Understanding Sources of Heavy Metals in Cannabis and Hemp: Benefits of a Risk Assessment Strategy – Part 1

The pharmaceutical industry took over 20 years to move from the semi-quantitative monitoring of a small group of heavy metals to finally arrive at regulations for 24 elemental impurities in drug products, classified by their permitted daily exposure (PDE) limits and categorized by toxicological impact and method of administration (oral, parenteral, inhalation, transdermal). The entire premise was based on carrying out a comprehensive risk assessment study of the elements’ toxicity and the likelihood of finding them somewhere in the drug manufacturing process, which was fully documented in ICH Q3D guidelines for elemental impurities.

The cannabis industry cannot move beyond testing just for heavy metals until this type of risk assessment study is carried out. This objective of this white paper is to offer guidance as to which elemental contaminants are worthy of consideration, based on likely sources derived from the cultivation, extraction, processing, packaging and delivery of cannabis and hemp consumer products and to explore how this well-established pharmaceutical risk assessment process could be adapted by the cannabis industry.

The white paper will be broken down into a four-part series of articles outlined below:

1. The pharmaceutical risk assessment approach
2. Can risk analysis be adapted for the cannabis industry?
3. Sources of elemental contaminants derived from cultivation practices
4. Contributions from the cannabis manufacturing process

Part 1: What we can learn from the pharmaceutical industry?

The lack of federal oversight with regard to heavy metals in medicinal and consumer cannabis products in the US has left individual states to regulate its use. Cannabis is legal in 37 states, while 18 states and Washington, DC, allow its use for adult recreational consumption¹. However, the cannabis plant is known to be a hyper-accumulator of heavy metals in the soil, so it is critical to monitor levels of elemental contaminants to ensure cannabis products are safe to use. Unfortunately, there are many inconsistencies with heavy metal limits in different states where cannabis is legal. The vast majority of these states define the “big four” heavy metals: lead (Pb), arsenic (As), cadmium (Cd), and mercury (Hg). New York State also requires the testing for chromium (Cr), nickel (Ni), copper (Cu), antimony (Sb) and zinc (Zn), while Michigan requires inorganic As (not total As) and also adds Cr, Ni, and Cu. Maryland and a few other states also include Cr as well as the big four.

Some states base their limits directly in the cannabis, while others are related to human consumption per day. Others take into consideration the body weight of the consumer, while some states do not even have heavy metal limits. To complicate the situation, certain states only require heavy metals in the cannabis plant/flower, while some give different limits for the delivery method such as oral, inhalation, or transdermal². These inconsistencies and the fractured nature of state-based limits would make it extremely complicated to monitor at the federal level, because currently all regulations apply only in the state where the cannabis is grown, processed, and sold. And since the federal government still considers cannabis a Schedule I drug there should be no interstate commerce with regard to cannabis products. However, it is now legal to grow hemp anywhere in the US for the production of CBD-based consumer products, so it will be interesting to see how the Department of Agriculture regulates the hemp industry at the federal level, when cannabis is regulated by the individual states where it is legal.

Expanding the panel of elemental contaminants

So clearly there is a need for more consistency across state lines, particularly as the industry inevitably moves in the direction of federal oversight. This is further compounded by the fact that there is compelling evidence in the public domain that only monitoring the big four heavy metals is totally inadequate to ensure consumer safety. But how many metals should there be in an expanded list? At a recent ASTM workshop dedicated to the measurement of heavy metals in cannabis and hemp consumer products, compelling evidence was presented by a number of researchers that suggested 10-15 elemental contaminants are worthy of consideration³. Moreover, the National Institute of Standards and Technology (NIST) is developing a 13-toxic element hemp certified reference material (CRM) through its CannaQAP Program to include Pb, Cd, As, Hg, beryllium (Be), cobalt (Co), Cr, manganese (Mn), molybdenum (Mo), Ni, selenium (Se), uranium (U), and vanadium (V)⁴. In addition, ASTM International's D37 Committee is in the process of developing a standardized ICP-MS method for over 20 different elemental contaminants in cannabis (method in review). So, what will be a realistic panel of heavy metals to monitor in cannabis consumer products, particularly as there is no comprehensive understanding of the sources of elemental contaminants in the cannabinoid production processes. Moreover, besides the big four, there is no consensus on the toxicity impact of other heavy metals in cannabis and hemp, as there has been no risk assessment study carried out with regard to heavy metal contaminants and for that reason, consumer safety is likely being compromised.

