FDA, USP Advance Standardization, Regulation of Cannabis Nationally

The US Pharmacopeial Convention (USP) is championing cannabis quality standards with a new cannabis monograph that recently closed for public comment.¹ USP’s first cannabis monograph was published in 1851, but after continued development in subsequent editions, a reference to cannabis was last published in the US Pharmacopeia (USP) in 1936 because of regulator prohibition.¹ With a lack of federal standards for cannabis, state legislative initiatives and subsequent promulgation of state regulation have led to a heterogeneity of standards, ranging from patient safety considerations around labeling to acceptable microbial contamination levels.² “As part of the safety net that protects and promotes public health in the United States, USP is taking steps to prevent harm to patients resulting from exposure to substandard, superpotent, contaminated, or adulterated cannabis for medical use under state law,” the authors wrote 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. Although 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, chemical decarboxylation, extraction, and sample preparation, clinicians will likely find the codified terminology, labeling standards, standardization of potency, and contamination as noteworthy improvements in patient safety (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 (FDCA). Although the hemp and cannabis industries try to get established outside of the DEA Schedule I drug status, the conflict with state and federal laws have led to various interpretations of whether different products comply with and could be defined as food, dietary supplements, or drugs. The USP is working to support the FDA in the quality of cannabis for medicinal use.^3-6

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 publica-tion 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 FDA. Further, the act also deemed the USP and the National Formulary official compendia under federal law.³

In 1938, the FDCA was 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 stan-dards for medicines and made USP standards binding for dietary supplement manufacturers that label their products as USP compliant.³ Further, the FDA has incor-porated 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 the role of cannabis as a medicine that requires the same oversight as other medicines in the supply chain.^3,5

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,” the 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 the FDA through the new drug application [NDA] or abbreviated new drug application [ANDA] process, or (2) for certain [OTC] 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 Janet Woodcock, MD, principal deputy commissioner, 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, because 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 Labeling

For the proposed monograph, USP declares that it subscribes to the opinion that cannabis consists of 1 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 (Cannabis ruderalis would be included, although whether it is extinct remains under debate).¹

In the language of the monograph, USP leaves the door open, stating that 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,” the USP wrote.¹

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

USP lists constituents of interest, including 14 cannabinoids and 5 terpenes, for the purpose of appropriate labeling (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 cannabinoid 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 (NMT) 120% of the labeled amount of cannabinoids measured in mg/g. This levels the playing field for cannabis processors, because some states have set more narrow standards for in-state dispensaries, such as plus or minus 10%, which has required in-state cannabis processors to comply with rules twice as strict as the US pharmaceutical industry (FIGURE 2).^1,4

In the current proposed monograph, USP also establishes a standardized ratio expressing THC:CBD in a consistent order. This alone is a major step in patient safety with regard to inconsistent labeling 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 (TABLE 3).¹ Additionally, the label must state the dominant cannabinoid and the codominant terpene, with the microbial information also required in specific instances.

Microbial and Chemical Contaminants

Although all states with regulated cannabis production have some regulations speaking to microbial contamination, significant variability can exist becauseof the multitude of microorganisms that can be present. For acceptable limits of aerobic bacteria, bile-tolerant gram-negative bacteria, and total yeast and mold, some states are prescriptive for its components, whereas other states only provide limits (or note that it must be undetectable) for specific pathogenic organisms, such as Salmonella, Aspergillus, and Pseudomonas 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 USP <61>: “Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests.” According to this established standard, the total aerobic bacterial count is 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 USP <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 health care practitioners and patients that such products, [particularly for inhalation products], have a reduced microbial load” (TABLE 4).¹

Industry members have made formal requests to increase the leniency in specific states’ regulations, including requests not to have labeling that will disclose whether 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 patients can make informed decisions.¹

Pesticide Contamination

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 the US Environmental Protection Agency (EPA) to define this type of contamination, as granted by the Federal Insecticide, Fungicide, and Rodenticide Act of 1996. Further, the current state of contamination is concerning, with cumulative data from 15 laboratories 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.⁹ 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.¹⁰

Arguably, contaminants on cannabis should be evaluated both from the perspective of the formulation and route of administration. Because of a lack of current federal guidance, pesticide and insecticide regulation vary by state, with their threshold of acceptability swinging significantly in magnitude. Although 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 the top 50 pesticides were “32-fold higher than the most stringent tolerances for food commodities by the US EPA.”¹⁰

