This presentation provides an overview developments around quality requirements and standards for manufactured and raw material for medicinal cannabis.

1. Medicinal cannabis cultivation
and manufacture update
John Skerritt
Deputy Secretary for Health Products Regulation
Commonwealth Department of Health
Brisbane, Thursday 13 July 2017

2. Today’s program (discussion time after each item)
10.00 - 10.15 Welcome and purpose of the meeting
John Skerritt, Commonwealth Department of Health
10.15 - 11.15 Developments on cultivation and manufacture
Thomas Stoddart, Office of Drug Control
group discussion
11.15 - 12.00 Quality requirements and standards
John Skerritt, Commonwealth Department of Health
Quality requirements for manufactured products
Quality standards for the raw material (TGO 93)
group discussion
12.00 - 12.45 Lunch
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3. Manufacturing quality
requirements and
product standards
John Skerritt
Deputy Secretary for Health Products Regulation
Commonwealth Department of Health
Brisbane, Thursday 13 July 2017

4. “Home made” cannabis extracts are from
illegally sourced materials, often of varying
strengths and may contain contaminants
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5. Concerns about the quality of medicinal
cannabis products
… they may be given to immunocompromised patients
• Variation in cannabinoid content, in particular of active ingredient(s)
• Contamination with pesticides
• Microbial contamination
• Mycotoxins (aflatoxins and ochratoxin A)
• Contaminants arising from the manufacturing process e.g. solvents
• Adulteration with synthetic psychoactive compounds
• Fortification with synthetic THC
• Mis-identification of the plant material
• Adulteration with other plant material
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6. CBS NEWS February 7, 2017, 11:08 AM
Contaminated medical marijuana
believed to have killed cancer patient
Is your medical marijuana safe?
UC Davis doctors say dangerous
bacteria, fungi can lurk in pot
www.sacbee.com/news/local/health-and-
medicine/article131391629.html#storylink=cpy
Health Canada orders medical marijuana
growers to test for banned pesticides
OTTAWA SUN SATURDAY, MAY 06, 2017
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7. Therapeutic Goods Order 93
1. Sets out minimum requirements for the quality of:
• medicinal cannabis products
• the cannabis plant used in the manufacture of medicinal cannabis products
• any ingredient used in the manufacture of medicinal cannabis products
2. Sets out requirements on the manufacturing process for
medicinal cannabis products, and applies to:
• any medicinal cannabis product imported into, exported from, or supplied in
Australia
• cannabis plant used in the manufacture of medicinal cannabis products
• any other ingredients used in the manufacture of medicinal cannabis
products, such as excipients
• steps and procedures carried out in the manufacture of medicinal cannabis
products
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8. TGO 93 incorporates the requirements of the
European Pharmacopeia general monograph for
Pharmaceutical Preparations (2619)
This encompasses the requirements of:
• specific monographs of the Ph.Eur. for pharmaceutical raw materials
(e.g. active ingredients, excipients)
• general texts (e.g. Residual Solvents (5.4)) and
• other general monographs of the Pharmacopeia including:
- Herbal Drugs (1433)
- Herbal Drug Preparations (765)
- Herbal Drug Extracts (765)
- Substances for Pharmaceutical Use (2034)
- dosage form monographs e,g. Oromucosal Preparations (1807)
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9. Source of active ingredients and adulterants
• The cannabis plant used in the manufacture of medicinal cannabis
products must be positively identified using macroscopic and
microscopic examination and chromatographic procedures
• All active ingredients and cannabinoids in medicinal cannabis
products must be manufactured from the cannabis plant only
(synthetic cannabinoids are not allowed in “medicinal cannabis”)
• Decontamination of cannabis plant material (e.g. by gamma
irradiation) is allowed provided it does not affect product quality
• The formulated medicine or any of its ingredients must not be
adulterated with undeclared substances, although use of an
excipient or processing aid in manufacture is permitted
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10. Cannabis plant tests
Sponsors/manufacturers must ensure
that the cannabis plants used to
manufacture products meet requirements
1. Aflatoxins (Ph. Eur requirements)
2. Ochratoxin A (< 20 µg/kg)
3. Foreign matter (Ph. Eur requirements < 2 %)
4. Heavy metals (As < 3.0 ppm, Cd < 0.5 ppm,
Pb < 5.0 ppm, Hg < 0.5 ppm)
5. Pesticides (Ph. Eur. requirements)
6. Total ash (< 20 %)
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11. The acid form dominates in plant material
OH
HO
H
O
OH
COOH
H
O
OH
H
THC-acid THC
CBD-acid CBD
OH
COOH
HO
H
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12. Assay limits for dosage forms
Dosage form
Average content of active ingredient
(including corresponding acids)
(% stated content)
Herbal final form 80.0 - 120.0
Tablets and capsules
(unregistered)
90.0 - 110.0
Other dosage forms 90.0 - 110.0
Any suitably validated test method can be used. Examples include :
• Monograph Cannabis Flos Version 7.1 (Nov 28, 2014) 40953, Dutch Office of
Medicinal Cannabis
• Recommended methods for the identification and analysis of cannabis and
cannabis products United Nations Office on Drugs and Crime.
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13. GMP requirements
• Domestically manufactured APIs are subject to both current
GMP and TGO93
• For manufactured products planned for SAS/ Authorised
Prescriber pathways, the currently PIC/S Guide to GMP applies
• For clinical trial products, Annex 13 of the Code is important
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14. GMP for medicinal cannabis APIs
The API is the active ingredient that is
the starting material for the
manufacturing process of the finished
product. For medicinal cannabis, the API
could be:
• An extracted/ purified cannabinoid from
the cannabis plant
• An extract of specified parts or
powdered parts of the cannabis plant
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15. Medicinal cannabis API manufacture
(TGO 93 also applies to APIs)
Type of
manufacturing
The Code of GMP (Part II)
is applied to processes highlighted in red
API extracted
(plant)
Collection of
plants
Cutting/initial
extraction(s)
Introduce the
API starting
material
Isolate and
purify
Process
and pack
Herbal extracts
(used as API)
Collection of
plants
Cutting/initial
extraction(s)
Further
extract
Process
and pack
API powdered
herbs
Collection of
plants and/or
cultivation and
harvesting
Cutting and
commuting
Process
and pack
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16. GMP requirements for domestically-
manufactured products for clinical trials
Annex 13 of the PICS Guide applies. Key points:
• Quality Management system
• Receiving/storage/usage/security (S8 requirements)
• Personnel/training
• Premises/Equipment
• Manufacturing: Operation/Critical parameters
• Packaging: operation/packaging materials/labelling/expiry/
blinding operation
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17. GMP requirements for domestically-
manufactured products to be provided through
SAS/ Authorised Prescriber pathways
• The finished medicinal cannabis product is the dosage
form in which the medicinal cannabis is intended to be
administered to the patient, e.g. oil, tincture, extract,
capsule, tablet etc
• The domestic manufacture of the finished medicinal
cannabis product is required to be in compliance with
– Code of GMP, relevant Annexes
– Relevant product standards - TGO 77 (Microbiological),
and TGO 93 (Medicinal Cannabis)
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18. Termed “approved access” in the Guidance ….
• Quality control/verification, effectiveness of blinding
• Review/assessment/release of batches
• Shipping/security codes/storage conditions
• Complaints/recalls/returns/destructions
• Documentation: specifications/methods/in-process
• Approved labelling/clinical trials protocols/technical
agreements/stability/storage records/manufacturing and
packaging instructions and records
• Supplier qualification:
– Understanding the nature of the starting material
– Approval of starting material suppliers/specifications
– Reduced sampling and testing considerations
– Periodic review 17