The only point of reference we have at this current time for what could be a federally regulated panel is the FDA approved CBD-based drug Epidiolex, which is available in the US to treat childhood seizures. Manufactured by UK-based GW Pharmaceuticals, it went through the regulatory process four years ago to get it approved in the US and had to show compliance by meeting permitted daily exposure (PDE) limits for up to 24 elemental impurities as defined in USP Chapter 232 and ICH Q3D guidelines. In fact, it’s worth pointing out that the USP recently published for public comment in its pharmacopeial forum (PF 48-1), a draft monograph for CBD intended for use as an API for drug formulations, which stated that:

“Elemental impurities in official drug products are controlled according to the principles defined and requirements specified in Elemental Impurities—Limits 〈232〉, as presented in the General Notices 5.60.30.”

In the long term, this could possibly indicate that the FDA will regulate CBD products for up to 24 elemental contaminants when it eventually has oversight of the cannabis industry. But more importantly, in the short term it implies that CBD being manufactured in the US for recreational or medicinal purposes is not pure enough for federally-approved drugs, because it only has to comply with the state’s maximum limits for heavy metal contaminants, which in most US states is typically only Pb, Cd, As, and Hg.

However, it’s important to stress that a panel generated by pharmaceutical regulators isn’t necessarily one that should be used by the cannabis industry, as the process for manufacturing cannabinoids is very different to drug products. So, the objective of this white paper is not to provide evidence as to what elemental contaminants the industry should be monitoring, but to offer guidance on which ones are worthy of consideration by implementing a comprehensive risk assessment study supported by evidence from information in the public domain and other sources about what metals are likely candidates.

The pharmaceutical industry?

The cannabis industry can learn a great deal from the pharmaceutical industry, as it went through this process over 20 years ago when it updated its 100-year-old semi-quantitative sulfide precipitation colorimetric test for a small suite of heavy metals to eventually arrive at a list of 24 elemental impurities in drug products defined as permitted daily exposure (PDE) limits and classified by their toxicity and the probability of inclusion in the drug product.

These procedures were described in United States Pharmacopeai Chapters 232 - Elemental Impurities⁵ and 233 - Procedures⁶ together with the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q3D guidelines on elemental impurities⁷.

Note: The ICH is an international consortium of pharmaceutical regulatory authorities and pharmaceutical industry groups to discuss scientific and technical aspects of pharmaceuticals and develop guidelines.

These new guidelines defined maximum PDE limits based on well-established elemental toxicological data for drug delivery methods (including oral, parenteral, inhalation, and transdermal), together with the analytical methodology using techniques such as plasma spectrochemistry to carry out the analysis. This meant that pharmaceutical manufacturers were required to not only understand the many potential sources of heavy metals in raw materials and active ingredients, but also to know how the manufacturing process contributed to the elemental impurities in the final drug products.

The beginning of the journey to regulate elemental impurities in pharmaceuticals in the late 1990s can be compared to the production of cannabis and hemp derived products today, where the sources of elemental contaminants, the toxicological impacts of the contaminants and the methodology to perform the measurements were not fully understood or developed. In particular, the elemental toxicological guidelines to regulate the cannabis industry are being taken very loosely from a combination of methods and limits derived by the pharmaceutical, dietary supplements, food, environmental, and cosmetics industries. Even though the process of manufacturing cannabinoids might be similar in some cases to drugs and herbal medicines derived from natural products, the consumers of cannabis and hemp products are using them very differently and in very different quantities, particularly compared to pharmaceuticals, which typically have a maximum daily dosage. The bottom line is that heavy metal toxicological data generated for pharmaceuticals over a number of decades cannot simply be transferred to cannabis, hemp, and their multitude of products. So, let’s take a detailed look at how the pharmaceutical industry approached bringing in comprehensive regulations using a risk assessment approach of those elements that are not only known to be toxic but also likely to be potentially found somewhere in the drug manufacturing process.

