How to Develop a Pharmaceutical Approach to Medical Cannabis Production

GMP is a compilation of procedures, standards and practices that need to be employed as part of company’s effective Quality Assurance system. GMP principles cover a broad range of areas which have a direct or indirect impact on final product’s safety, quality and efficacy. GMPs that were originally created for the pharmaceutical industry are now being applied to food, medical devices, cosmetics and supplements industries.

Both GPP and GMP require implementation of standard operating procedures, sanitation programs and systems to track products and conduct recalls if necessary. Both systems are means of ensuring product safety, quality and environmental protection, but GMP takes these steps further.

GMP covers many aspects related to the quality of cannabis products. These include control over raw materials, manufacturing process, in-process testing and controls, storage and distribution and validation. GMP is also concerned with the quality of the final product and therefore ensures the accuracy of cannabinoids content as well as batch to batch consistency.

An appropriate level of quality assurance and control, inspection and documentation are required whether the cannabis products are being grown and produced for local distribution or for export. The central purpose of GMP in the cannabis industry is to achieve “pharmaceutical-grade” cannabis product.

Many LPs in Canada are now producing cannabis to the higher GMP standard, specifically EU-GMP certification. A number of Canadian companies have become EU-GMP certified.  Many of these companies are exporting cannabis to the European Union. The implementation of GMP is therefore paramount if these companies are looking to enter the cannabis space globally, not just the EU.

The first step in becoming GMP-certified is to carry out a gap assessment. This involves assessing your current quality management system and determining what else is necessary. You are basically looking at what is missing to bridge the gap between GPP and GMP.

Some of the requirements set out in EU-GMP which are missing in GPP include:

• A robust quality management system
• An organizational chart demonstrating the relationship between the “heads of Production, Quality Control, Quality Assurance or Quality Unit with their job descriptions.
• Monitoring of environmental conditions in certain areas of the facility.
• Implementation of Good Documentation Practices (GDP).

In addition to GPP and GMP, there is another set of regulations called Good Agricultural and Collection Practices (GACP) developed by World Health Organization (WHO). GACP along with EU-GMP is applied by Europe to herbal medicinal products like cannabis. EU-GMP also requires the implementation of the standards set forth in Annex 7-Manufacture of Herbal Medicinal Products.

GACP requirements are applied to cultivation and collective practices (outside of the pharmaceutical industry). GMP, on the other hand covers primary processing of cannabis material. This includes the transformation of raw materials into active pharmaceutical ingredients (APIs) and of APIs into pharmaceutical products.

GMP requires all processing instructions for herbal substance to be described. This includes drying time, temperature, and all methods involved to control cut size or particle size. GMP also requires traceability from the beginning to the end of the process. This cover providing information on the scientific name of the plant and all relevant information required to characterize and describe the material and herbal plant.

Documentation of all treatments needed to reduce fungal and microbial contamination is required by both GMP and GACP. Audits and self-inspections are also important under both regimes. Both guidelines also require training such as personal hygiene and botanical training before performing tasks. This training needs to be documented. Training on good documentation practices is also required.

A robust risk management and quality assessment program is required throughout the cultivation and production process. These assessments increase the understanding by staff of risk concepts, leading to better compliance with GACP, GMP, and product safety, quality, and efficacy.

As in the pharmaceutical industry, GMP requires testing at every point in the supply chain and at every manufacturing step of medical cannabis. You will have to perform a cannabinoid profile on your raw plant material. A terpene profile of the hemp biomass will also be required. You will have to test the biomass for pesticides and heavy metals. Tests for molds, fungi, mycotoxins, moisture and water activity will also be required.

The extraction of cannabidiol (CBD) from a cannabis plant to its presence in an oil tincture bottle, for example, involves many chemical processes. A typical extraction process involves extraction, precipitation, distillation and dissolution chemical processes. Tests required during these steps include tests for cannabinoids and tests for residual solvents, e.g. ethanol.

With increase in use of therapies and other consumer products derived from cannabis and its components including CBD, it is critical to set high standards of compliance to ensure the safety of consumers.

The Cannabis Act and the Cannabis Regulations, sets out a comprehensive set of controls for edible cannabis, cannabis extracts and cannabis topicals. This includes good production practice, limits on Tetrahydocannabinol (THC) content, restrictions on harmful ingredients and strict packaging and labelling requirements.

The EU-GMP (Annex 7) guidelines for manufacture of herbal medicinal products which are applicable to medical cannabis and its products require compliance in many areas. This includes premises and equipment including storage areas, documentation including specifications for starting materials and processing instructions and quality control, e.g. in sampling.

Let us briefly look at some aspects of these guidelines.

The storage areas, for example, need to be protected from insects and other animals, e.g. rodents. Effective measures need to be taken to prevent the spread of micro-organisms, mold growth and cross-contamination. The storage area needs to be well aerated. Storage areas should be clean and well maintained. Humidity, temperature and light should be monitored.

The production area should allow cleaning to avoid cross-contamination during sampling, weighing, mixing and processing operations. The equipment used in the manufacturing process must be compatible with the extraction solvent. This would prevent any release or undesirable absorption of substance that could affect the product.

Documentation on starting materials (that are manufactured in accordance with GMP) and on audits of the starting material suppliers is required. The suppliers of the herbal substance/preparation should comply with GACP.  Any treatment used to reduce fungal/microbial contamination or other infestation should be documented.

Specifications and procedures should be available and should include details of process, tests and limits for residues. The processing instructions should describe the different operations that are carried out upon the herbal substance. This includes how each container of herbal substance is examined to detect any adulteration/substitution or presence of foreign matter. Instructions on how the herbal preparation is produced should include details of solvent, time and temperature of extraction, details of any concentration stages and methods used.

Quality Control personnel should have particular expertise and experience in herbal substances, herbal preparations and/or herbal medicinal products. Sampling should be carried out with special care by personnel with particular expertise. Each batch should be identified by its own documentation.

With strict, GMP manufacturing standards already in place, pharmaceutical companies are prepared to produce higher quality products. Epidiolex, a seizure treatment approved in 2018, was the first cannabis-derived CBD drug to be approved in the U.S.

Pharmaceutical companies also have the means to conduct clinical studies to determine the efficacy of CBD in their drugs for various medical conditions. This allows the companies to add another portfolio of treatments to their current pipelines.

Any CBD product used as part of a finished dosage form for a pharmaceutical application needs to be prepared as an Active Pharmaceutical Ingredient (API) under the required GMP regulations.

Synthetically derived CBD products have a well-defined impurity profile. These products can be prepared easily and reproducibly according to the required specifications. However, to control the impurity profile during natural hemp production is challenging.  Batch to batch variations must also be well understood. The isolation of CBD therefore needs to be carried out by adherence to the required GMP regulations.