19. Domestic product GMP: Process validation
• Any risk based approach should be consistent with Annex
20 of current GMP Code
– Prior to validation, all requirements of equipment
qualification and validation of test methods should have
been appropriately completed
– Concurrent or prospective validation would normally be
expected for new dosage forms/processes
– Product Grouping validation should be based on
scientific justification which may be difficult to achieve for
medicinal cannabis, so each dosage form and batch size
should be validated
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20. Domestic product GMP: Testing
• Testing requirements in process validation studies should
consider the physical characteristics of a particular ingredient to
ensure homogeneity/strength are addressed
• Successful validation would ensure that all critical process
parameters are assessed as consistently controlled and typically
covers extraction, concentration, drying, mixing into the dosage
form, and packaging into finished product
• Release of a batch used for a Process Validation is acceptable if
the batch meets release specifications
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21. Domestic product GMP: Sampling and stability
testing
• Sufficient samples should be taken for any Process
Validation study to permit statistical analysis
– In the case of extractions, sampling from the critical
control points of the process is important to verify controls
– Sampling of dosage forms is important to ensure
homogeneity in manufacturing
• Ongoing stability would not normally be applicable for the
manufacture of a medicine for use in a clinical trial.
– However, stability would be required according to Annex
13 and in support of expiry date for the material
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22. Summary
• GMP or a TGO 93 declaration are required for overseas
manufactured products
• GMP is required for domestically manufactured products with
particular emphasis on Annex 13 of the GMP Guide
• The application of quality risk management in the
manufacture of medicinal cannabis could be utilised subject to
the principles of Annex 13. Important to address:
– supplier qualification
– Sampling and testing requirements
– process validation
• TGA guidance documents for complementary medicines may assist
in manufacturing medicinal cannabis products
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23. Further information?
TGA’s website www.tga.gov.au has:
• TGO 93 as well as all the other TGOs
• Guidance documents for the TGOs
Manufacture of medicinal cannabis for
supply under SAS/ AP
• www.tga.gov.au/book-page/related-guidance-
and-further-information
• www.tga.gov.au/publication/manufacture-
medicinal-cannabis-supply-under-approved-
access-provisions
Code of GMP for medicinal products Q&A
• www.tga.gov.au/questions-answers-code-
good-manufacturing-practice-medicinal-
products
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24. Questions?
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