Cannabis and related compounds are being used in a range of research studies. This has prompted the U.S. Food and Drug Administration (FDA) to issue draft guidance on sources of cannabis, quality control for the release of cannabis products, and methods of tetrahydrocannabinol (THC) calculation, in order to assess levels of the psychoactive compound. Assessing quality for cannabis products manufactured within GMP environments is important and over the past few years, solvent residues (in the finished product), pathogenic microorganisms, and toxic heavy metals (such as from fertilizers) have each presented contamination risks and posed regulatory challenges. With the timing of the document itself, guidance is overdue, but the issuing of the document became complicated due to different positions as to the legal status of the drug at state and federal level.
The new document, issued in July 2020, is titled “Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research Guidance for Industry.” (1) There are many applications for medicinal cannabis, such as epidiolex for people with epilepsy; nabilone for chemotherapy patients; nabiximols for multiple sclerosis; and for the treatment of long-term pain.
In setting out the requirements for cannabis, the document’s scope signals the wider acceptance of cannabis as a product capable of being manufactured to scale. The regulations proposed in the guidance document seek to apply the same regulatory standards to cannabis as would be applied to any other botanical raw material, botanical drug substance, or botanical drug product.
The first section of guidance looks at cannabis sources. Taking a legal position, the guidance notes that the cannabis source must meet the requirements of the U.S. Controlled Substances Act together with other provisions put in place by the Drug Enforcement Administration. These requirements come in to force when the cannabis material exceeds the limit of 0.3% Δ-9 THC, as assessed by dry weight. At present, in the U.S., cannabis for medical research can only be obtained from the U.S. National Institute on Drug Abuse and Drug Supply Program. Other approved sources may emerge in the future, so the guidance lays down the expectation for future approved suppliers. This classification means that hemp, at less than 0.3% (delta) Δ-9 THC, is excluded from the definition of cannabis.
The second substantial section looks at quality control. The assessment of cannabis samples that the receiving laboratory must make include chromatographic tests for the identity, quality, purity, and potency or strength. This includes assessing for dangerous levels of the solvents used in the extraction process, such as butane and propane (which tend to be favored by the less legitimate processors of the raw material). From the perspective of the recipient, aspects like aroma and flavor will form part of the release process.
In addition to chemical testing, standards for microbiological contamination must be met (2). Cannabis plants and products will be contaminated with fungi or bacteria while growing (particularly if they are grown outdoors or in a non-sanitary indoor environments) or during subsequent handling and processing. The concern is with the types of microorganisms (such as pathogenic species of the mold Aspergillus and associated aflatoxins) (3) and the population, especially where products are intended for immunocompromised patients (4).
The laboratory aspects help to push the quality aspects to process control. These means controlling each factor that comes in contact with the product during the growing and packaging processes. As with more established medicines, controlling the quality of the process controls the quality of the end product that is produced. Drawing on lessons from larger pharmaceutical operations, this is an area that can be improved through automation.
The third area considers how cannabis will be delivered to the patient, such as via an inhaler. The holding materials must not adversely affect the cannabis material (as might occur through a reaction triggering leachables or extractables). A further packaging consideration is with the integrity of the container closure system. The guidance also extends to the use of cannabis with another substance (this making it a combination medicinal product).
The fourth section looks at how the level of the cannabinoidvΔ-9 THC can be expressed. Different calculations will apply to the cannabis product in solution compared to the product in a solid oral dosage form (like a tablet). The suggested methods of assessing Δ-9 THC levels is based on the composition of the formulation with the amount of water removed. The assessment should be conducted as early as possible in the drug development process, in order to build in sufficient manufacturing controls. For example, for cannabis in solution:
- Determine the density of the liquid formulation and convert 1 mL of the formulation to mass units (mg).
- Calculate water content (in mg) of each active and excipient component present in 1 mL of the formulation.
- Sum the water content (in mg) for all components present in 1 mL of the liquid formulation and subtract this amount from the total mass of 1 mL (from step 1).
- This is the water-adjusted total mass of 1 mL of the formulation.
- Calculate the mass, or mg amount, of delta-9 THC present in 1 mL of the liquid formulation.
- Calculate the percentage delta-9 THC by dividing the mass of delta-9 THC from step 4 by the total water-adjusted mass in step 3 and multiplying by 100.
The guidance concludes with advice on generating a suitable certificate of analysis, developing appropriate analytical methods, and filing instructions. The last aspect provides information about transportation.
The new FDA guidance seeks to:
- Outline federally compliant research into cannabis and cannabis derived compounds for therapeutic and adverse effects.
- Establish a regulatory framework that treats cannabis in the same manner as other controlled substances.
- Helps to advance scientific research into cannabis.
- The guidance represents the first specific advice for the GMP environment, and compliments other more general texts such as Annex 13 of the PIC/S Guide to GMP for medicinal products (5).
- FDA (2020) Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research Guidance for Industry, July 2020, US Food and Drug Administration, Bethesda, at: https://www.regulations.gov/document?D=FDA-2020-D-1079-0001
- Cundell, T. Microbiological Attributes of Cannabis-derived Products. Cannabis Science & Technology 2(3): 6-14 2019
- Holmes M, Vyas JM, Steinbach W, McPartland J. (2015) Microbiological Safety Testing of Cannabis. Cannabis Safety Institute. http://cannabissafetyinstitute.org/wp-content/uploads/2015/06/Microbiolo...
- Bal, A., A.N. Agarwal, A. Das, S. Vikas and S.C. Varma. (2010) Chronic necrotizing pulmonary aspergillosis in a marijuana addict: a new cause of amyloidis. Pathology; 42: 197-200
- PICS (2020). PIC/S guide to GMP for medicinal products, PE009, version 02, at: https://www.tga.gov.au/sites/default/files/pe009-pics-guide-gmp-medicina...