The pharmaceutical risk assessment approach

ICH Q3D recommends that manufacturers conduct a product risk assessment by first identifying known and potential sources of elemental impurities⁷. Manufacturers should consider all potential sources of elemental impurities, such as elements intentionally added, elements potentially present in the materials used to prepare the drug product, and elements potentially introduced from manufacturing equipment or container closure systems. Manufacturers should then evaluate each elemental impurity likely to be present in the drug product by determining the observed or predicted level of the impurity and comparing it with the established PDE. If the risk assessment fails to show that an elemental impurity level is consistently less than the control threshold (defined as being 30 percent of the established PDE in the drug product), additional controls should be established to ensure that the elemental impurity level does not exceed the PDE in the drug product. These additional controls could be included as in-process controls or in the specifications of the drug product or substance.

Benefits of using a risk assessment approach

Rather than routinely testing drug products against a broad specification for elemental impurities, which may cause delays in product delivery, correct use of the risk assessment process will ensure that targeted and appropriate testing of materials will be performed where control is needed, and this creates the possibility that the manufacturer will be able to:

• Test for specific metals only.
• Test occasional batches or lots.
• Require minimum testing post approval.

This scientific-based and data driven risk assessment ensures that the control strategy is appropriate and does not impact the product quality or patient safety.

Performing risk assessment

The first thing that is needed before starting the risk assessment is the route of administration and dose range for the product since the systemic exposure of the human system to elemental impurities varies with the route of administration: oral, inhaled, parenteral, or transdermal. In addition, some metals exhibit higher toxicity in some forms of administration than others. This type of information is shown in Table 1, which is taken from the most recent ICH Q3D (R1) and (R2) guidelines^{7, 8}.

From these data, it can be determined what the maximum limits will be for the product provided it has an oral, parenteral, inhaled, or transdermal administration.

Note: Transdermal (via the skin) PDEs were not included in the first draft of this guideline but are currently going through the review and approval process and are included here for information purposes only.

It’s also important to emphasize that these are maximum limits per day. So, to calculate the allowable limit in the drug, these data must be divided by the recommended dosage for that drug. For example, if 10 grams (g) per day is the maximum dose these values must be divided by 10 to calculate the concentration in microgram per gram (µg/g) in the drug material. From these PDE data the control threshold can be calculated for any element that is considered worthy of a risk assessment.

Table 1: ICH Q3D (R2) guidelines for elemental impurities (7, 8).

How are the PDEs calculated?

Acceptable exposure levels for elemental impurities were established by calculation of PDE values according to the procedures for setting exposure limits in pharmaceuticals and the methods adopted by International Program for Chemical Safety (IPCS) for assessing human health risk of chemicals⁹. These are very similar to the US EPA’s Integrated Risk Information System¹⁰, and the FDA’s Guidance for Industry: Toxicological Principles for the Safety Assessment of Food Ingredients¹¹ and are based on the most relevant animal studies using the following calculation:

PDE = NO(A)EL x Mass Adjustment/Modifying Factors [F1 x F2 x F3 x F4 x F5]

Where:

NO (A)EL is No-Observed Adverse Effect Level as defined by IUPAC as the greatest concentration or amount of a substance, found by experiment, which causes no detectable adverse alteration of morphology, functional capacity, growth, development, or life span of the target organism under defined conditions of exposure.

Mass adjustment is based on an arbitrary adult human body mass for either sex of 50 kilograms (kg). This relatively low mass provides an additional safety factor against the standard masses of 60 kg or 70 kg that are often used in this type of calculation.

Modifying Factors (F1-F5) are individual factors determined by professional judgment of a toxicologist and applied to bioassay data to relate the data to human safety.

