'Minimum' quality standards

TGO 101 sets out requirements which together comprise the 'minimum quality standard' for tablets, capsules and pills supplied in Australia. In some instances tighter limits or additional requirements may be necessary to ensure that certain medicines are safe and effective.

For example, tighter limits on assay results might be applied to active ingredients with a narrow therapeutic index; or additional tests may be included in product specifications to control synthetic impurities that pose a safety risk.

TGO 101 recognises that a medicine may have multiple applicable monographs. Even when these exist, a sponsor may choose to comply with the requirements of Division 3 - Australian specific requirements instead. If this decision is made, the sponsor should consider how the two sets of requirements align and note that the requirements in the Order take precedence over requirements in a default standard only when these are inconsistent.

Sponsors of listed medicines must be aware of, and comply with, any other requirements that affect the eligibility of their medicine for listing on the ARTG.

Please refer to the relevant regulatory guidelines for further information on each medicine type.

Once approved, a medicine must comply with its marketing authorisation. A medicine supplied in contravention of its authorisation is supplied unlawfully, even if it complies with the requirements of TGO 101.

General monographs and general chapters in the default standards

Applying the requirements of an applicable monograph draws in requirements from both the specific monograph and the general monograph (or their equivalents) in the relevant pharmacopoeia.

Similarly, consideration of the general monographs of the BP or EP or the general chapters of the USP is necessary when applying the Australian specific requirements.

The requirements of the default standards apply except where the Order includes a conflicting requirement. Where the requirements are inconsistent, the Order takes precedence.

Impurities

Medicines that adopt the requirements of an applicable monograph, must comply with any impurity requirements set out in the relevant pharmacopoeia. These include related substances, degradants, solvents and elemental impurities. Impurity limits are usually found within the general monographs of the pharmacopoeias.

Limits for residual solvents and heavy metals are identified in the Australian specific requirements. While these may replicate the requirements in general monographs or general chapters, they have been included in the Order for clarity and consistency.

The need for testing

In many cases, existing controls on impurities in the ingredients included in the medicine and compliance with GMP requirements may be sufficient to establish compliance of the finished good with the Order. Sponsors and manufacturers may be able to justify the absence of an impurity test in finished goods specifications or the use of reduced or rotational testing.

Residual solvents

The requirements for residual solvents are identified in the Order as being those provided in Ph. Eur 5.4. This section of the EP incorporates the ICH Q3C guideline. The reference is made in this way to ensure consistency with the requirements provided in the default standards.

Elemental impurities

Where an applicable monograph is not followed, the Order specifies limits on the heavy metals lead, cadmium, arsenic and mercury. Other elemental impurities should also be considered as appropriate.

For lead, arsenic, cadmium and mercury, compliance to either USP<2232> or ICH Q3D is acceptable. Both documents provide guidance on methods for establishing maximum values for elemental impurities based on the permitted daily exposure (PDE) of each element.

How is compliance determined?

Not all of the specified tests set out in the Order must be performed on all medicines, or on all batches of a medicine.

A manufacturer does not have to perform all tests in the selected applicable monograph, or in the Australian specific requirements, before the release of every batch. The basis of the design of the medicine, together with its control strategy and validation or stability data can demonstrate that the standard will be met.

For example:

• Manufacturing documentation can show that no organic solvents are used in any step of manufacture of the medicine. In this case, routine testing for residual solvents is not expected.
• Dissolution testing may be done on a rotational basis, if it can be demonstrated through data derived from manufacturing validation studies that the medicine adheres to the dissolution requirements of the Order.

However, if a released batch of the medicine was found to contain unacceptable levels of solvent residues, or failed the relevant dissolution test, it would not comply with the Order and regulatory action could be taken.

Updating agreed testing specifications

Sponsors can update the testing specifications and limits that apply to their medicines within the confines of TGO 101.

TGO 101 recognises that where a medicine meets the definition of an individual monograph in more than one pharmacopoeia (i.e. in the EP, BP or USP), compliance with one standard is sufficient. Similarly, the Australian specific requirements in TGO 101 are considered equivalent to an applicable monograph. Therefore, a sponsor can request that an approved medicine be varied to adopt alternative, equivalent sets of requirements within TGO 101.

These requests are considered minor variations to registered medicines and must be approved by the TGA before implementation. The same change can be made to listed medicines without approval by the TGA but must be made in line with the requirements for the Code of Good Manufacturing Practice (PIC/S Code).