Quality Standards for Medical Cannabis - Update on Pharmacopoeial Monographs
Currently there is a growing interest in the use of medical Cannabis in the global healthcare sector. Thus, comprehensive quality standards and regulatory measures for these natural substances are needed. In Europe, several national pharmacopoeial monographs for Cannabis Flower (e.g. Germany (Deutsches Arzneibuch, DAB), Denmark, Switzerland (Ph. Helv.) and Cannabis Extracts (DAB) exist. However, these monographs are currently not harmonized and differences in the quality requirements still exist. Therefore, compendial monographs, like, for example, in the United States Pharmacopeia (USP) and in the European Pharmacopoeia (Ph. Eur.), would be very helpful for defining harmonized quality requirements and for facilitating the release and distribution of medical Cannabis on a global market. Recently, the USP and the Ph. Eur. published several draft monographs for medical Cannabis and CBD (Cannabidiol). This article provides a short overview of the issued draft monographs.
USP, Ph. Eur. and FDA
The Ph. Eur., the USP and the FDA recently published the following guidelines and pharmacopoeial monographs:
- FDA's Guidance on Quality Considerations for Clinical Research with Cannabis (final)
- Ph. Eur. Cannabis Flower Monograph (draft published in Pharmeuropa 34.4)1
- USP HMC Cannabis Flower Monograph (draft published in USP´s Herbal Medicines Compendium)2
- Ph. Eur. Monograph for CBD (draft published in Pharmeuropa 34.3)1
- USP Monograph for CBD (draft published in Pharmacopeial Forum (PF) 48.1)
- USP <1568> Quality Considerations for Cannabis and Cannabis-Derived Products for Clinical Research (draft published in Pharmacopeial Forum (PF) 49.3)
Cannabis Flower Monographs
As cannabis is a heterogeneous matrix, appropriate sampling procedures, as well as tests, analytical procedures, and acceptance criteria to define the identity, content of constituents (e.g., cannabinoids), and limits for contaminants are required. According to the USP draft chapter <1568> (and the USP HMC draft), three main cannabis chemotypes (with specific Cannabinoid Acceptance Criteria) have been identified as useful for labeling purposes based on the following cannabinoid constituents:
- Tetrahydrocannabinol (THC)-dominant
- THC / CBD (Cannabidiol) intermediate
Cannabis plants in each of these chemotypes could be further sub-categorized based on the content of other cannabinoids and/or terpene profiles. In addition, morphologic and chromatographic tests are provided for the identification and quantitative determination of critical constituents.
Limits for loss on drying (LOD) and correction of cannabinoid content for moisture content are not included in the USP proposal, to avoid potential inflation of cannabinoid content expression by dry weight. In order to control the water available to microbes in the Cannabis flower to prevent microbial growth, the water activity should be controlled at 0.60 ± 0.05. The proposed limit for (other) foreign organic matter (e.g., seeds) is max. 2 % (max. 5 % of the sample consists of Cannabis species inflorescence stems of 3 mm of more in diameter). In addition, the total ash should be max. 20.0 % and acid-insoluble ash should be max. 4.0 %.
Heidelberg, Germany18/19 June 2024
GMP and Quality Requirements for Radiopharmaceuticals
Limits for contaminants (e.g., pesticide residues, microbial contaminants, mycotoxins, and elemental impurities) are presented based on toxicological considerations and aligned with the existing USP procedures for general tests and assays (provided in USP chapter <561> Articles of Botanical Origin). Considering the potential inhalation use of Cannabis, the following acceptance criteria for heavy metals are proposed:
- Arsenic: max.0.2 ppm
- Cadmium: max. 0.2 ppm (USP HMC: 0.3 ppm)
- Lead: max. 0.5 ppm
- Mercury: max. 0.1 ppm
Moreover, the Appendix of the proposed USP chapter <1568> provides useful photos of the following:
- Macroscopic and microscopic characteristics of Cannabis flower,
- HPTLC / HPLC profiles of cannabinoids,
- Fingerprints of the three cannabis chemotypes before and after decarboxylation,
- Commonly observed dominant and co-dominant terpenes in commercial Cannabis flower.
