USP, FDA Propose Quality Standards for Cannabis, Highlighting its Role as Medicine

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This action is of considerable significance as it supports the regulation of cannabis and cannabis-derived products as medicine under the Federal Food, Drug and Cosmetic Act.

US Pharmacopeia (USP) is championing cannabis quality standards with a proposed new cannabis monograph that recently closed for public comment.1 USP’s first cannabis monograph was published in 1851 (3rd edition), but after continued development in subsequent editions, cannabis was last published in USP in 1936 (11th edition) due to regulator prohibition.1 With a lack of federal standards for cannabis, state legislative initiatives and subsequent promulgation of state regulation has led to a heterogeneity of standards, ranging from patient safety considerations around labelling to acceptable microbial contamination levels.2

“As part of the safety net that protects and promotes public health in the US, USP is taking steps to prevent harm to patients resulting from exposure to substandard, super-potent, contaminated or adulterated cannabis for medical use under state law,” wrote the authors of the new USP monograph.1

In the current proposed USP Cannabis Species Inflorescence monograph published in the Herbal Medicines Compendium, the authors seek to set acceptance criteria for: plant chemotypes, content of cannabinoids, microbial contamination, elemental impurities, pesticide residues, terpenes, and foreign organic matter. While some sections detailing laboratory analytical methods that create standards may not be of interest to clinicians, such as those for high performance thin layer chromatography (HPTLC), chemical decarboxylation, extraction, and sample preparation; clinicians will likely find the codified terminology, labelling standards, standardization of potency and contamination as noteworthy improvements in patient safety (See Table 1).1

Regulatory Landscape and Oversight

USP’s action is of considerable significance in support of the FDA’s regulation of cannabis and cannabis-derived products as medicine under the Federal Food, Drug and Cosmetic Act. While the hemp and cannabis industries try to get established outside of the DEA schedule 1 drug status (federally illegal), the conflict with state and federal law have lent the situation to various interpretations on whether different products comply with and could be defined as food, dietary supplements, or a drug. USP is working to support the FDA in the quality of cannabis for medicinal use.6

The Pure Food and Drug Act of 1906 was established by Congress to prohibit the sale of misbranded or adulterated food and drugs in interstate commerce. It was established following a public outcry after the publication of Upton Sinclair’s 1906 novel The Jungle, which focused on food adulteration and unsanitary practices in meat production. This laid the foundation for the nation’s first consumer protection agency, the Food and Drug Administration (FDA). Further, the act also deemed the USP and the National Formulary official compendia under federal law.3

In 1938, the Federal Food, Drug and Cosmetic Act (FDCA) was then passed by Congress to establish the FDA as an oversight body for the safety of food, drugs, medical devices, and cosmetics. In addition, the FDCA expressly recognized the USP’s quality standards for medicines and makes USP standards binding for dietary supplement manufacturers that label their products as USP compliant.3 Further, the FDA has incorporated more than 200 regulations for food substances through USP’s Food Chemicals Codex.2,3

Because of USP’s established role under the FDCA, action by USP and other federal regulatory bodies to create oversight and standards for cannabis and cannabis-derived products helps to clarify cannabis's role as a medicine that requires the same oversight as other medicines in the supply chain.6

FDA Guidance on Cannabis Quality Considerations in Clinical Research

In January 2023, the FDA released a guidance for the industry on quality considerations for cannabis in clinical research. The guidance explicitly establishes that cannabis or cannabis-derived products with marketing that claims the product provides therapeutic benefit will require the manufacturer to follow the same process for FDA premarket approval as other drugs on the market.7

“In general, this means any product (including one that contains cannabis or cannabis-derived compounds) marketed with a claim of therapeutic benefit, or with any other disease-related claim, is considered a drug,” FDA wrote in the guidance. “To be legally marketed in interstate commerce, drugs that are not biological products generally must either (1) receive premarket approval by FDA through the new drug application (NDA) or abbreviated new drug application (ANDA) process, or (2) for certain over-the-counter nonprescription drugs, meet the requirements in the [FDCA] for marketing without an approved NDA or ANDA.”7

Later that same week, after the release of the industry guidance, the FDA published a statement from the principal deputy commissioner Janet Woodcock, MD, explaining the FDA has concluded that existing regulatory frameworks for foods and supplements are not appropriate for cannabidiol (CBD). Additionally, the statement from Woodcock clarifies matters further regarding the FDA’s position on the need for oversight for CBD products in particular.5

“The FDA has concluded that a new regulatory pathway for CBD is needed that balances individuals’ desire for access to CBD products with the regulatory oversight needed to manage risks,” Woodcock wrote in the statement. “A new regulatory pathway would benefit consumers by providing safeguards and oversight to manage and minimize risks related to CBD products.”7

In industry, some manufacturers have responded to the FDA guidance and Woodcock’s statement welcoming the opportunity for standardization, as it has the potential to bring cannabis further into the fold of standardized medicine. However, others in the industry have responded less positively, noting the potential for additional product analysis to drive up cost for patients.

