V1.0 December 2015
This guidance applies to biological medicines, and outlines the current processes we use to test them during and after registration.
Although these policies and processes have been in place since 2007, we are now publishing them as part of TGA's ongoing transparency initiatives.
Please note
Although included in the definition of biological medicines, this guidance does not apply to vaccines, anti-venoms and toxins.
Post-registration testing of vaccines complies with internationally accepted guidelines (most recently published in Annex 2 of the WHO Technical Report Series (TRS 978) (pdf,439kb)). This will be described within guidance we are currently developing for post-registration testing of vaccines.
Version | Description of change | Author | Effective date |
---|---|---|---|
V1.0 | Original publication | TGA | 22/12/2015 |
V1.0 December 2015
Applications to register new biological medicines are:
Variations to an ARTG entry use the normal Category 3 and self-assessable request processes.
If there is a significant change in manufacturing process, a comparability study between the pre- and post-change product will be required.
Where significant changes are made to the manufacturing process as a variation of the ARTG entry, a risk assessment is done (see Risk assessment) and if the risk level is increased sufficiently, the product may be placed on batch or protocol release.
We assess the requirements for batch/protocol release testing during the evaluation process, and any recommendations are passed to the Delegate for consideration for inclusion in the approval letter.
If assays used in the analysis of a new biological medicine are complex and where the approval of the new biological medicine seems likely and usually shortly after the second round of evaluation, the TGA may request:
V1.0 December 2015
We apply a risk-based strategy that directs increased testing to high risk products, while allowing lower risk products to be tested either less frequently, or with less labour-intensive methods.
To objectively assess the risk posed by a therapeutic good, we developed a risk assessment tool, which addresses the risks:
During development (and adaptation for biological medicines), the risk assessment tool was extensively and rigorously tested against a wide range of products which confirmed the process was objective, reliable and robust.
In addition, the risk assessment tool was reviewed by an external academic specialist, who found it 'comprehensive and well thought out'.
The risk assessment tool assigns numerical weightings based on answers to relevant questions.
For example, as medicines in schedule 4 or 8 pose a greater risk to consumers, they have a higher weighting than those in schedules 2 or 3, which in turn have a higher weighting than unscheduled medicines.
The issues we examine are:
Each of the issues has their own numerical weighting. Issues of consequence are added together, as are those for likelihood. The total values for consequence and likelihood are then multiplied to give a numerical risk factor, and from this, the product is allocated a calculated risk group.
We may consider other mitigating or exacerbating factors, such as:
These factors are recorded in both the review of the calculated risk group, and the final risk group.
The risk assessment tool uses the inherent risk of a product (consequence x likelihood scores) to calculate a testing interval, and a risk assessment interval (as illustrated by the fictitious ongoing monitoring example).
A table in the risk assessment tool is then used to record:
This image represents a screenshot from TGA's risk assessment tool for biological medicines testing.
It is one of the final report screens which displays how frequently a biological medicine should be tested based on the information provided.
It displays the test group (product type) showing its final risk score (consequence of risk multiplied by likelihood of risk).
It then displays recommended testing intervals (in years) and risk assessment intervals (also in years). It shows the date these were last assessed, and when they are next due.
There is a field for further information, such as name of analyst, and action taken.
V1.0 December 2015
The five (5) risk groups in the risk assessment tool (and the quick-reference colours used for each) are:
Samples submitted before registration for method development and validation are placed in this risk group.
As testing methods have to be validated (see Validating a method for use) when products are placed in Risk Group 1, we then request*:
*usually after we complete the second round of evaluation.
This risk group aims to demonstrate batch consistency of new, or significantly modified, biological prescription medicines:
We require:
These should be sent to the Biochemistry Section with sufficient lead time to allow for the appropriate testing.
In some cases, we may also require you to send raw data for specified assays, including:
We will assess the data, and test the samples, as quickly as possible to ensure you can distribute the product as soon as possible. We will email you with the release letter when this is completed.
Arrangement for the delivery of the requested items can be made by contacting Biochemistry.Testing@tga.gov.au.
It can be helpful to give us prior notice of the arrival of samples so we can schedule testing at the earliest opportunity, however testing time will vary depending on the test. For example:
They will remain in place until batch consistency has been demonstrated, (usually 5 independent drug substance batches).
When batch consistency has been demonstrated, we will:
You may request early release based on the data you supplied on the understanding that:
This risk group aims to monitor and test high risk medicines associated with severe GMP problems, life-threatening adverse events, repeated testing failures and/or product recalls.