The Ph. Eur. (draft) Cannabis flower monograph includes specific requirements (including specific Cannabinoid Acceptance Criteria) for the following 3 chemotypes:
- High THC type (THC-dominant type)1
- THC/CBD type (THC/CBD-intermediate type)1
- High CBD type (CBD-dominant type)1
However, in contrast to the proposed USP monographs no requirements for terpenes are included.
The suggested limit for loss on drying (Ph. Eur. 2.2.32) was max. 10.0 (finally 12.0)1 % and max. 2 % for foreign matter (Ph. Eur. 2.8.2). If the herbal drug is to be prescribed to patients, it does not contain any seeds and the whole herbal drug does not contain any leaves more than 1.0 cm in length.
The limits for heavy metals (Ph. Eur. 2.4.27) if the herbal drug is to be prescribed to patients as a medicinal product1 are significantly lower compared to those provided in the general Ph. Eur. monograph Herbal Drugs (presumably due to the potential inhalation use). But, they are aligned with the limits proposed in the USP HMC monograph. Regarding other contaminants, like, for example, mycotoxins (according to Ph. Eur. 2.8.18 for Aflatoxins), pesticides (Ph. Eur. 2.8.13) and microbiological quality (i.e., according to Ph. Eur. 5.1.8 or 5.1.4, depending on the route of administration), it is still required to refer to the general Ph. Eur. monograph Herbal Drugs.
Update on the German Pharmacopoeia (Deutsches Arzneibuch, DAB)
Growers and importers of cannabis flowers have reported to the BfArM (German Federal Institute for Drugs and Medical Devices) that, in particular with low cannabinoid contents (i.e. CBD and THC), the specification requirements of the DAB (Deutsches Arzneibuch, German Pharmacopoeia) Monograph Cannabis Flower cannot be met. It was stated "that too many individual factors in cultivation that cannot be directly controlled influence the result".
As a compromise solution, in regard of applications for the
- Authorization of a treatment with ionizing radiation according to AMRadV
- Granting of a License according to the BtMG (German Narcotics Law)
the BfArM has now developed a specification for cannabis flowers as "dispensing drug", which in the opinion of the BfArM should be acceptable for growers and importers. For the aforementioned applications and permits, the following approaches for cannabis flowers as "dispensing drug" for use in magistral preparations are accepted:
- For contents > 15.0%, the existing DAB approach of +/- 10% (relative) will continue to apply.
- For contents < 15.0%, an absolute deviation of +/- 1.5% is accepted.
Microbiological Quality - Does Heating in a Vaporizer Reduce the Microbial Load?
There is currently an ongoing discussion about the microbiological quality requirements for medical Cannabis depending on the route of administration. In this context, certain microbial requirements were proposed in the USP Herbal Medicines Compendium draft monograph Cannabis Species Inflorescence published last year2. These include, e.g., requirements for oral use, more strict requirements for inhalation use, as well as special requirements for vulnerable user groups, such as immunosuppressed patients. However, there are currently no specific microbial limits provided in the Ph. Eur. draft monograph for Cannabis flower. To proceed with this question authors from the FDA recently published an article about a microbiological study of bulk Cannabis in the Journal Frontiers in Cellular and Infection Microbiology (13 January 2023, Volume 12 - 2022).
The authors conclude the following:
- Heating of the cannabis materials using standard vaporization parameters of 70 seconds at 190°C (settings suggested by the manufacturer) did not lead to significant reductions of the existing microbial bioburden.
- The findings demonstrate that heating with a vaporizer may not be considered effective to limit microbial risks associated with inhaled cannabis use.
- Other decontamination methods, such as gamma irradiation, ultraviolet germicidal irradiation or pasteurization may thus be needed to limit microbial contamination in Cannabis.
Cannabidiol (CBD) Monographs
The USP already contains the two official monographs Dronabinol and Dronabinol Capsules. However, there is currently no existing USP monograph for Cannabidiol (CBD).
According to the USP, the proposed CBD monograph aims to provide specifications for highly purified CBD from Cannabis sativa. In order to differentiate the naturally derived CBD from synthetically derived CBD potential synthetic substances (e.g., Olivetol, 4-Monobromo-CBD) are included in the tests for organic impurities besides the natural impurities (like Cannabinol (CBN), for example). Interested stakeholders were invited to comment whether these specifications need any changes to appropriately define the quality of CBD (e.g., whether additional impurities should be considered).
