A summary on relevant regulations, on access to products, and details on requirements for Good Manufacturing Practice.

1. Manufacture of Medicinal Cannabis Products
under PIC/S Code of GMP
Brief on regulations/Access to products
Manufacturing and GMP requirements
Maurice Makdessi
Senior GMP Inspector
Inspection Section, Manufacturing Quality Branch
Medical Devices and Produce Quality Division, TGA
RACI Supply and Use of Medicinal Cannabis Seminar
28 March 2017

2. Sections/content
• Cannabis – Main components of interest
• Brief Regulation/Access to Cannabis products
• GMP requirements/Products/APIs
• ‘Approved Access’ Products and GMP
• References/useful sites for more information
Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 1

3. Cannabis – main components
Cannabis includes the seeds, extracts, resins, and the plant as well
as any part of the plant. The main two components reported to have
medicinal properties:delta-9-tetrahydrocannabinol and cannabidiol
Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 2

4. Brief regulations/access to products
The Therapeutic Goods Act 1989 provides a number of
mechanisms to enable access to unapproved therapeutic
goods ‘Approved Access’. For medicinal cannabis products
these include:
• Authorised Prescriber Scheme (APS)
• Special Access Scheme (SAS) - Category B ONLY
• Clinical trials (CTX-CTN)
Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 3

5. Summary Table : Regulations/access/licencing
Process Therapeutic Goods
Act
Narcotic Drugs Act States and
territories involved?
Patient need
Medical
authorisation
Special access scheme
Authorised prescriber
Licence
Permit
Yes
Clinical trials
Importation
CTN
CTX
Sponsor clearance
Licence
Permit
Yes
Finished dosage
form manufacture
Licence required
Licence
Permit
Yes
API Manufacture Licence required
Licence
Permit
No
Harvest N/A
Licence
Permit
No
Cultivation N/A
Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 4

6. GMP requirements/medicinal cannabis
Domestically Manufactured Products/Materials
• Manufactured products with intended access via the ‘approved access’
pathway, the currently adopted PIC/S Guide to GMP applies
• For Clinical trial products, Annex 13 of the Code would be of particular
importance
• Domestically manufactured APIs are subject to current GMP and
TGO93
Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 5

7. GMP requirements/medicinal cannabis
• Exemptions for products manufactured in Australia
– extemporaneous compounding (i.e. for identified patient):
 Products compounded by pharmacist in public hospital not
required to be under GMP if for supply for hospital from the
premise and in same State or Territory
 Products compounded by any other extemporaneous
compounder required to be under GMP
– Australian manufacturer with GMP (using imported starting
materials) can supply CTN, CTX, SAS Cat A or B, authorised
prescriber, under a contract with a public or private hospital
(where product is not ‘substantially similar’ to one on the
ARTG)
Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 6

8. Medicinal cannabis API manufacture
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 and purified active component of the cannabis
plant (for example a cannabinoid)
• An extract of specified parts of the cannabis plant
• Powdered specified parts of the cannabis plant
Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 7

9. Medicinal cannabis API manufacture
GMP requirements increasingly applies in the API
manufacturing process as the process advances for example:
• For extracted cannabinoids: GMP does not apply up to
cutting and initial extraction but increasingly applies from
the introduction of the API starting material into the process
onwards
• For herbal cannabis extracts: GMP does not apply up to
cutting and initial extraction but increasingly applies from
further extraction onwards
Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 8

10. Medicinal cannabis API manufacture
• For powdered cannabis plant parts: GMP does not apply up
to cutting and commuting but increasingly applies from the
moment of physical processing and packaging of the
powder onwards
Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 9

11. Medicinal cannabis API manufacture
Type of
manufacturing
Application of Part II of the Code of GMP
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
Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 10