Example of a PDE calculation

As an example, consider a toxicity study of cobalt in humans. The NOAEL for polycythemia (a blood cancer that increases the number of red blood cells in the body) is 1 milligram per day (mg/day). The PDE for cobalt in this study was calculated as follows:

PDE = 1 mg/day /[1 x 10 x 2 x 1 x 1] = 0.05 mg/day= 50 μg/day

Where:

F1 = 1 study in humans

F2 = 10 to account for differences between individual humans

F3 = 2 because the duration of the study was 90 days

F4 = 1 because no severe toxicity was encountered

F5 = 1 because a NOAEL was used

This is an example of how the PDE for cobalt has been calculated, but every elemental impurity in each of the four routes of administration defined in ICH Q3D will have a PDE maximum limit defined in µg/day, which is based on well-established animal studies. Detailed information about the toxicity of each elemental impurity, together with how the PDEs were calculated are included in these guidelines. As a result, every element in Table 1 will be categorized by its toxicity classification and the likelihood of finding it somewhere in the drug manufacturing process. So, let’s take a closer look at these elemental classifications.

Elemental classification

With knowledge of the route of administration the information in Table 1 allows us to refine the number of elements that should be considered in a risk assessment study since most elements not used in the process may be discounted. This is due to the very low risk of certain elements being present unexpectedly in raw materials and process equipment due to their low abundance in natural sources. At a high level, risk is assessed as a combination of the toxicity of the element and its likelihood of occurrence, along with its likelihood of detection (simply stated: you won’t find it if you don’t look).

Class 1 and 2A metals, Pb, Cd, As, Hg, Co, V, and Ni must always be assessed irrespective of the route of administration. However, this does not mean they must be routinely tested for in an approved product, rather that data should be collected during the assessment phase to determine whether they are likely to occur in the finished product at levels at or near the PDE.

Class 2B elements, Au, Pd, Ir, Os, Rh, Ru, Se, Ag, and Pt have a reduced probability of occurrence related to their low abundance and as a result, can be excluded unless they are intentionally added during the manufacture of the drug product. An example of Class 2B would be platinum group metals, which are used as catalysts in the organic synthesis of certain drugs.

Class 3 metals, Li, Sb, Ba, Mo, Cu, Sn, and Cr have relatively low toxicities by the oral route of administration but could warrant serious consideration for inhalation and intravenous routes, as discussed in detail in ICH Q3D.

ICH Q3D provides a clear structure for companies to follow in designing their risk assessment process, which is summarized as a fishbone diagram with the most common routes of potential contamination shown in Figure 1.

Figure 1: ICH Q3D Risk Assessment Fishbone Diagram.

Potential sources of elemental contamination

There are five likely routes for the introduction of elemental impurities, so if these inputs are well characterized and considered to be “clean” with respect to the relevant elemental impurity limits then the drug product will be acceptable without testing for elemental impurities. The ICH has provided pragmatic guidance as follows:

The applicant’s risk assessment can be facilitated with information about the potential elemental impurities provided by suppliers of drug substances, excipients, container closure systems, and manufacturing equipment. The data to that support this risk assessment can come from a number of sources that include, but are not limited to:

• Prior knowledge.
• Published literature.
• Data generated from similar processes.
• Supplier information or data.
• Testing of the components of the drug product.
• Testing of the drug product.

In summary, testing is not the mandated requirement, but data are absolutely critical. This means that as a company becomes more familiar with the elemental impurity risk assessment process, they will be able to leverage information gained in the development of previous products enabling them to streamline the process. Similarly, as information is published in the scientific literature the reliance on analytical testing will be reduced. If we consider the five sources of elemental impurities it is clear that some are more likely to problematic than others. In order of complexity they are: water, manufacturing equipment, container closure system, drug substance and excipients. Let’s take a closer at each of these areas.

Water

ICH Q3D says “The risk of inclusion of elemental impurities from water can be reduced by complying with compendial (e.g., European Pharmacopoeia, Japanese Pharmacopoeia, US Pharmacopeial Convention) water quality requirements, if purified water or water for injection is used in the process.” In practice monitoring of water purification is a focus of FDA facility audits and therefore, as long as no significant changes to the quality of the water supply to the site occur, it is unlikely that the purification process supporting the claim of compliance to pharmacopeial standards will fail to also control unwanted elemental impurities. As long as these requirements are met, water can be used without testing for elemental impurities. For pharmaceuticals, the rationale for the acceptability of USP Purified Water is presented in a Pharmacopeial Forum Stimuli for Revision article in PF39(1) – Elemental Impurities in Pharmaceutical Waters, p.434.