In addition, there is a German CBD DAC (Deutscher Arzneimittel Codex) monograph available. The DAC/NRF is a national formulary used in German pharmacies. It also includes CBD preparations, Cannabis flower “preparations” (e.g. for inhalation use or for tea preparation), Dronabinol preparations etc. The pharmacist can prepare these dosage forms for patients on prescription ("Formula officinalis"). The DAC CBD monograph states that CBD is obtained from flowers and leaves of Cannabis sativa L. from controlled cultivation, by synthesis or fermentation.
The Ph. Eur. draft CBD Monograph defines that CBD is isolated from natural sources1. For comparison: The USP draft monograph defines that CBD is obtained from Cannabis sativa. The proposed limit for impurities (total) is: max. 0.8 per cent (USP CBD draft monograph: max. 2.0 per cent; DAC CBD monograph: max. 0.5 per cent).
Need for Harmonization
There are still some important distinctions between the available (draft) monographs for Cannabis Flower and Cannabis-derived substances like CBD. The USP's draft monograph specifies that CBD should be derived from Cannabis sativa, while the Ph. Eur. draft proposes a more generic source, stating that CBD should be isolated from natural sources1. The DAC monograph offers another perspective, describing CBD as a product obtained from flowers and leaves of controlled cultivation of Cannabis sativa L., either by synthesis or fermentation. The quality standards set by the pharmacopoeias also differ when it comes to the stipulated limits for impurities in CBD. Such variations underscore the need for harmonized global standards, given that these quality parameters play a crucial role in the safety and efficacy of CBD.
On the other hand, the Ph. Eur.'s draft monograph for Cannabis Flower doesn't prescribe any requirements for terpenes, unlike the proposed USP HMC monograph2. Terpenes, aromatic compounds found in cannabis and other plants, contribute to the characteristic odor of cannabis and are thought to have potential therapeutic benefits. The omission of terpenes in the Ph. Eur. draft monograph again emphasizes the differing focus areas and approaches across these pharmacopoeias. Moreover, the USP and Ph. Eur. draft monographs propose different Cannabinoid Acceptance Criteria (for THC/CBD, including CBN limit) for each of the three mentioned chemotypes. In comparison to the Ph. Eur. draft monograph, the proposed USP monographs do not include a limit for loss on drying (LOD). Instead, the water activity should be controlled in order to prevent microbial growth.
Another area of discrepancy across these monographs involves the provisions for microbial and pesticide contamination and the presence of mycotoxins in cannabis-based medicinal products. In these areas, the Ph. Eur. draft Cannabis flower monograph still directs the user to refer to the general monograph on Herbal Drugs. However, all mentioned (draft) monographs do currently not include an explicit requirement to test for Ochratoxins and there are also no proposed specific limits for Ochratoxins in medical cannabis.
The challenges of harmonizing the quality requirements across different countries and regulatory bodies still exist. Moving forward, it's clear that ongoing dialogue, collaboration, and the sharing of scientific research will be crucial in creating a consistent, global framework that ensures the safety and efficacy of medical cannabis.
1 The EDQM recently announced that the final Ph. Eur. Monographs for Cannabis flower and CBD, isolated from the Cannabis sativa L. plant, will be published in European Pharmacopoeia (Ph. Eur.) Supplement 11.5 (January 2024), with an implementation date of 1 July 2024. Due to the exceptionally high interest from stakeholders the EDQM pre-published the final text of the Ph. Eur. Cannabis flower Monograph in October 2023.
2 Based on the comments received, the USP Herbal Medicines Compendium (HMC) published a revised version of the previously proposed Cannabis Species Inflorescence monograph in August 2023. The comment end date was 1 November 2023. In the revised version terpenes are know mentioned only as constituents of interest.
Dr Andrea Kühn-Hebecker
... is Operations Director and organizes and conducts courses and conferences on behalf of the ECA Academy in the area packaging, herbal medicinal products, development and lifecycle management.