Defining Cannabis and its Proper Labelling

For the proposed monograph, USP declares that they subscribe to the opinion that cannabis consists of one highly variable species, with many subspecies and varieties. Under a single cannabis category, the monograph can be used to apply to all varieties and subspecies, regardless of whether the product is from a subspecies of sativa or indica (C. ruderalis would be included, though whether it is extinct remains under debate).1

In the language of the monograph, USP leaves the door open, stating the definition may be modified if a more definitive taxonomic consensus is reached. “The quality standards set out in this monograph are broadly applicable to the cannabis inflorescence subspecies, varieties, and cultivars currently in commerce,” USP wrote.1

Further, although the monograph only mentions the word “hemp” once, these statements, alongside the definitions of CBD dominant products, allow for applicability to cannabis products which are currently described as hemp under the DEA definition of less than 0.3% THC (see Chart 1).1,6

USP lists constituents of interest, including 14 cannabinoids and 5 terpenes, for the purpose of appropriate labeling (See Table 2).1 Further, current research shows that there is no consistent genetic differentiation between sativa and indica cannabistypes, and samples within strains are notgenetically similar. Because of these genetic differences, quantitative chemical analysis of cannabinoids and terpene constituents in products is essential for users, and especially patients, to mitigate unexpected effects.8

For this reason, USP proposed that cannabis species inflorescence must be labeled with the name and amount of any cannabinoid present in an amount of 10 mg/g or more. Further, USP specifies in the monograph that the content must be not less than 80% and not more than 120% of the labelled amount of cannabinoids measured in mg/g. This levels the playing field for cannabis processors, as some states have set more narrow standards for in-state dispensaries, such as +/-10%, which has required in-state cannabis processors to comply with rules twice as strict as the US pharmaceutical industry.1

In the current proposed monograph, USP establishes standardized ration expressing THC:CBD in a consistent order as well. This alone is a major step in patient safety with regard to inconsistent labelling that may confuse patients, with examples leading to unintended adverse effects. Further, USP stipulates that the label must indicate the cultivar using the USP defined definitions for THC-dominant, CBD-dominant, or THC/CBD intermediate (See Table 3).1 Additionally, the label must state the dominant cannabinoid and the codominant terpene, with the microbial information also required in specific instances.1

Microbial and Chemical Contaminants

While all states with regulated cannabis production have some regulations speaking to microbial contamination, significant variability can exist due to the multitude of microorganisms that can be present. For acceptable limits of aerobic bacteria, bile-tolerant gram-negative, and total yeast and mold, some states are prescriptive for its components, while other states only provide limits (or note that it must be undetectable) for specific pathogenic organisms such as Salmonella, Aspergillus, Pseudomona aeruginosa.1

More than 25 states define total yeast and mold colony forming units per gram (cfu/g) of cannabis material, and more than 10 states specifically highlight microbial limits for inhalation formulations. However, Colorado, Oklahoma, and Virginia go further by defining microbial contamination levels for vaginal suppositories.1

USP adopts thresholds pulled from its current standards, such as Microbial Enumeration Tests <61>. According to this established standard, the total aerobic bacterial count is not more than (NMT) 105 cfu/g (100,000 cfu/g), and the total combined molds and yeasts count should be NMT 104 cfu/g (10,000 cfu/g). Additionally, USP highlights Chapter <1111> which employs more stringent requirements, with aerobic bacterial NMT 102 cfu/g (100 cfu/g) and the total combined molds and yeasts count NMT 101 cfu/g (10 cfu/g) to “indicate to healthcare practitioners and patients that such products (particularly for inhalation products) have a reduced microbial load” (See Table 4).1

Industry members have made formal requests to increase the leniency in specific state’s regulations, including requests not to have labelling that will disclose if a product has undergone “microbial remediation.” Currently, USP requires that the label must indicate whether the product has been treated to reduce the microbial load and the method used so that patients can make informed decisions.1

