Cannabis Derived Dosage Formulations for Investigational and Therapeutic Use in the US

Cannabis Derived Dosage Formulations for Investigational and Therapeutic Use in the US

For more than 6,000 years cannabis and humans have crossed paths. There are many uses for cannabis in the pharmaceutical, food and textiles industries. Due to the fact that Cannabis sativa L. is a common species in nature and the cannabis plant and its products consist of active components such as Δ9-tetrahydrocannabinol (Δ9-THC) and Cannabidiol (CBD) as well as terpenes and flavonoids. Cannabis has therapeutic efficacy and is used to treat disease or alleviate symptoms. Medical cannabis can be administered using a variety of methods, including inhalation, oral digestion of extracts, cookies, capsules and more.

While the diversity of cannabis dosage formulations and medical claims continues to increase dramatically, there remains considerable uncertainty about accuracy, consistency, quality control, and the impact of chemical diversity and variation in chemical composition on pharmacological or adverse effect end-points.

For example, a variety of formulations purchased in US dispensaries failed to meet basic label accuracy standards for pharmaceuticals; in one case, more than 50% of the products evaluated had significantly less cannabinoid content than indicated on the label. Other products had significantly more THC than labeled, placing patients at risk of adverse effects.

In addition to inaccurate concentrations, there is concern about the presence of pesticides, fertilizers, fungicides, molds, microbes, heavy metals, and other chemical adulterants that may be health and environmental hazards.

A basic requirement in the pharmaceutical industry for quality, safety, and efficacy of botanically derived drugs is the consistency in the chemical constituents of feedstock material and finished dosage formulations. The chemical consistency of cannabis feedstock for pharmaceuticals is best ensured through good laboratory and agricultural practices.

 The DEA requirements

Although cannabis is classified as a schedule I controlled substance in the US federally, which means that it has no medicinal value and production is legally restricted to a single supplier, and distribution to researchers is tightly controlled, many countries have changed their policy relating to production, distribution, and use of herbal cannabis and its dosage formulations.

According to current federal statutes, the bulk manufacture of cannabis and its formulations in the US is controlled by the Drug Enforcement Administration (DEA).

The DEA is required by the Controlled Substances Act (CSA) to limit the number of bulk manufacturers to a minimum in order to produce an adequate and uninterrupted supply of cannabis-derived substances. The DEA must also ensure that manufacturers are appropriately registered and adhere to the system of controls required by the agreement, which include maintaining a monopoly on the distribution of material for research.

The DEA works with the National Institute on Drug Abuse (NIDA) to set the annual limit to meet the needs of the US and may include the production of a particular strain or specific extract or purified natural product.

The market value is so great that some growers use a chemical arsenal to feed and protect their crops from microbial and animal infestation and disease to realize the largest yield possible. Consumers should recognize the potential risks from cannabis obtained through dispensaries because of the potential presence of pesticides or herbicides in the products.

Dosage formulations Manufacturing

Sampling and analytical characterization methods before, during and after production are specific to the nature of the product and its processes using good laboratory and manufacturing practices and validated analytical methods.

Concentration and homogeneity can be dramatically increased when cloned, non-fertilized female plants are grown indoors under controlled conditions, harvested at the optimal time of flowering and senescence, and carefully manicured to isolate the inflorescence. The inflorescence must be dried, processed, and packaged to deter fungal and microbial growth, prevent contamination and pest infestation, and protect the material from light and environmental exposure.

By maintaining low humidity and moderate temperature (20–40°C), the drying process can be expedited up to 5%-10% in order to reduce the risk of mold while maintaining the terpenes constituents of the inflorescence. Overextended aging time, decarboxylation converts the phytocannabinoid acids, and terpenes isomerize to create more complex polyterpenes with unique tastes and aromas.

To facilitate manufacture, the bulk plant material needs to be processed to acceptable particle sizes and consistency.

