Table of Contents
The introduction of the Cannabis Flower monograph in the latest edition of the European Pharmacopoeia (Supplement 11.5, released January 2024) marks a pivotal moment for both the pharmaceutical industry and patients seeking alternative treatments. This milestone not only legitimizes the medicinal use of Cannabis flowers but also sets a precedent for standardization and quality control in herbal medicine. With an increasing number of countries legalizing Cannabis for medical purposes, the need for a comprehensive, scientifically-backed reference standard has never been more acute. The European Pharmacopoeia’s response, the detailed Cannabis Flower monograph, provides an authoritative guide for the testing of Cannabis for therapeutic use.
A New Chapter for Cannabis Flower in the European Pharmacopoeia
Main materials/sources that were employed in the elaboration of this monograph were the national monographs in Germany, Denmark and Switzerland. The newly released Ph.Eur. monograph for cannabis flower covers the herbal drug as raw material for the production of standardized extracts, or to be taken by patients by inhalation or oral administration, prescribed as a medicinal product (prescribed as is).
Main sections of the Cannabis Flower Ph.Eur. Monograph
In the following text, we will discuss each section of the Ph.Eur. Cannabis flower monograph.
Title and Definition
The title Cannabis flower (cannabis flos) includes an established term for the herbal drug, i.e. “the flower” and a DEFINITION section where the herbal drug is described accurately.
These terms are picked very carefully as they accurately describe the herbal drug. For example, in the cannabis flower, there are thousands of fully developed female flowers (2mm long) that are found in fully developed female inflorescences.
Cannabis Flower Classification According to Ph.Eur
Content of cannabinoids (total THC / total CBD) in cannabis flowers is defined from a patient safety perspective by setting tight requirements (+/- 10 %) if the herbal drug is meant to be prescribed to patients as a medicinal product. Due to the high bioactivity of both THC and CBD, ensuring a high degree of certainty about their potency is of utmost priority.
This stringent criterion is not considered necessary if the herbal drug is utilized for extraction, as there are other elements that influence the potency of a product independent of the raw material.
THC-dominant type
In this category falls a cannabis flower that has a minimum of 5.0 per cent (dried drug) of total tetrahydrocannabinol, expressed as d9THC (delta-9 tetrahydrocannabinol). Total cannabidiol (CBD) on the other hand can go up to a maximum of 1.0 per cent (dried drug).
THC/CBD – intermediate type
For the intermediate type of cannabis flower, the limits go up to a minimum of 1.0 per cent (dried drug) for both total tetrahydrocannabinol and total cannabidiol, The ratio between these two values should be between 0.2 and 5.0, on a dried basis.
CBD-dominant type
A CBD-dominant type of cannabis flower is considered the one with minimum 5.0 per cent (dried drug) of total cannabidiol, and a maximum of 1.0 per cent (dried drug) for total tetrahydrocannabinol.
Production
Statements that are present in the Production section of the monograph for Cannabis flower draw attention to particular aspects of the manufacturing steps but are not considered necessarily exhaustive.
When describing the herbal drug, to be prescribed to patients as a medicinal product, special attention is directed to the limitation of the presence of the rachis/stalk, as it is a particular aspect of the manufacturing process (cutting the inflorescence from the rest of the plant). Additionally, an excess of rachis/stalk may make the inhalation of the heated herbal drug very unpleasant.
This part of the plant is often described based on the maximum diameter. It appears, however, prescribing the limit on the presence of rachis/stalk in cannabis flowers is not very practical.
Identification
Macroscopic Examination (Identification A)
The macroscopic identification of Cannabis Flower is to provide a clear identification through the main botanical characteristics of the herbal drug. Guide on the elaboration of monographs on herbal drugs and herbal drug preparations is a document created by EDQM that helps users of Ph.Eur. to better understand the principles behind the drafting and revision of herbal monographs.
It is important to note that leaves are not mentioned in this identification test, because they can be easily mistaken with bracts, a part of the inflorescence rich with trichomes.
There is a limitation on the quantity of leaves included in the foreign matter test, which is also mentioned in this article.
Microscopic Examination (Identification B)
The microscopic examination of Cannabis flowers, as meticulously detailed in the European Pharmacopoeia, provides an essential analytical perspective, magnifying the minute characteristics that are invisible to the naked eye.
