Medicinal Cannabis Access and GMP

Maurice MakdessiSenior InspectorManufacturing Quality BranchHealth Products Regulation GroupMedical Devices and Product Quality Division, TGA

21 NOV 2019

OverviewMedicinal Cannabis

– Access– Regulations and Licensing (TGA/ODC)– GMP requirements and guidelines Import/export APIs and Finished products

– Cases/Examples of License requirements

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Medicinal cannabis

Cannabis describes all plants of the Cannabis genus. 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:

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Brief regulations/medicinal cannabis product access

• The Australian Government Department of Health regulates medicinal cannabis products through:– The Office of Drug Control (ODC), which regulates controlled substances to prevent

diversion and illicit use. ODC administers the Narcotic Drugs Act 1967.– The TGA, which regulates medicines by administering the Therapeutic Goods Act

1989

Note:The states and territories have local regulations regarding access to Medicinal Cannabis products to be adhered to when manufacturing and supplying in the relevant state/territory

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Access to products• The TG Act provides a number of mechanisms to enable access to unapproved

therapeutic goods “Approved Access Schemes’. For medicinal cannabis products:– Authorised Prescriber Scheme (AP) – Special Access Scheme (SAS)– Clinical trials (CTX- CTN)

• Otherwise, Access via product registration pathway (ARTG) and Clearance for overseas manufacturers via sponsors

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Access to products• Authorised Prescriber Scheme (AP):

– Applies only to medical practitioners, 6 monthly reporting to TGA applies per product/ imported medicine per patient

– Compounding Pharmacy /Hospital Pharmacy (Item 2, Item 3 Schedule 8)

• Special Access Scheme (SAS): – SAS category A: notification for a patient defined as seriously ill– SAS category B: application pathway (Not A or C)– SAS category C: notification of use of specified therapeutic goods:

established history• Clinical Trials: CTN/CTX

The Department of Health regulates Medicinal Cannabis Products through:• The TGA which administers the Therapeutic Goods Act 1989

– Quality (identity, purity, safety, efficacy)– Access to unapproved medicines including clinical trials– Access and controls implemented via the Poisons Standard (SUSMP)

– There may be other laws to be considered/states and territories

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Multiple laws

Multiple LawsThe Department of Health also regulates Medicinal Cannabis Products through:

• The Office of Drug Control (ODC), which administers the Narcotic Drugs Act 1967– Regulates controlled substances to prevent diversion/illicit use which includes quantities.– Regulates the Cultivation of medicinal cannabis– Regulates certain aspects of manufacture of medicinal cannabis– Regulates aspects of Import/Export

– There may be other laws to be considered/states and territories 7

Scheduling States and Territories play a vital role in implementing controls in their jurisdiction

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• Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription – e.g., cannabidiol containing < 2% other cannabinoids

Schedule 4 (Prescription Only

Medicine)

• Substances which should be available for use but require restriction of manufacture, supply, distribution, possession and use to reduce abuse, misuse and physical or psychological dependence – e.g., nabilone, dronabinol, nabixomols, cannabis, THCs (these can be of natural origin or synthetic)

Schedule 8 (Controlled Drug)

• Substances which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities e.g., cannabis, THCs

Schedule 9 (Prohibited Substance)

Cannabis that does not meet Schedule 4 or 8 are classified as Schedule 9

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Differences between TGA and ODC licensing

TGA licence to manufacture• GMP Manufacturing of APIs and Finished

Goods: includes all licensed steps of manufacturing and packaging

• Marketing Authorisation/RFS

• Clinical trials

ODC licence to manufacture Narcotic Drugs

• Cultivation licence/ experimental /research licence

• Manufacture of extracts/resins including purifying/concentrating/isolating

• Converting/transforming from one to another (ie.Cannabinoid to another)

TGA and ODC licences serve different purposes

Lic/Permit

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Process TG Act ND Act/ ODC States/Territories

Patient needMedical authorisation SAS/ AP Y Y

Clinical Trials CTN/CTX ≥ Phase 2 Y Y

Importation Sponsor Clearance YY

Finished DosageManufacture

Licence Required Y Y

API manufacture Licence Required Y Y

Harvest N/A Y Y

Cultivation N/A Y Y

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Terminology can be different (TGA/ODC)• In the context of the Therapeutic Goods Act ‘production’ refers to the actual preparation of an

active pharmaceutical ingredient or a finished medicinal product. As such, ‘production’ is considered a subset of ‘manufacture’.

• In the context of the Narcotic Drugs Act ‘production’ refers exclusively to the harvesting of the specified plant parts, separating resin from plant by physical/water extraction, physical separation of the trichomes from the cannabis flowers or cannabis plant (eg. sieving, ice water separation etc..)

• The plant or separated resin might then undergo a processing step (e.g. solvent extraction) which is termed ‘manufacture’. As such, ‘production’ is a separate step that is usually followed by ‘manufacture’.