Pesticide Contamination

However, USP notably does not thoroughly tackle pesticide contamination and instead requires conformation with “the relevant regulatory body requirements.” Technically, it is within the scope of US Environmental Protection Agency (EPA) to define this type of contamination, as granted by the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) of 1996. Further, the current state of contamination is concerning, with cumulative data from 15 labs across 13 states detecting 80 different pesticides in cannabis flower samples. Specifically, 29 pesticides were detected in cannabis flower samples from 3 or more states.14 Even illegal synthetic cannabis products have documented contamination, most notably brodifacoum, the vitamin K antagonist in rodenticide. Currently, the EPA does not have any pesticides registered specifically for use on cannabis, but labeling for use on industrial hemp has emerged.9

Arguably, contaminants on cannabis should be evaluated both from the perspective of the formulation and route of administration. Due to a lack of current federal guidance, pesticide and insecticide regulation vary by state, with their threshold of acceptability swinging significantly in magnitude. While the wide range of acceptable limits of chemical contamination is partly due to a lack of clear scientific information, one study identified that on average the action levels for top 50 pesticides were “32-fold higher than the most stringent tolerances for food commodities by the US EPA.”9

At least 6 states have adopted the EPA’s pesticide residue action levels for food commodities, which is a good start but does not adequately address the effects of inhalation nor processing and incineration. Consider the pesticide myclobutanil, which is concentrated during specific cannabis extractions, and undergoes toxic transformation to hydrogen cyanide upon pyrolysis. For these reasons, there is much left to understand regarding the impact of each pesticide on patient health, with research currently ongoing to better understand the negative health effects these chemicals can impart.9

Notably, despite a lack of thorough analysis in this area, the USP does note that “the limits for contaminants in cannabis—including pesticide residues, microbial load, aflatoxin levels and elemental contaminants—should be based on scientific considerations.” Further, USP highlights the applicability of USP General Chapter <232> on Elemental Impurities - Limits and USP General Chapter <561> Articles of Botanical Origin, with specific elemental impurities acceptance criteria provided for arsenic (NMT 0.2 µg/g), cadmium (NMT 0.3 µg/g), lead (NMT 0.5 µg/g), and mercury (NMT 0.1 µg/g).1

USP Improving Cannabis Quality from the Past to Present

The data presented by USP in this monograph establishes a significant step forward in the advancement of potency analysis since the “physiologic assays” employed by USP over 100 years ago. USP, which was founded in 1820 by a group of physicians seeking to establish quality and consistency of medicinal products, established that potency of cannabis would be tested on dogs, and then based on the dogs’ physiologic response, the product would be diluted.11

While cannabis was only noted in USP’s 1851 version (3rd edition) without additional expansion on prior standards, the 1882 version does show an expansion of the medical uses of cannabis, including the discovery of different species of cannabis and procedures for fluid extraction and tincture formulations.11,12 Following this, USP noted that biologic assays performed on dogs would be required to analyze all fluid extracts and tinctures of cannabis in the 9th edition published in 1916, arguably indicating this time as a high point of medical cannabis use in the United States.13

Furthermore, the 9th edition details the specific dosages for assays on dogs: Dogs should receive fluid extracts that are not more than 0.03 mL/kg and tinctures that are not more than 0.3 mL/kg of preparation. This practice, which helped ascertain the dose of preparation needed to produce the desired “muscular incoordination” effect without overt toxicity, was designed to confirm the appropriate strength of the product made.13

Further, USP outlined in the 1916 edition that there was a significant difference in response to the drug based on the breed of dog. USP had determined that fox terriers were particularly susceptible to the effects of cannabis, making them a better marker for efficacy and safety in a biological assay than other breeds.13

This USP edition detailed other interesting controls to employ as well for these assays using dogs, such as waiting at least an hour after dosing, maintaining a quiet and controlled room environment, and ensuring the person conducting the test knew the animal well. The USP even detailed that the dogs could be reused in subsequent biological assay studies as long as it was at least 3 days apart due to the development of drug tolerance.13 Then, in the 12th edition published in 1940, cannabis extract was dismissed from the USP monograph.

Over a century old, these prior standards for cannabis assays outline the importance of standardization of cannabis alongside other pharmaceuticals. Additionally, accurate characterization of drugs is also necessary for their safe use. However, medical research on cannabis that could support its characterization has suffered due to federal prohibition that limits the scope and methods of these studies. Further, lack of quality standards inhibits the ability to aggregate data due to product variability in the studies that are successfully conducted.