This examination illuminates the cellular architecture of the cannabis flower, highlighting the presence of glandular trichomes that are pivotal for the synthesis and storage of cannabinoids, terpenes, and other therapeutic compounds. Specifically, it delineates the characteristics of capitate-stalked trichomes, which are large, multicellular, and contain a resin-rich secretory head, contrasted against the smaller, sessile trichomes.
The monograph also provides criteria for identifying the covering and glandular trichomes, cystolithic hairs, and the shape and size of epidermal cells and stomata. The presence of foreign matter, such as other plant species or contaminants, is also scrutinized under the microscope, to ensure the material’s purity and compliance with pharmacopeial standards.
Microscopic examination is to be performed on the milled and ground herbal drug (not sieved), using chloral hydrate solution.
HPTLC Identification (Identification C)
High-Performance Thin-Layer Chromatography (HPTLC) represents a pivotal analytical technique described in the European Pharmacopoeia for the qualitative assessment of herbal drugs and herbal drug preparations (Ph.Eur. 2.8.25), including the phytochemical constituents of Cannabis flowers.
This sophisticated chromatographic method facilitates the identification of cannabinoids, such as THC and CBD, among others, by separating them on a thin-layer chromatographic plate. The monograph details the specific conditions under which the HPTLC should be performed, including the solvent systems for the mobile phase, the visualization methods post-development, and the interpretation of the chromatogram patterns.
The interpretation of the results is narrowed down to the visualization of zones present in the obtained chromatograms of the reference solutions and the test solution.
This analysis provides a fingerprint of the chemical profile of the Cannabis sample, aiding in the detection of contaminants and the assurance of medicinal quality.
Tests Described in the Monograph
Total CBN / Assay
When it comes to the quantitative determination of cannabinoids (total CBN, total THC, total CBD), Ph.Eur. provides a very simple and convenient approach by using only one type of certified reference material (CRM). This means that CBD, CBDA, THC, THCA, CBN, and CBNA can be quantified by using cannabidiol for cannabis CRM.
All calculations for the quantitation of cannabinoids are adjusted using correction factors for each compound with reference to cannabidiol and correction factors for the ratio of the molecular mass between the acid (CBDA/THCA/CBNA) and its neutral form (CBD/THC/CBN).
Compared with the German Pharmacopoeia (DAB) where cannabinoids are quantified using CRMs for each component, covering a specific concentration range (preparing reference solutions in a minimum of six concentration points) using a calibration curve, Ph.Eur. monograph for cannabis flower presents a new approach of determining cannabinoids where preparation of reference solutions has taken into consideration the complexity of dilution (multiple concentration ranges) by using a single point external standard quantitation.
System suitability for this method is tested by running reference solution samples prepared using cannabis flower for system suitability HRS (herbal reference standard). There are two different system suitability solutions with two separate system suitability requirements for total CBN and Assay, requesting resolution and peak-to-valley ratio requirements between different cannabinoids.
Additionally, Ph.Eur has taken into consideration the availability of reference materials for cannabinoids in pure form, and the inconvenience of handling and storing reference standards commercially diluted in organic solvents.
The calculation of total cannabinol (CBN) is expressed as the sum of cannabinol (CBN) and cannabinolic acid (CBNA).
There are two main degradation processes of the components in cannabis flower:
- Thermal: Acid forms of the cannabinoids are decarboxylated to their corresponding neutral forms (d9-THCA to d9-THC; CBDA to CBD, CBNA to CBN)
- Oxidation (d9-THC to CBN)
Foreign Matter
Determination of foreign matter in cannabis flower is carried out using 25-50 g of the herbal drug. If the herbal drug is to be prescribed as a medicinal product, it should not contain any seeds and or any leaves that are more than 1.0 cm in length. Seeds and excess leaves may make the inhalation of the heated herbal drug unpleasant.
For the general application of this method, it is also recommended to abide by the general chapter 2.8.2. For the general application of this method, it is also recommended to abide by the general chapter 2.8.2. With regards to the presence of powdery mildew or other moulds, there is no specification in the monograph but following the general chapter on foreign matter (2.8.2). Producers need to perform quality risk evaluation for controlling mould according to GACP (Good Agricultural and Collection Practice).