Manufacturing equipment

The risk of inclusion of elemental impurities can be reduced through process understanding, equipment selection, equipment qualification, and good manufacturing practice (GMP) processes, as called out in Q3D:

“The specific elemental impurities of concern should be assessed based on knowledge of the composition of the components of the manufacturing equipment. The assessment of this source of elemental impurities is one that can be utilized potentially for many drug products using similar process trains and processes.”

It can be argued that a specific plant configuration could be qualified for elemental impurity leaching by testing the qualification batches produced as part of the NDA submission process and that subsequent process using that configuration will not need test data provided that the reagents are not significantly different.

Container closure systems

This term refers to all the packaging components potentially contacting the drug product. It is known that packaging components can leach impurities and manufacturers have to provide studies on extractables and leachables as part of the product registration. ICH Q3D provides the following guidance:

“The probability of elemental leaching into solid dosage forms is minimal and does not require further consideration in the assessment. For liquid and semi-solid dosage forms there is a higher probability that elemental impurities could leach from the container closure system into the drug product during the shelf-life of the product. Studies to understand potential extractables and leachables from the final/actual container closure system should be performed (Q3D).”

There are two very useful publications on elemental impurities that can be used in the risk assessment process^{12, 13} and these studies by pharmaceutical industry experts cover a wider range of elements than those covered by ICH Q3D in over 100 test articles. The information provided can be used in the elemental impurity risk assessment process by providing the identities of commonly reported elements and data to support probability estimates of those becoming elemental impurities in the drug product. Furthermore, recommendations are made related to establishing elements of potential product impact for individual materials.

Drug substances

Drug substance manufacture uses catalysts that are a known potential contaminant and will have a control strategy in place as part of the process development, so are considered low-risk but may have input materials that have non-GMP precursors and therefore provide a high risk of introducing unexpected elemental impurities.

Excipients

ICH Q3D explains that “Elemental impurities are often associated with mined materials and excipients. The presence of these impurities can be variable, especially with respect to mined excipients, which can complicate the risk assessment. The variation should be considered when establishing the probability for inclusion in the drug product.”

Excipients sourced from plants (cellulose, for example), mined (talcum powder) or from animals (lactose and gelatin) can potentially be contaminated through man-made pollution or natural sources, particularly with As, Cd, Hg, and Pb and other heavy metals.

It is considered that highly refined excipients are low risk with respect to elemental impurities; examples are cellulose and lactose. However, data shows that elevated levels of class 1 and 2A metals are commonly encountered in mined excipients such as talcum powder and calcium carbonate, so these should be considered a high risk.

A paper on elemental impurities in excipients was published in Pharmaceutics, Drug Delivery and Pharmaceutical Technology which reported testing of 190 samples from 31 different excipients and 15 samples from eight drug substance provided through the International Pharmaceutical Excipient Council of the Americas¹⁴. In addition, the Elemental Impurities Pharma Consortium has published a commercial database comprising analytical data on elemental impurities from over 100 different materials, including pharmaceutical excipients, and dyes, etc.¹⁵.

Risk assessment frequency

A full risk assessment will need to have been completed as part of the regulatory submission for a new product filing and appropriate actions taken ready for manufacture. Once a product is approved then the manufacturer will need to update the risk assessment whenever changes are made to the process – for example, when a packaging change is made or a new raw material supplier is introduced to the supply chain. The updated risk assessment may require the introduction of additional testing or could justify reduction of testing. In the new risk assessment, any actions should be submitted as part of the annual report to the FDA as per the Chemistry Manufacturing and Controls (CMC) Guidance for Industry¹⁶.

