Medicinal cannabis cultivation and manufacture update

John Skerritt Deputy Secretary for Health Products Regulation Commonwealth Department of Health Brisbane, Thursday 13 July 2017

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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Manufacturing quality requirements and product standards

John Skerritt Deputy Secretary for Health Products Regulation Commonwealth Department of Health Brisbane, Thursday 13 July 2017

“Home made” cannabis extracts are from illegally sourced materials, often of varying strengths and may contain contaminants

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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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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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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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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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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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 %) 9

The acid form dominates in plant material

OH

HO

H

O

OH

COOHH

O

OHH

THC-acid THC

CBD-acid CBD

OH

COOH

HO

H

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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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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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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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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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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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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) 16

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

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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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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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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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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 21

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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Questions?

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