Loss on Drying
The test for Loss on Drying, as specified in the European Pharmacopoeia for Cannabis Flowers, is designed to quantify the moisture content of the plant material. This test is conducted by accurately weighing a pre-determined amount of the Cannabis flower and then subjecting it to a specified temperature and duration in a drying oven. The loss in weight reflects the amount of moisture or volatile substances that have been evaporated.
It is also important to highlight that the test is determined on 1.000 g of cut or milled herbal drug (not sieved), by drying at a low temperature (40°C) and under a medium vacuum for 24 hours, in order to minimise the evaporation of volatile content other than due to water (e.g. essential oils, terpenes).
Test for Elemental Impurities (As, Cd, Pb, Hg)
If the herbal drug is not used as a medicinal product, the same limits apply as in the general monograph Herbal drugs (1433). Otherwise, ICH Q3D limits for Class I elements based on inhalation permitted daily exposure apply.
The tests are conducted according to Ph.Eur.’s chapter “Heavy Metals in Herbal Drugs and Fatty Oils” (2.4.27).
Tests Applicable According to the General Monograph Herbal Drugs
Under the umbrella of the European Pharmacopoeia’s ‘General Monograph Herbal Drugs’, specific tests are outlined to address universal concerns applicable to all herbal medicines, including Cannabis flowers.
Pesticides
The presence of pesticides in herbal drugs like Cannabis flowers can compromise their safety and efficacy, making this test essential for certifying the pharmacological quality of herbal medicines and protecting patients from possible adverse effects.
This test employs sophisticated analytical methods to detect and quantify trace levels of pesticides within the herbal material, ensuring they do not exceed the stringent maximum residue limits (MRLs) established to protect consumer health.
When addressing pesticides in dried herbal drugs, the requirements take into account the nature of the plant, the preparation in which the plant might be used, and where available the knowledge of the complete treatment record of the batch of the plant.
Aflatoxin B1
The European Pharmacopoeia mandates testing for aflatoxin B1 in herbal drugs due to its potent carcinogenic and mutagenic properties. Produced by the Aspergillus species of fungi, aflatoxin B1 can contaminate herbal drugs under certain conditions of storage and humidity.
According to the general monograph for Herbal drugs, where necessary, limits for aflatoxins may be required. In the general chapter “Determination of aflatoxin B1 in herbal drugs” (2.8.18) it is stated that unless otherwise indicated in the monograph, herbal drugs should contain not more than 2µg/kg of aflatoxin B1. Some national authorities may also require compliance with a limit of 4µg/kg for the sum of aflatoxins B1, B2, G1, and G2.
Generally, herbal medication batches with more than 2µg/kg of aflatoxin B1 cannot be marketed.
Microbial Contamination
For herbal drugs like Cannabis flowers, which are prone to microbial proliferation due to their natural composition and storage conditions, the Microbial Contamination test ensures that the product is free from pathogenic bacteria, yeasts, and molds. By maintaining strict microbial standards, the pharmacopoeia aims to guarantee the safety and efficacy of herbal medicines, protecting patient health from microbiological hazards.
Despite the fact that this is the first monograph on a herbal medication used for inhalation, no restrictions for microbiological contamination are specified, since users are expected to be familiar with reading chapters 5.1.8 (Microbiological quality of herbal medicinal products for oral use and extracts used in their preparation) and 5.1.4. (Microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use).
Different limits are given in these chapters depending on whether the herbal drug is intended for the preparation of infusion and decoctions using boiling water, whether the method of processing or pre-treatment reduces the levels of microorganisms to certain levels, or depending on the route of administration.
Conclusion
The release of the Cannabis Flower monograph by the European Pharmacopoeia in Supplement 11.5 marks a significant advancement in the standardization and quality control of medicinal Cannabis products. This milestone is particularly relevant for pharmacists and professionals in the pharmaceutical industry, who are now equipped with a comprehensive and authoritative framework for the testing and validation of Cannabis flowers used in medicinal preparations. The monograph not only legitimizes the medicinal use of Cannabis flowers but also establishes rigorous standards to ensure the consistency, purity, and safety of these products.
By setting clear, scientifically-backed standards for the production and testing of Cannabis flowers, the monograph not only enhances the reliability of Cannabis-based therapies but also supports the broader acceptance and integration of Cannabis into the pharmaceutical realm. This development is a critical step forward in optimizing patient care through the provision of standardized, high-quality medicinal Cannabis products.