Active pharmaceutical ingredient (API - Part II)
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
- a trituration of specified parts of the cannabis plant
- the dried flower of the cannabis plant separated from leaves and stem
The term 'API starting material' refers to the starting material from which the API is made, not to the API.
If your medicinal cannabis product is being used as an API in clinical trials, compliance with chapter 19 of Part II of the PIC/S Guide to GMP is of particular importance.
GMP does not apply to the cultivation and harvesting of cannabis plants for medicinal use. Table 1 in the introduction chapter of Part II of the PIC/S Guide to GMP provides guidance on the process steps from where GMP is expected to be increasingly applied, depending on the API manufacturing process.
The relevant entries of that table are copied in the table below:
|Type of manufacturing||Application of Part II of the Code of GMP to this type of product|
|API extracted from plant||Collection of plants||Cutting and initial extraction(s)||Introduction of the API starting material into the process||Isolation and purification||Physical processing and packaging|
|Herbal extracts used as API||Collection of plants||Cutting and initial extraction(s)||Further extraction||Physical processing and packaging|
|API consisting of powdered herbs||Collection of plants and/or cultivation and harvesting||Cutting and comminuting||Physical processing and packaging|
The blue shading (last three columns of the table) indicates manufacturing steps to which the PIC/S Guide to GMP applies, which means:
- 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.
- For powdered cannabis plant parts: GMP does not apply up to cutting and comminuting but increasingly applies from the moment of physical processing and packaging of the powder onwards.
You may need to seek advice from a GMP consultant or legal advice if you are unclear as to where GMP is required for your manufacturing process.
Some examples to illustrate where GMP starts and licensing is required for API manufacture including Quality Control:
- The processing steps of growing, cultivating, harvesting, cutting and early extraction using CO2 are not considered manufacturing steps where GMP applies if further processing, such as a purification or decarboxylation step, is performed. Both an ODC Medicinal Cannabis Licence and Narcotic Manufacture Licence are required for the steps before GMP. If there is no further purification or decarboxylation step performed on the initially extracted cannabis oil, then GMP may apply for the CO2 extraction, dependant on the final use of the material produced.
- The steps of further refinement and/or distillation of the cannabis oil, and concentrating to high percentage (selective cannabinoid i.e. THC), are considered manufacturing steps where GMP does apply and TGO 93 for quality control is required. A Narcotic Manufacture Licence is also required if the cannabinoids (such as THC or CBD) are being isolated.
- A GMP licence to manufacture would be required where GMP applies to the final API processing and packaging.
- In the case where already extracted API was purchased to be refined/undergo further API isolation/refining processes, the extract may be considered as the API starting material; GMP would start for material further processing to the final medicinal cannabis API form and packaging. A GMP licence would be required. An ODC licence would only be required if the API was undergoing refining to isolate cannabinoids such as CBD and THC.
- In the case where a powdered medicinal cannabis API was obtained for further processing to decrease the particle size or packing into final pack. The processing is subject to GMP with a GMP licence required.
- In the case of a medicinal cannabis oil, where GMP didn't apply to its production, was used to manufacture a finished product at a contract manufacturer, the oil would be treated as starting material (API) and would need to be quality control assessed before processing. A GMP licence is required, An ODC licence would only be required if the API was undergoing refining to isolate cannabinoids such as CBD and THC.
- In the case of packaging a medicinal cannabis API at a contract manufacturer, this is considered a GMP step of manufacture. The contract packaging company is required to hold a TGA licence.
- With respect to testing the API to TGO 93 requirements where the manufacturer has no testing capability on site, a contract laboratory may be used provided that the laboratory holds an appropriate TGA licence. The contract laboratory would be required to be GMP licensed for testing of APIs.
- In the case where cultivated medicinal cannabis plant or plant part does not undergo extraction but are comminuted/powdered, dried, packed and released for consumption or to be used as an API, GMP requirements would apply to the powder processing, drying and packing stages. The processes of herb drying and packing would not require a GMP licence if the material is to be used for further production at a GMP licenced manufacturer.
- In the case of a dried and/or milled medicinal cannabis plant (or plant part), where GMP didn't apply to its production, was further processed, extracted or used to manufacture a finished product at a contract manufacturer, the dried and/or milled medicinal cannabis plant (or plant part) would be treated as starting material (API) and would need to be quality control assessed before processing. A GMP licence is required. An ODC licence would only be required if the API was refined, concentrated and isolations occurred.
Cannabis oil and herb manufacture
A Licence to manufacture therapeutic goods (GMP) is required for the manufacture of cannabis oil in Australia unless exempt.
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. The exemption does not apply to ground/powdered herbs or herbal substances.
Note that these exemptions do not apply to any requirement to hold a Narcotic Manufacture Licence.
Air quality for crude plants
The environment for drying, crushing and sifting of crude plants should be clean and enclosed but does not need a filtered EU7 air environment.
Air quality for the manufacture of the API
For herbal manufacturing environments, where GMP applies, and during the final stages of manufacture where the API is exposed to the environment, a minimum of EU7 filtered air environment is expected.
The air control system is expected to be monitored and serviced with an appropriate environmental monitoring program.A separate storage area for crude plants (i.e. unprocessed) should be used, however, if common storage areas are used for crude plants and other materials, including packaging materials, then the manufacturer must be able to justify this practice.
A separate storage area for crude plants (i.e. unprocessed) should be used, however, if common storage areas are used for crude plants and other materials, including packaging materials, then the manufacturer must be able to justify this practice.
The water quality for the manufacture of the API should meet its intended purpose.
Process water used in the early stages of manufacture, unless otherwise justified, it should, at a minimum, meet World Health Organization (WHO) guidelines for drinking (potable) water quality.
Where water used in the process is treated by the manufacturer to achieve a defined quality, i.e. for final stages of API manufacture, the treatment process should be validated and monitored with appropriate action limits. This includes chemical and microbiological limits.
Purified water is expected to be used in the final API manufacturing stage to avoid any chemical and microbial impact on the final API where applicable.