conditions are far more stable
and constant, it is likely the levels of heavy metals will be much lower. Other cultivation derived contamination sources include fertilizers, nutrients, pesticides, growth enhancers, and the water itself.
Second, processing and manufacturing sources. These include the extraction and purification process
including blending equipment, mixing containers, storage vessels, plus edible product recipe ingredients, and tablet or capsule formulations are all is used to dilute the extracts. And thirdly, packaging and delivery sources such as metallic components in vaping pens and inhalers, low quality plastic or glass bottles, and even things used for graduated droppers which are all notorious for having metallic
contaminants.
So, what elements could be potentially of concern in growing cannabis and in growing cannabis and hemp and the manufacture of cannabis and hemp consumer products? If the plants are grown outdoors there are about 15 heavy metals found in natural ecosystems and contamination from industrial activities such as mining, metal refineries, iron steel plants, petrochemical and petroleum plants, fossil fuel power plants, and any type of industrial activity, there could be potential sources of contaminants in the plant. Also, decades of using lead-based paint, lead water pipes, and later gasoline, have all left their mark on the environment. For example, it is well recognized that soil near major highways has much higher levels of lead beneath the surface from using leaded gasoline. Certain fertilizers, nutrients and growth enhancers, can have elevated levels of metals including mercury, nickel and silicon. The list of elements shown here are ones taken from compelling evidence in the public domain of heavy metals
having been taken up in various levels by cannabis and hemp plants. It is also the potential for elemental
contaminants during the extraction and purification of the cannabinoids there is no question that if the elemental contaminants find its way into the plant and the flower there's a good very good chance it will
end up to some degree in the cannabinoid extract. The degree of extraction will be impacted by the extraction method, the solvent used, and the temperature and pressure used for extraction. In addition, the manufacturing process could compound the problem based on the metallic equipment such as stainless steel used to grind the cannabis plant material, or mixing the cannabinoid extract with delinquent oils or cutting agents which could be contaminants or just putting them into dirty glass
dropper bottles or contamination deliveries in the system of things like vaping pans. There have been a number of product recalls over the past six to twelve months which emphasize this point.
Let me give you a few examples. I have tracked down 15 reports of product recalls over the past 12 months of elevated levels of heavy metals in consumer products. Five of them are shown here, two in
Florida and one each in Michigan, Maryland and Hawaii. In fact one of the cases in Florida showed lead levels were approximately 30 times higher than the regulated action limit for 0.5 ppm for lead in the state. There have been many other reports like this.
So, let me finish off by summarizing my thoughts on future regulations for heavy metals in cannabis. The current list of four heavy metals, lead, cadmium, arsenic, and mercury is clearly inadequate. However, the 24 elements required by the pharmaceutical industry might be an overkill. However, it is absolutely critical that the cannabis industry has a much better understanding about the many potential sources of
heavy metals in its products. I think that elemental contaminants derive from the cultivation and
manufacturing process would warrant regulating at least an additional 10 elements, in addition to the big four. So, a a future federally regulated list of potential heavy metal contaminants in cannabis and hemp could include the big four plus additional five elements required by New York, Maryland and
Michigan, plus an additional six elements based on compelling evidence in the public domain, making a total of fifteen. I wrote a recent article about this in the journal Analytical Cannabis which addressed this topic, this link is available on request. An indication that the industry is slowly moving towards an extended panel of elemental contaminants is evidenced by the National Institute of Standards and Technology, NIST for short, who are developing a hemp certified reference material for 13 toxic elements. The proposed list includes lead, cadmium, arsenic, mercury, beryllium, cobalt, vanadium, chromium, manganese, molybdenum, nickel, selenium, and uranium. Yes, it includes uranium.
These scientists argue that hemp is more in line with tobacco products and should be regulated in a similar manner. In addition, I sit on an ASTM subcommittee that is currently in the process of writing an ICP-MS method for measuring up to 21 elements in cannabis and hemp.
Finally, USP has just published a draft monograph for CBD to use in FDA approved drug formulations which requires up to 24 elemental impurities defined in USP chapter 232 to meet compliance. But, at the end of the day, the only way the industry is going to know what element contaminants are worthy of
consideration is to carry out a comprehensive risk assessment of its own, similar to the pharmaceutical industry to identify where these sources are and at what levels. It is only then can we specify the panel
of elemental contaminants to monitor and the toxicity impact on cannabis and hemp consumer products.
With that, I thank you for your time, and I just like to point out three books which I have in the public domain which I've used the sources for this talk including my most recent book which is the one in
the middle, which is Measuring Heavy Metal Contaminants in Cannabis and Hemp which includes a chapter dedicated to regulations. And by the way all three books are available now in paperback edition. And with that, I thank you for your time, thanks a lot.
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