• Where the terminology is similar (e.g. manufacture) the definitions are quite different under the respective legislations.

– A TGA GMP licence focuses on quality, whereas the narcotic manufacture licence specifies what drug may be produced and in what quantities. For this reason a manufacturer may require both licences. A licence issued under the Therapeutic Act does not remove the requirement for a licence under the Narcotic Drugs Act and vice versa.

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Terminology can be similar (TGA/ODC)

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Imported medicinal cannabis• Tightly controlled internationally /international drug conventions• Approval must be granted by both countries importing/exporting • In the case of importation for a particular patient CAT A. The doctor/dispensing

pharmacist must have an import licence and apply for import permission.• In the case of CAT B patient, TGA approval required under the SAS CAT B (AP or• Other). Evidence to ODC for import permit.• Sponsors required to demonstrate compliance to SAS access (ie. AP, storage, QTY,

records, patients).• Import to manufacture if manufacturer holds required import permit & ODC licence:

cannabis material including extracts for use in manufacture.

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Medicinal cannabis quality• TGO 93 Standard for Medicinal Cannabis:

− Specifically for medicinal cannabis and incorporates the

requirements of the various general monographs of the

European Pharmacopoeia for herb drugs/extracts

− Identification Physical/Chromatographic

− Chemical constituents/Assay

− Others: pesticide, aflatoxin, ochratoxin A, heavy metal, total ash, foreign matter

− Decontamination by Ɣ / X ray allowed where product impact is assessed not to adversely affect

product quality. Ethylene oxide use is not allowed

GMP requirements: Finished products manufacturers• Finished 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.

• Manufacturing medicinal cannabis finished product must comply with various product quality standards.

− Manufacturing principles- PIC/S Guide to GMP PE009-13 unless exempt in Schedule 7 or 8 of the Therapeutic Goods Regulations 1990.

− TGOs may apply to both locally manufactured/imported products e.g. microbiological TGO 100, tablet and capsule quality TGO 101, Medicinal Cannabis minimum quality testing TGO 93 (mainly for natural origin).

− Guidance Documents: eg. Medicinal Cannabis, complementary medicines

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GMP requirements/Guidance document • Complementary Medicines Guidance Documents:

– Sampling and testing

– Supplier assessment

– On going stability testing

– Validation

– Product quality reviews

• Sampling and testing/ Supplier assessment– The two guides allow for reduced sampling and testing (rotational) when certain

requirements are met.

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GMP/Guidelines

Material type Pre-qualification

Post qualification

Excipients – starting materials

√ n +1 Apply √n +1 OR

reduced sampling plan if:

– material is from a site that manufactures only one product

– Scientifically justified

Actives – starting materials

Sample all containers.

GMP/Guidelines• Sampling and testing/ Supplier assessment

– Rotational Testing: May be used for material from a qualified a supplier: Perform critical tests on each delivery plus one non-critical test. Rotate through all non-critical tests Do not skip any non-critical tests without adequate justification.

– Where supplier performance changes/deteriorates then rotational testing should be assessed (for the material in question or other)

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GMP/Guidelines• Process Validation: Critical/assuring the quality of products

– Qualified equipment is a must

– Risk base approach (monitoring critical process parameters, critical quality attributes- via sampling)

– Use statistical tools to justify consistency of process (3 batches unless justified otherwise)

– Selection of active ingredients to monitor (in the case of mixed actives)

– QBI not accepted (TGO 93)

– Bracketing strategy: by concentration lowest/highest

– Visual/color/weight uniformity/assay

– Grouping approach (same process/equipment/ingredients)

• On-going stability testing

– Generally the responsibility of the sponsor

– Supporting product shelf life/covering the Marketing Authorisation

– One product a year from each group of product/justified grouping/rotating representative of the group

– To be assessed when significant formulation/pack change

– Monitor level of impurities, especially for registered/ingredient mix/synthetic

– Always using stability indicating testing methods

– Reduced testing protocol may be acceptable where justified through risk assessment

– At a minimum microbiology testing - start and end of study

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GMP/Guidelines

• Product Quality Review (PQR)

– PQR is a mechanism to ensure that data captured by the Pharmaceutical Quality System (PQS) is reviewed for trends as well as changes affecting all quality elements.

– Verifies the consistency of process (statistics)/ current specifications

– Causes of quality incidents/identify impacts/ identify potential improvements

– Annually conducted unless justified

– Grouping may be used. However all incidents must be considered for all products in the group/trend results.

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GMP/Guidelines

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Medicinal cannabis APIs

• The active ingredient (API) for Medicinal Cannabis 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 (ie. flower extract)

– a trituration of specified parts of the cannabis plant (ie. leaf trituration)

– Dried parts (ie. the dried flower of the cannabis plant separated from leaves and stem).