Analytical characterization and stability testing

Process control samples taken before, during, and after production are characterized analytically to monitor physical (weight) and chemical (phytocannabinoid concentration) parameters, and to determine batch uniformity and other characteristics required for the data sheets and certificates of analysis that are distributed with the materials.

The raw material is sampled for homogeneity and characterized for potency through quantitative measurement of its most active or abundant phytocannabinoids, many of which may be present in their biosynthetic acid or decarboxylated forms, such as Δ9-THC, CBD, tetrahydrocannabivarin (THCV), cannabinol (CBN), cannabigerol (CBG), and cannabichromene (CBC).

To eliminate pesticides and hazardous chemicals used in production or suspected to be present, Limit tests must be performed. The microbial burden must be adequately assessed and controlled. Other measurements such as moisture content and chemical content may be measured as warranted.

All processes are reviewed and documented by quality control systems, equipment calibration, and performance verification procedures. Human-use materials are subject to further review and release by quality assurance systems.

In some cases, analytical information must be obtained before the completion of processing. Time-zero samples are taken from the final product by documented procedures, analyzed for batch uniformity, and stored in qualified stability chambers or storage facilities where temperature and humidity are monitored and controlled over varying storage times. Critical performance specifications for dosage formulations are tested and documented on data sheets supplied to researchers, such as weight and unique parameters for particular formulations.

Cannabinoid dosage formulations distribution

Special DEA registration is needed for researchers who wish to do studies with cannabis. In addition to the application on DEA Form-225 for the appropriate schedule I drug code, the researchers need to pay a one-year registration fee and submit a research protocol showing the amount of drugs needed, and a copy of the researcher’s curriculum vitae.

After all the documentation is submitted, a DEA investigator conducts a site visit to verify that security procedures and diversion controls are adequate for storage and use. The DEA also sends the research protocol to the FDA for review and approval.

When NIDA approves and authorizes the distribution of a schedule I controlled substance to a researcher or patient, materials are released, packaged, and distributed for use in preclinical and clinical studies or for medicinal use.

A barcode-based electronic inventory management system tracks every batch, providing independent, automated verification of all compound supplies, allocations, and distributions.

Materials classified as for human-use require release by quality assurance staff, who are responsible for the oversight of all processes involved with human-use materials to ensure good practice quality guidelines and regulations (GxP) compliance.

Each batch has a certificate of analysis or a data sheet that is provided to the researcher or end user containing information on the particular batch along with recommendations for its proper handling, storage, and use.

When refrigeration is required, the material may be shipped on cold packs at −20 or on dry ice at −70°C.

All processes should be performed within 2-4 weeks.

About Cannabis GxP consultancy

Cannabis GXP is proud to stand at the forefront of the Cannabis industry in Israel and worldwide thanks to many years of experience in these areas.

Our team is compelled to spread the message of the importance of cannabis science, regulation and standardization as the world enters a new era of cannabis legislation.

We aim to position our clients with their best foot forward when it comes to anything and everything cannabis related.

Our vast expertise allows us to assist companies in a wide range of services and needs: Anything from Cannabis R&D, growing and manufacturing, new products development, facility design, technology, Quality Assurance, Good Practices (GAP/GMP/GLP/GDP/GCP), staff training, local and global regulations.

Cannabis GxP is a subsidiary company of Bio-Chem Ltd. (2007), a consultancy firm for the Pharmaceutical field, medical devices, Cosmetics and food supplements industry based in Israel.

Our cannabis consultancy services include:

  • Product development, delivery system & clinical trials
  • Growing, Manufacturing and Lab Facilities Design
  • Quality Assurance and Good Practices (GxP)
  • Cultivation & Product Manufacturing Technology
  • New product Regulations and Submissions
  • Qualification & Validation
  • Risk Assessment
  • Staff training

If you need one or several of our services, we will be more than happy to assist.

Please do not hesitate to contact us for further information.

2019-06-26T17:36:40+00:00

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