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Quality control (Chapter 6, Part I - finished dosage form)
In addition to the requirements outlined in the PIC/S guide to GMP, there are various standards that apply to medicinal cannabis products, including but not limited to, the Therapeutic Goods (Standard for Medicinal Cannabis) (TGO 93) Order.
Reduced or rotational testing of the cannabis plant used in the manufacture of the product can be carried out provided that this is justified on good manufacturing practice grounds.
For example, a manufacturer may be able to justify reducing or not conducting pesticide testing if no pesticides are used in the cultivation of the cannabis plant. The manufacturer should ensure that the product will meet all the requirements of the standard.
Conducting on-going stability studies
Principles for conducting on-going stability studies
In general, on-going stability studies should be based on the principles of ICH Q1.
Ongoing stability would not normally be applicable for clinical trial material. Stability would be required according to Annex 13 to support the expiry date for the material. The clauses that would be applicable for stability of clinical trial material include Annex 13, clauses 6, 9, 20, 26j and 40.
Use of on-going stability program results in release for supply
The results of the on-going stability program are expected to be available to the authorised person who should consider the results before releasing a batch for supply.
On-going stability studies in a GMP certified laboratory
Ongoing stability testing does not need to be conducted in a GMP certified laboratory, because ongoing stability testing is not considered to be a step in manufacture, as defined by the Therapeutic Goods Act 1989.
However, the results from these studies are required to be reliable and meaningful. It is the responsibility of the contract giver (typically a manufacturer or sponsor) to ensure that any laboratories used for ongoing stability testing is appropriate.
For that reason, other certification may be used in lieu of a GMP certification, such as a licence issued by a regulatory authority acceptable to the TGA or a current ISO 17025 accreditation. Stability test methods used by the laboratory should be appropriately validated and documented according to the requirements of the PIC/S Guide to GMP.
The results from the on-going stability monitoring studies must be considered as part of release for supply, which is the final step in manufacturing.
Responsibility for ongoing stability studies of imported medicines
In the case of imported medicines, the responsibility to conduct an on-going stability monitoring program is with both the manufacturer and the sponsor:
- The manufacturer who carries out release for supply needs to ensure that the batch meets its marketing authorisation, and that an on-going stability monitoring program is conducted and data is available to support the expiry date.
- The sponsor is responsible for the marketing authorisation and ensures an on-going stability testing program is performed and has access to the stability results.
In the contract manufacturing agreement, the responsibility for on-going stability may be contracted out to the manufacturer or other parties.
Bulk medicine on-going stability studies
Where bulk medicines are imported into Australia to be packaged by an Australian manufacturer, the Australian manufacturer cannot use the on-going stability program of the bulk manufacturer to support the packed product stability.
On-going stability is required to be performed in the packaging material in which the product is marketed in Australia. The overseas bulk manufacturer will use different packaging equipment and processes although the packaging materials might be the same.
Grouping for the purposes of stability testing
Grouping (also known as bracketing or matrixing) could be acceptable, if scientifically justified. This will be assessed during inspections on a case-by-case basis. This is applicable to medicinal cannabis products provided the active cannabinoid type is considered in the grouping.
Review of on-going stability data during inspections
During inspections, the operation of an appropriate on-going stability program is normally reviewed, including the results of on-going stability studies, where appropriate. If there are any concerns, the inspector can refer the evaluation to the area of the TGA responsible for regulating the product ARTG entry.
Notifying TGA of on-going stability issues
Although it is acknowledged that some normal variability in the results of on-going stability studies can be expected, all statistically significant departures from established stability profiles must be notified to the area of the TGA responsible for regulating the product ARTG entry. In general, 'significant change' for a medicinal product is defined as:
- a 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures
- any degradation products exceeding its acceptance criterion
- failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g. colour, phase separation, re-suspendibility, caking, hardness, dose delivery per actuation); however, some changes in physical attributes (e.g. softening of suppositories, melting of creams) may be expected under accelerated conditions
- as appropriate for the dosage form:
- failure to meet the acceptance criterion for pH
- failure to meet the acceptance criteria for dissolution for 12 dosage units