Final thoughts

The first part of this white paper has explained the historical importance of why the measurement of elemental impurities in pharmaceutical products was mandated to change from a very imprecise semi-quantitative assay to one that used modern instrumental plasma spectrochemistry and maximum limits based on the toxicological impact using well-established animal studies. Part two of the series will focus on whether a well-established risk assessment strategy for pharmaceuticals could be adapted by the cannabis industry.

References 

1. Marijuana Policy by State: https://www.mpp.org/states 

2. The Importance of Measuring Heavy Metal Contaminants in Cannabis and Hemp, R. Thomas White Paper, Analytical Cannabis, https://cdn.technologynetworks.com/ac/Resources/pdf/the-importance-of-measuring-heavy-metal-contaminants-in-cannabis-and-hemp-312957.pdf 

3. A Recap of ASTM’s Workshop on Measuring Elemental Contaminants in Cannabis and Hemp Consumer Products, R. Thomas, Analytical Cannabis, August 2021 https://www.analyticalcannabis.com/articles/a-recap-of-astms-workshop-on-measuring-elemental-contaminants-in-cannabis-and-hemp-consumer-313229 

4. NIST Tools for Cannabis Laboratory Quality Assurance, NIST CannaQAP Program, https://www.nist.gov/programs-projects/nist-tools-cannabis-laboratory-quality-assurance 

5. United States Pharmacopeia General Chapter <232> Elemental Impurities – Limits: First Supplement to USP 40–NF 35, 2017, https://www.usp.org/chemical-medicines/elemental-impurities-updates 

6. United States Pharmacopeia General Chapter <233> Elemental Impurities – Procedures: Second Supplement to USP 38–NF 33, 2015, https://www.usp.org/chemical-medicines/elemental-impurities-updates 

7. ICH Guideline Q3D on Elemental Impurities (R1), European Medicine Agency Website: https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-32.pdf 

8. ICH Guideline Q3D on Elemental Impurities (R2), European Medicine Agency Website: https://www.ema.europa.eu/en/documents/scientific-guideline/draft-ich-guideline-q3d-r2-elemental-impurities-step-2b_en.pdf 

9. IPCS. Principles and Methods for the Risk Assessment of Chemicals in Food, Chapter 5: Dose-response Assessment and Derivation of Health Based Guidance Values. Environmental Health Criteria 240. International Program on Chemical Safety. World Health Organization, Geneva, (2009), https://www.who.int/publications/i/item/9789241572408 

10. US EPA’s Integrated Risk Information System (2021), https://www.epa.gov/iris/basic-information-about-integrated-risk-information-system 

11. US FDA, Guidance for Industry and Other Stakeholders: Toxicological Principles for the Safety Assessment of Food Ingredients (Redbook 2000) http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/IngredientsAdditivesGRASPackaging/ucm2006826.htm 

12. Materials in Manufacturing and Packaging Systems as Sources of Elemental Impurities in Packaged Drug Products: A Literature Review, D. R. Jenke, et al., PDA Journal of  Pharmaceutical Science and Technology, 69, 1-48 (2015), https://pubmed.ncbi.nlm.nih.gov/25691713/ 

13. A Compilation of Metals and Trace Elements Extracted from Materials Relevant to Pharmaceutical Applications such as Packaging Systems and Devices D. R. Jenke, et al., PDA Journal of Pharmaceutical Science and Technology, 67 354-375, (2013)., https://pubmed.ncbi.nlm.nih.gov/23872445/ 

14. Elemental Impurities in Pharmaceutical Excipients G. Li et.al., Pharmaceutics, Drug Delivery and Pharmaceutical Technology Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24650, https://pubmed.ncbi.nlm.nih.gov/26398581/ 

15. Elemental Impurities Pharma Consortium - A Database to Facilitate the Risk Assessment of Active Ingredients and Excipients, (2014), https://www.gmp-compliance.org/gmp-news/elemental-impurities-a-database-to-facilitate-the-risk-assessment-of-active-ingredients-and-excipients 

16. CMC and GMP Guidances, US FDA, Elemental Impurities in Drug Products; Guidance for Industry, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/elemental-impurities-drug-products-guidance-industry