12. ‘Approved Access’ domestic product GMP
• The finished medicinal cannabis product is the dosage form
in which the medicinal cannabis is intended to be
administered to the patient, for example as an 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, and relevant TGOs. i.e.
TGO 77 (Microbiological STD),TGO78 (Capsules and
Tablets STD), and TGO 93 (Medicinal Cannabis STD)
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13. ‘Approved Access’ domestic product GMP
Where Clinical trials products are domestically manufactured
Annex 13 of the PICS Guide applies. Annex 13 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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14. ‘Approved Access’ domestic product GMP
• 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
Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 13

15. ‘Approved Access’ domestic product GMP
The application of quality risk management in the
manufacture of medicinal cannabis could be utilised subject
to the principles of Annex 13.
The TGA had developed guidance documents for
complementary medicines that contain information that may
assist in manufacturing products to be made available via
clinical trials or investigational product pathways.
Particularly supplier qualification/sampling/testing/process
validation.
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16. ‘Approved Access’ domestic product GMP
• Supplier qualification:
– Understanding the nature of the starting material
(includes packaging) and acquisition of relevant
information from starting material manufacturers
– Approval of starting material specifications
– Approval of starting material suppliers
– Reduced sampling considerations
– Reduced testing considerations
– Periodic review
Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 15

17. ‘Approved Access’ domestic product GMP
• Testing
– Identification testing is critical. Active component testing
is critical if component reported on label. Microbiological
testing as required. Heavy metals tested on a rotational
basis. C of A result acceptable for other criteria, including
pesticides and residual solvents (where relevant).
– If extracts are sourced from a manufacturer that is TGA
licensed or has a TGA GMP clearance then extracts can
be accepted on a C of A without further testing provided
that supply chain and examination of packaging for
integrity of seal are verified.
Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 16

18. ‘Approved Access’ domestic product GMP
• Process Validation: Any risk based approach should be
consistent with Annex 20 of current 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. Therefore each dosage form and
batch size are required to be validated
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19. ‘Approved Access’ domestic product GMP
• 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 to verify those controls (e.g.
extraction completion, conversion completion, completion
of separations/concentration etc.)
• Dosage forms: sampling to ensure homogeneity in
manufacturing, (e.g. blender/mixing tank, throughout
compression, encapsulation and packaging
Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 18

20. ‘Approved Access’ domestic product GMP
• 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
19Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP

21. ‘Approved Access’ domestic product GMP
• Stability:
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. The clauses
in Annex 13 that would be applicable for stability of a
medicine that is manufactured for use in a clinical trial
include 6, 9, 20, 26j and 40.
Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 20

22. Summary
• Current GMP applies to ARTG registered medicinal
Cannabis products including APIs
• Medicinal Cannabis products accessed via the Authorised
Prescriber, CTN/CTX and SAS CAT B schemes:
– GMP is required for domestically manufactured products
with particular emphasis on Annex 13 of the GMP Guide.
– GMP declaration requirements applies for overseas
manufactured products (this is in process of being
reviewed).
Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 21

23. Summary
• Medicinal Cannabis products accessed via the
Authorised Prescriber, CTN/CTX and SAS CAT B
schemes:
– GMP applies to extemporaneous compounding.
Exemptions to public hospital operated pharmacies
under public hospitals (not independent) providing
medicines for identified patients
Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 22

24. References/useful sites for more information
ODC website
• https://www.odc.gov.au/
Accessing unapproved products
• https://www.tga.gov.au/accessing-unapproved-products
Medicinal cannabis Q&A
• https://www.tga.gov.au/access-medicinal-cannabis-products-questions-and-answers
Manufacture of medicinal cannabis for supply under 'approved access' provisions
• https://www.tga.gov.au/book-page/related-guidance-and-further-information
• https://www.tga.gov.au/publication/manufacture-medicinal-cannabis-supply-under-
approved-access-provisions
Q&A on the code of GMP for medicinal products
• https://www.tga.gov.au/questions-answers-code-good-manufacturing-practice-medicinal-
products
Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP
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25. Questions?
Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 24