In 1887, physician Hobart Amory Hare, MD, outlined the critical role that cannabis plays in combatting all forms of pain in the Therapeutic Gazette. He specifically highlighted the critical role of the indica strain for this purpose.10

“Cannabis indica has been in the profession for many years as a remedy to be used in combating almost all forms of pain, yet, owing to the variations found to exist as to its activity, it has not received the confidence which I think it now deserves,” Hare wrote. “At present certain improvements made in the method of obtaining the extract from the crude drug have very materially increased its reliability, so that by selecting an article made by a responsible firm we may be fairly sure of receiving a preparation in which we can place confidence.”10

Notably, Hare mentions the need for quality regulations and oversight for cannabis in 1887.10 With the release of the USP’s proposed monograph this year, perhaps USP’s efforts to champion cannabis quality standards in January 2023 will bring Hare’s hopes to fruition.

About the Authors

Christine Roussel, PharmD, BCOP, BCSCP, is the senior executive director of Pharmacy, Laboratory and Medical Research at Doylestown Health in Doylestown, Pennsylvania. While Roussel is currently appointed the Commonwealth of Pennsylvania’s Board of Pharmacy and Medical Marijuana Advisory Board, the views expressed in this article are her own and do not reflect on her appointed roles within the Commonwealth.

Megan Schwartz, BS, PharmD Candidate 2024, has a BS in Pharmaceutical Sciences and is a PharmD student at the University of Pittsburgh School of Pharmacy in Pittsburgh, Pennsylvania.

References

  1. Cannabis Species Inflorescence Proposed for Comment Version 0.1. Herbal Medicines Compendium. Sep 21, 2022. https://hmc.usp.org/monographs/cannabis-species-inflorescence-0-1
  2. US Capitol Visitor Center. The Pure Food and Drug Act. US Capitol Visitor Center website. Accessed February 16, 2023. https://www.visitthecapitol.gov/exhibitions/congress-and-progressive-era/pure-food-and-drug-act
  3. USP. USP and FDA Working Together to Protect Public Health. USP website. Accessed February 16, 2023.https://www.usp.org/public-policy/usp-fda-roles#:~:text=FDA%20and%20USP%20work%20together,more%20efficient%20standards%20development%20process
  4. Sarma ND, Waye A, ElSohly MA, et al. Cannabis Inflorescence for Medical Purposes: USP Considerations for Quality Attributes. Journal of Natural Products. 2020;83(4):1334–1351. doi:10.1021/acs.jnatprod.9b01200
  5. FDA. FDA Concludes that Existing Regulatory Frameworks for Foods and Supplements are Not Appropriate for Cannabidiol, Will Work with Congress on a New Way Forward. FDA website. January 26, 2023. Accessed February 16, 2023. https://www.fda.gov/news-events/press-announcements/fda-concludes-existing-regulatory-frameworks-foods-and-supplements-are-not-appropriate-cannabidiol
  6. DEA. Drug Scheduling. DEA website. Accessed January 26, 2023. https://www.dea.gov/drug-information/drug-scheduling
  7. FDA. Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research Guidance for Industry. FDA website. January 2023. Accessed January 26, 2023. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cannabis-and-cannabis-derived-compounds-quality-considerations-clinical-research-guidance-industry
  8. Schwabe A and McGlaughlin M. Genetic tools weed out misconceptions of strain reliability in Cannabis sativa: implications for a budding industry. J Cannabis Res. 2019;1,3. doi:10.1186/s42238-019-0001-1
  9. Pinkhasova D, Jameson LE, Conrow KD, et al. Regulatory status of pesticide residues in cannabis: Implications to medical use in neurological diseases. Current Research in Toxicology 2. 2021;140-148.
  10. Clinical & Physiological Notes on the action of Cannabis Indica. Therapeutic Gazette. Vol. II, 1887, pp225-228. Reprinted in Mikuriya TH. Marijuana: Medical Papers 1839-1972. V.1, Nevada City, CA: Symposium Publishing; 2007.
  11. The Pharmacopoeia of the United States of American (3rd Edition, 1851); http://antiquecannabisbook.com/Appendix/USP1851.htm
  12. The Pharmacopoeia of the United States of American, Sixth Decennial Revision (1882); http://antiquecannabisbook.com/Appendix/USP1882.htm
  13. The Pharmacopoeia of the United States of American, Ninth Decennial Revision (1916); http://antiquecannabisbook.com/Appendix/USP1916.htm
  14. National Cannabis Laboratory Council (NCLC). Standardizing Cannabis Lab Testing Nationally. NCLC website. 2022. Accessed February 16, 2023. https://www.perkinscoie.com/images/content/2/5/253590/Standardizing-Cannabis-Lab-Testing-Nationally-FINAL-7-1-1.pdf
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