In 2016, the TGA conducted targeted compliance reviews for listed medicines that are subject to the Aristolochic acids condition of listing.
Background
For safety reasons Aristolochic acids and all plant species that might contain Aristolochic acids are prohibited from supply, sale or use in medicines in Australia.
Some listed medicines contain plant species that look very similar or have a name that sounds very similar to plant species that are likely to contain aristolochic acids. This means these listed medicines are at risk of containing aristolochic acids due to inadvertent substitution of plant species that do not contain aristolochic acids with ones that do during the manufacture of the medicine.
To address this risk, the TGA places a condition of listing on these particular at-risk listed medicines. This condition of listing requires that sponsors of these medicines confirm the absence of aristolochic acids in their medicine (they are undetectable by suitable testing methods) and get TGA approval before releasing each batch of the medicine.
The TGA received signals that not all sponsors of medicines which had the condition of listing, were seeking batch release approval. As a result, we had concerns about potential compliance breaches of the condition of listing.
Findings
- We identified 89 listed medicines on Australian Register of Therapeutic Goods (ARTG) which needed to comply with the aristolochic acid condition of listing.
- Of these, 60 were available at the time for sale in the Australian marketplace.
- We reviewed these 60 medicines to check their compliance with the requirements related to aristolochic acids.
What did the TGA find?
- Only 42% of the 60 medicines had sought approval before batch release.
- However, 83% were found to hold the right data as required and were able to supply the data when requested.
- Around 17% did not hold the correct data to comply with the condition of listing and further regulatory action was taken.
What did industry do well?
- We received a 100% response rate from sponsors.
- 83% of the medicines were found to have the acceptable data when requested.
How can industry improve?
- We identified the common reasons for non-compliance and have summarised these below.
- We would like industry to use this information to improve their compliance with regulatory obligations.
- Know and understand that medicines at risk of containing aristolochic acids are subject to special conditions.
- Have agreements in place with your manufacturer(s) to obtain the raw data.
- Submit your data and seek TGA approval before batch release.
What will the TGA do in the future?
- We will conduct a further targeted investigation (compliance and testing).
- We will continue to give consideration to which of the species are still suitable for listed medicines.
- We will continue to monitor the suitability of the condition of listing and any scope for amendment as required.
If you require further information please contact the complementary medicines helpdesk at nonprescriptionmedicines@health.gov.au.
Information for sponsors
If you are the sponsor of one or more listed medicines which have the aristolochic acids condition of listing, you should review your records and ensure that you:
- hold evidence to confirm the absence of aristolochic acids (that they are undetectable by suitable testing methods); and
- provide this evidence to us at the TGA for evaluation and approval, prior to supply of each batch in Australia.
Further technical advice for sponsors to comply with the Condition of Listing
Chemical testing
- The confirmation must be undertaken by chemical analysis using Liquid Chromatography Mass Spectrometry (LC-MS). The methodology used should adhere to best practice according to contemporary scientific literature.
- Provide a certificate of chemical analysis by LC-MS, including raw data generated in the analysis, to the TGA. This data should include a sample spiked with aristolochic acid at the limit of detection clearly showing the presence of aristolochic acid. The method should be capable of detecting a level of 100 ppb or lower in a spiked sample, which the currently available literature indicates is an achievable detection limit with modern instruments.
- The limit of detection of an LC-MS method will depend on various factors including the sensitivity of the instrument and the type of sample matrix.
- While the LC-MS test method may be approved with a particular limit of detection for the purposes of the condition of listing, this does not prevent regulatory action from being considered should TGA testing of a sample of a batch by a different method find an amount of aristolochic acid below that particular limit.