Medical cannabis: from definition to strict quality control

The enactment of Law of Ukraine No. 3528-IX laid the legal foundations for the integration of cannabis-based medicines into medical practice. This law has completely removed cannabis, its resin, extracts and tinctures from the list of particularly dangerous substances, placing them under strict medical control. 

In this article, we explore why this decision is important, how GACP, GMP and laboratory quality control are linked in this field, and which analytical methods are used to assess products.

Medical cannabis refers to the plant material or preparations derived from it, which are used exclusively on the advice of a doctor to alleviate the symptoms of serious illnesses. Unlike recreational cannabis, medical cannabis is subject to strict state supervision and laboratory control in accordance with the standards of Good Agricultural and Collection Practices (GACP) and Good Manufacturing Practices (GMP).

Medical cannabis contains over 100 unique chemical compounds — cannabinoids. The main ones are CBD (cannabidiol), which has no psychoactive effect and reduces inflammation, and THC (tetrahydrocannabinol), which relieves pain but has a psychoactive effect. In Ukraine, medical cannabis is defined as dried plants with a THC content of 0.3 per cent or more. Medicines based on it are produced in the form of oils, capsules, tinctures or dried inflorescences for inhalation using medical vaporisers.

As cannabis-based medicines are prescribed to patients with severe and chronic conditions, compromises regarding safety and dosage accuracy are unacceptable.

Unlike standardised synthetic substances, plant-based raw materials are characterised by natural variability in their composition. The content of THC, CBD and other components may depend on the plant’s genetics, cultivation conditions, and the timing of harvesting, drying, processing and storage. Furthermore, plant-based raw materials may contain undesirable impurities — pesticide residues, heavy metals, microorganisms and other contaminants.

Laboratory testing of medical cannabis must therefore fulfil several objectives simultaneously: 

It is precisely for this reason that pharmacopoeial requirements stipulate the monitoring of key parameters — the cannabinoid profile, CBN, loss on drying, elemental impurities, pesticide residues, aflatoxin B1 and microbiological quality. Monitoring these parameters makes it possible to confirm that the herbal substance or medicinal product complies with the established specifications and can ensure predictable quality and safety for the patient.

Laboratory analysis and quality control are carried out during the harvesting of plant-based raw materials (GACP standard) and directly during the production of batches of finished medicinal products (GMP standard).

Pharmacopoeial analysis involves the use of validated methods and suitably qualified laboratory equipment. The choice of analytical method depends on the parameter being monitored: liquid chromatography is used for the quantitative analysis of cannabinoids, mass spectrometry for trace impurities, and for microbiological control, culture-based and molecular methods are used. The main instrumental methods are:

HPLC is used as the reference standard for the quantitative determination of cannabinoids. The advantage of HPLC-UV / HPLC with diode array detection (HPLC-UV / HPLC-PDA) is that separation takes place at room temperature. This allows the acidic forms of cannabinoids (THCA and CBDA) to be distinguished from their neutral decarboxylated forms (THC and CBD), which is critical for the accurate calculation of drug doses during routine monitoring.

LC-MS/MS is a highly efficient and practical method for the highly selective multi-residue analysis of pesticides and mycotoxins at trace levels. The cannabis plant matrix is extremely complex due to its high content of resins, waxes and terpenes. Thanks to the multiple reaction monitoring (MRM) mode, the tandem mass spectrometer completely filters out the plant’s background ‘noise’ and enables the detection of trace amounts (at parts per billion, ppb) of the most complex pesticides and mycotoxins (aflatoxins B1, B2, G1, G2, ochratoxin A).

LC-MS/MS is also widely used in clinical practice for toxicology and bioanalysis — the determination of microconcentrations of THC, CBD and their metabolites (11-OH-THC, THC-COOH) in patients’ plasma or urine, as well as for the precise separation of isomers and impurities with similar molecular weights.

Due to the high volatility of terpenes and residual solvents, gas chromatography with mass spectrometric detection (GC-MS / GC-MS) is the primary tool for establishing a terpene profile (determination of myrcene, limonene and pinene) and for detecting ultra-trace amounts of pesticide residues and organic solvents used during extraction.

ICP-MS is used for highly sensitive quantitative analysis of heavy metals. The method enables the determination of toxic elements with an accuracy of parts per billion (ppb), thereby ensuring the complete toxicological safety of the finished products.

These are used in parallel for microbiological monitoring. Conventional culture determines the total number of viable aerobic microorganisms (TAMC) and moulds (TYMC). PCR is used for the rapid detection of DNA from specific pathogens, such as toxin-producing fungi of the genus Aspergillus (A. fumigatus, A. flavus).

For analytical chemists and laboratory technicians, working with medical cannabis requires rigorous validation of analytical methods and daily reporting to the state record-keeping system. For an accredited laboratory, traceability of results, documented quality control procedures and proper management of analytical data are essential.  For doctors and hospital pharmacists, the availability of a detailed Certificate of Analysis (CoA), confirming the exact THC/CBD and purity in accordance with European standards using HPLC and HPLC-MS/MS methods, is a vital component of assessing patient safety before commencing treatment.

Waters Corporation’s comprehensive solutions for cannabis quality control

To minimise risks when validating analytical methods and implementing the requirements of the European Pharmacopoeia, quality control laboratories use off-the-shelf hardware and software packages and specialised laboratory equipment. One of the recognised global benchmarks in this field is the equipment from Waters Corporation, which covers the full range of analyses:

To detect pesticide residues and mould metabolites (aflatoxins) in the extremely complex plant matrix, Waters supplies tandem mass spectrometry systems:

The most important component for laboratories licensed by the State Service of Ukraine on Medicines and Medical Devices is the Empower Chromatography Data Software. It fully complies with strict data integrity criteria, the requirements of FDA 21 CFR Part 11 and GMP standards. The system records every step taken by the analyst (Audit Trail), ensuring the traceability of changes and reducing the risk of unauthorised or accidental deletion or alteration of the results of drug testing.

The legalisation of medical cannabis in Ukraine under Law No. 3528-IX is a historic step for Ukrainian medicine, one which places an enormous responsibility on the laboratory and pharmaceutical sectors. 

The implementation of the stringent requirements of the European Pharmacopoeia (Ph. Eur.) requires Ukrainian laboratories to use modern analytical methods.  Instrumentation – ranging from liquid chromatography systems to HPLC-MS/MS and GC-MS/MS systems from laboratory equipment manufacturers such as Waters Corporation – enables a comprehensive approach to quality control.  Waters’ comprehensive analytical solutions guarantee:

Thus, establishing a transparent ‘seed-to-patient’ quality control system based on international technological standards is the only reliable foundation for building trust within the medical community and ensuring safe treatment for Ukrainian patients.