Minimum Informational Requirements for Establishing an FDA Drug Master File for Cannabis

Minimum Informational Requirements for Establishing an FDA Drug Master File for Cannabis: Questions To Be Answered by Potential Manufacturers

  1. Clarify how the chemical constituents of plant material were elucidated.
  2. Provide the data to support the specification for THC in Cannabis product and demonstrate how the specification was derived. Is extensive processing after growth what is reponsible for the high percentage of THC, as opposed to a high yield from the specific strain of cannabis? If so, it is important to describe that processing and that the procedure be consistent.
  3. What other products are manufactured by company? Are the other products marketed? Are they controlled substances? Provide CV’s of each employee demonstrating their technical capabilities and a description of each area (i.e., purpose, controls, etc.) of company’s facilitites. Floor plan should show more than security system, but where different manufacturing and labeling activities occur.
  4. Provide a flow chart of the manufacturing process.
  5. Verification of botanical identification of marijuana in the study and parent plants (precursors) needs to be provided. Provide critical features that are looked at in this regard by both, their specifications, and the raw data. What are specifications in selection criteria?
  6. What is strain selection process? What range of strains are acceptable? What controls and limitations are part of the selection process? What criteria are applied in selecting the strains? Is this process published or under patent? Provide relevant documentation, if available. Are the botanical identification criteria of the strain sufficient to distinguish it from other cannabis varieties? How can they be distinguished?
  7. Define flower/leaf ratio and significance of the flower/leaf ratio. Include commercial source(s) of the parent plant. Include descriptions of the pollen production and seed production process.
  8. Provide proof that analytical laboratory has the capabilities (HPLC or GC/MS or TLC) of determining THC and trace cannabinoid content.
  9. How long is the time period in which the plant material is dried? Provide soil analysis including that for heavy elements.
  10. Describe the photoperiod manipulation in flower induction to produce pollen. What is temperature at which pollen is stored in freezer? Describe all equipment in company. Provide sample of the label used on security barrels? Incineration of barrels should be addressed in the environmental assessment.
  11. What are drying conditions for plant after cut and criteria, and specifications?
  12. What is the water specification and how is it determined?
  13. In manufacturing process, how are flowers removed? By hand? What are final specifications?
  14. What are heat-sealed packets composed of? What are drying requirements and specifications for finished product?
  15. What in-process controls have been instituted? In-process laboratory controls for finished dosage form include minimizing fungal damage by consistent field inspection and immediate elimination of suspect plants, combined with careful control of greenhouse humidity and air circulation. Describe inspection system in detail. Finished drug product is closely re-inspected for fungal contamination before packaging. Describe re- inspection procedures.
  16. Specifications and methodology — Describe microscopic analysis procedure.
  17. Describe analytic laboratory.
  18. What are water specifications of dry plant material? Provide all standard curves and raw data that went into analytical development, as well as calculations. How efficient is extraction process? Has it been tested, e.g., by repeated extraction of extracted material to see how level of remaining THC and other cannabinoids remaining?
  19. There is a need to confirm analyses and chromatography by another methodology, e.g., HPLC.
  20. Establish acceptance criteria for marijuana.
  21. Purity profile: Ensure that the chemical profile of product produced by the cannabis strain remains consistent in subsequent manufacture. Identify the major impurities and specifications. Provide purity profile, along with detailed description of specifications and tests.
  22. Describe sterilization procedure and sterilization testing procedure? Submit protocol and results upon completion.
  23. Verify lack of fungal growth. Provide protocol fo study and results upon completion.
  24. Container (heat-sealed food grade plastic packets) — What are packets composed of? Heat sealing process needs to be provided. Assurance and verification needs to be provided that no decomposition or toxic components, that may contaminate product, are formed during heat-sealing.
  25. Reference Standard — Specify whether standard THC substance or cannabis plant material. Provide purity analysis results of botanical reference standards (i.e., if company has a library of male or female reference plants).
  26. Describe in detail the photoperiods maintaining the plant in a perpetual vegetative (non-flowering) state for extended periods. What commercial rooting hormones (i.e., source, analysis, certificate of analysis) are used?
  27. Stability — Justify the stability of cannabinoids under testing conditions. Stability protocols (temperature- humidity, freezing, acid, alkali, light and oxygen) should be submitted for review and then begun. Submit stability testing protocols for bulk drug as well as dosage form (each packet). Define “optimum” storage and “long-term” storage? Any proposed expiration dates must be supported by data.
  28. Production Operations — No batch records of actual production runs have been provided. At least three should be provided. Process validation, cleaning validation and rework procedural documents need to be provided. Full-scale production procedures need to be established. Records of what has been produced and available SOPs should be provided. Reprocessiong procedures should be provided.
  29. Environmental Assessement — Provide details about governmental inspections and results, relative to chemical residues, pesticides or artificial fertilizers used, or if biocontrol techniques (i.e. predatory insects, pheromonal traps, etc.) are applied to keep insect populations down, how did we get rid of predatory insects?
  30. Before using the marijuana, the patient needs to humidify the brittle material to avoid powdering and to lower the burning temperature (preventing harshness and excessive thermal decomposition of THC). Provide a copy of any directions that are given to the patient.
  31. The manufacturer needs to provide proof that the manufacture of the marijuana is conducted pursuant to provisions of the Single Convention on Narcotic Drugs. Is the manufacturing process conducted under authorization of the national government? To what extent? Provide a description of the diversion controls used in manufacture, storage and export of the substance which must be consistent with the provisions of the Single Convention. Provide a copy of the security protocols. Are any GMP-comparable chemistry manufacturing controls required by ministry of health and adhered to?
  32. A profile of the product after pyrolysis should be provided. The profile should include chemical identification of major components along with their quantification. Extent of pyrolysis needs to be determined, as well as pyrolyate.