– Powdered parts of the plants

Note: Plant material could be classified as herb or herbal substance (ie. milled)

GMP requirements APIs

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GMP requirements APIs• GMP is required for some aspects of the manufacturing process for example:

– For extracted cannabinoids: GMP does not apply up to cutting and initial extraction but 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 applies from further extraction onwards

– For powdered cannabis plant parts: GMP does not apply up to cutting and comminuting but applies from the moment of physical processing and packaging of the powder onwards.

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Exemptions from GMP requirements (APIs)

• item 2 of Schedule 7 of the Regulations:– ingredients, except water, used in the manufacture of therapeutic goods

where the ingredients: do not have a therapeutic action; or are herbs, bulk hamamelis water or oils extracted from herbs, the sole

therapeutic use of which is as starting materials for use by licensed manufacturers

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Exemptions from GMP requirements (APIs)

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• Exemptions may apply in limited circumstances: For example, where the oil extracted from cannabis is used solely as a

starting material for medicinal cannabis products by a GMP licenced manufacturer in Australia.

Similarly, this exemption applies to herbs, part of herbs, cut/chopped/dried herbs, the sole therapeutic use of which is as a starting material for medicinal cannabis products for use by a GMP licenced manufacturer in Australia, for example flos (dried cannabis).

The exemption does not apply to ground/powdered/milled herbs (ie. herbal substances).

Examples of Licence requirements/ for manufacturers

• A manufacturer performs the steps of growing, cultivation, harvesting, cutting and extraction of cannabis using carbon dioxide and no further steps were conducted on the extract.– Both an ODC Medicinal Cannabis cultivation Licence and ODC

Manufacturing Licence are required for the steps before GMP. – If there is no further purification or decarboxylation step performed on the

initially extracted material/ oil, then GMP may apply for the CO2 extraction, dependant on the final use of the material produced.

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• A cannabis oil manufacturer conducts an extraction to make cannabis oil and was exempt from GMP as the oil was solely used by a TGA licensed manufacturer for producing finished products.

• The manufacturer decided to conduct steps of further refinement and/or distillation of the oil -concentrating to a high percentage of purity (i.e. THC) and supply the product as a Finished Product.

• The manufacturer holds an ODC licence. How would this affect GMP/Licencing?? – The change in manufacturing steps, are considered manufacturing steps where GMP does

apply and TGO 93 for quality control is required/ TGA licence is required. – An ODC Manufacturing licence is also required to be amended as cannabinoids (such as THC

or CBD) are being isolated and concentrated.

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A manufacturer purchased an already extracted API to be refined/ THC isolation/purification processes. The final product would be for export only.What licencing may be required?

• ODC licence and permit for export• TGA licence to manufacture• Export listing on the ARTG• Full testing to TGO 93/ TGO 100

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A cultivator of medicinal cannabis collected, cut and dried the flower of the plant. The product was packed in sachets. What licences may be required?- ODC cultivation licence- ODC manufacturing licence- TGA licence.

The same manufacturer extracted the harvested plant into a resin and further decarboxylated to cannabinoids, to be further processed at another manufacturer under contract. What licences may be required?- ODC licence update/conversion step added- TGA licence variation / possibly new inspection - TGA and ODC licences (contract manufacturer)

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A sponsor would like to import finished cannabis oil to be re-packaged at a contract packaging company and stored at the company site. The product to be used by a pharmacist as required with a script issued by an Authorised Prescriber.What are the licencing requirements?

• The Pharmacist must have an licence to hold/dispense S8 medicines • The manufacturer must have a TGA licence as well as ODC licence/permit• The AP must have been registered to prescribe cannabis• The sponsor must have declared compliance of goods to TGO93 and product was

already prescribed in the country of origin and regulated to similar standard. Otherwise clearance pathway/ TGA inspection conducted at overseas manufacturer.

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• Medicinal Cannabis TGA licence Product Category:

“Registered” if product is on the ARTG.If the medicine is manufactured/supplied under the Unapproved Access (SAS and other). The category “Not applicable” would appear on the license with restrictions

stating manufacture and release for supply of therapeutic goods that are intended for export or exempt from registration and listing on the ARTG under the provisions of Section 18(1) or Section 19(1)(a) of the Therapeutics Goods Act 1989.

References https://www.odc.gov.au/ https://www.tga.gov.au/accessing-unapproved-products https://www.tga.gov.au/access-medicinal-cannabis-products-questions-and-

answers 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 https://www.tga.gov.au/questions-answers-code-good-manufacturing-practice-

medicinal-products

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References https://www.tga.gov.au/publication/process-validation-listed-and-

complementary-medicines https://www.tga.gov.au/book-page/3-guidance-use-term-quantified-input-listed-

complementary-medicines https://www.tga.gov.au/publication/product-quality-reviews-pqrs-listed-and-

complementary-medicines https://www.tga.gov.au/publication/stability-testing-listed-complementary-

medicines https://www.tga.gov.au/publication/supplier-assessment-approval-and-

qualification-listed-and-complementary-medicines https://www.tga.gov.au/publication/compositional-guidelines

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