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 or processing and incineration. Consider myclobutanil: This pesticide 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.¹⁰

Notably, despite a lack of thorough analysis in this area, 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.”¹ Further, USP highlights the applicability of USP <232>: “Elemental Impurities—Limits” and USP <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 Past to Present

The data presented by USP in this monograph establish a significant step forward in the advancement of potency analysis since the “physiologic assays” employed by the organization more than 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.¹²

Although cannabis was only noted in USP’s 1851 version 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.^12,13 Following this, USP noted that biologic assays performed on dogs would be required to analyze all fluid extracts and tinctures of cannabis in the ninth edition published in 1916, arguably indicating this time as a high point of medical cannabis use in the United States.¹⁴

Furthermore, the ninth edition details the specific doses for assays on dogs: Dogs should receive fluid extracts that are NMT 0.03 mL/kg and tinctures that are NMT 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.¹⁴

Further, USP outlined in the 1916 version 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 abiological assay than other breeds.¹⁴

This USP edition also detailed other interesting controls to employ 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. USP even detailed that the dogs could participate in subsequent biological assay studies as long as it was at least 3 days apart because of the development of drug tolerance.¹⁴ Then, cannabis extract was dismissed from the USP monograph in the 12th edition published in 1940.

These prior standards for cannabis assays are more than a century old and 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 because of federal prohibition that limits the scope and methods of these studies. Further, lack of quality standards inhibits the ability to aggregate data because of product variability in the studies that are successfully conducted.

In 1887, physician Hobart Amory Hare, MD, outlined the critical role that cannabis plays in combating all forms of pain in the Therapeutic Gazette. He specifically highlighted the critical role of the indica strain for this purpose.¹¹

“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 [that] 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.”¹¹

Notably, Hare mentions the need for quality regulations and oversight for cannabis in 1887. With the release of the USP’s proposed monograph, perhaps USP’s efforts to champion cannabis quality standards in 2023 will bring Hare’s hopes to fruition.

References

1. Cannabis Species Inflorescence Proposed for Comment Version 0.1. Herbal Medicines Compendium. Sep 21, 2022. Accessed February 16, 2023. https://hmc.usp.org/monographs/cannabis-species-inflorescence-0-1
2. The Pure Food and Drug Act. US Capitol Visitor Center. Accessed February 16, 2023. https://www.visitthecapitol.gov/exhibitions/congress-and-progressive-era/pure-food-and-drug-act
3. USP and FDA working together to protect public health. USP. 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. J Nat Prod. 2020;83(4):1334-1351. doi:10.1021/acs.jnatprod.9b01200
5. 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. 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. Drug scheduling. United States Drug Enforcement Administration. Accessed January 26, 2023. https://www.dea.gov/drug-information/drug-scheduling
7. Cannabis and cannabis-derived compounds: quality considerations for clinical research guidance for industry. FDA. January 24, 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 AL, McGlaughlin ME. Genetic tools weed out misconceptions of strain reliability in Cannabis sativa: implications for a budding industry. J Cannabis Res.2019;1(1):3. doi:10.1186/s42238-019-0001-1
9. Standardizing cannabis lab testing nationally. National Cannabis Laboratory Council. Accessed February 16, 2023. https://www.perkinscoie.com/images/content/2/5/253590/Standardizing-Cannabis-Lab-Testing-Nationally-FINAL-7-1-1.pdf
10. Pinkhasova DV, Jameson LE, Conrow KD, et al. Regulatory status of pesticide residues in cannabis: implications to medical use in neurological diseases. Curr Res Toxicol. 2021;2:140-148. doi:10.1016/j.crtox.2021.007
11. Hare HA. Clinical and physiological notes on the action of cannabis indica. Therapeutic Gazette. 1887;2:225-228.
12. National Medical Convention. The Pharmacopoeia of the United States of America. Third Edition. Lippincott, Grambo, & Co;1851.
13. National Convention for Revising the Pharmacopeia. The Pharmacopoeia of the United States of America. Sixth Decennial Revision. William Wood & Company; 1882.
14. United States Pharmacopeial Convention. The Pharmacopoeia of the United States of America. Ninth Decennial Revision. P Blakiston’s & Company; 1916.

About the Authors

Christine Roussel, PharmD, BCOP, BCSCP, is the senior executive director of pharmacy, laboratory, and medical research at Doylestown Health in Pennsylvania. Although Roussel is currently appointed to 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 Pennsylvania.