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

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

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

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

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

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

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

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

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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

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

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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

‘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)

Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 11

‘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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‘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

‘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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‘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

‘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

‘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

Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP 17

‘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

‘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

19 Manufacture of Medicinal Cannabis Products under PIC/S Code of GMP

‘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

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

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

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

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Questions?

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