They are placed in this group as a condition of registration (under section 28 of the Act) when directed testing will mitigate the risk factors that lead to the change of risk group. They will remain on batch release until the problems have been adequately dealt with and the conditions of registration are changed (in a section 28 letter).
This risk group aims to monitor high risk products which have been on ongoing batch release and/or have significant, but not severe, problems with:
Monitoring of the data may continue until there is adequate resolution of the original problems, even where:
In other cases, the problems are sufficient to:
We require:
We will email you a letter changing the conditions of registration (under section 28 of the Act) when all problems have been resolved.
We will usually assess the data within 5 working days.
This risk group aims to monitor relatively low risk biological medicines, where batch consistency and good compliance has been demonstrated.
The post market monitoring program involves:
The format of the Annual Report is in the template available on our website. It requires the number of:
All of these batch data and deviation reports and/or justifications should be immediately available to the sponsor under GMP requirements, and deviations should be relatively few in a well-controlled QA system.
We use information in the Annual Report to update information in the Risk Assessment tool; however, if inadequate deviation reports are submitted, we may request more information.
The timing is flexible, and you can negotiate this by contacting us via email at: Biochemistry.Testing@tga.gov.au.
We attempt to test all biological medicines on the market (at regular intervals) using a risk-based prioritisation. The interval is calculated in the risk assessment tool from the inherent risk of the product, as illustrated in the ongoing monitoring calculations example.
We request samples from all sponsors marketing products:
For example, all:
We inform sponsors of the testing results in a test report letter.
Any excursions from specification are dealt with in consultation with the sponsor and, if necessary, other Branches of the TGA.
We initiate a laboratory testing risk assessment once the second round of evaluation is completed. For most biological medicines, the risk assessment results in initial batch release.
We update the risk assessment once:
After this, we assign most biological medicines (excluding vaccines, anti-venoms, and toxins) to the post market monitoring program. From that time, we update the risk assessment on a regular basis (usually every three years).
If there are local or overseas reports of significant or severe problems with:
we will use these to update the risk assessment. This may trigger an immediate update if the severity warrants it. For example, where there are reports of life threatening adverse events or immunogenic reactions.
If the risk assessment tool identifies a change in the risk of the product, this may trigger a recommendation to change the risk group.
We will consider any mitigating or exacerbating factors (in consultation with the sponsor), before assigning the product to an appropriate risk group.
If this risk group is different to the current risk group of the product, we will vary the conditions of registration (under section 28 of the Act) and inform the sponsor by mail.
Where available, we use pharmacopoeial methodologies to test products, however we will apply the approved specifications if they differ from the pharmacopoeial standards.
We use methodologies detailed in the Certified Product Details (CPD) or general methods that have been validated for use against pharmacopoeial and/or CPD methods.
Before we use any method, we validate their use according to the following standards:
Because methods need to be validated before use in batch release, products are placed in Risk Group 1 before registration, and we then request*:
*usually after we complete the second round of evaluation.
Under some circumstances, general methodologies are developed, which are neither pharmacopoeial nor CPD methods but which apply to several products. For example, size exclusion content and purity tests for all monoclonal antibodies.
In these cases, we perform full validation of the methods according to ICH, ISO/IEC and NATA guidelines, and compare them to any available pharmacopoeial and/or CPD methods. We conduct all methods under a rigorous Quality System, which is audited and accredited by the National Association of Testing Authorities (NATA).
The samples are re-tested in independent assay(s); if possible, using a different accredited analyst.
If the assay giving the failure was not pharmacopoeial or CPD, we may repeat the tests with a pharmacopoeial or CPD assay (if one is available). We will inform you when we confirm the deviation, and negotiate an appropriate course of action:
We enter these testing results into the Risk Assessment tool, which may result in a change of Risk Group for the product.
In future, we may publish a brief summary of the testing results on the TGA website.
The Certified Product Details (CPD) of a biological medicine specifies its:
A template to prepare a CPD is on our website.
Once drafted, send it as a single pdf document to Biochemistry.Testing@tga.gov.au. You can also use this address as a first point-of-contact on any testing issue.
When a new biological medicine is registered, ensure you provide us with an electronic draft of the CPD, as described in Guidance 7: Certified Product Details (Australian Regulatory Guidelines for Prescription Medicines).
Ensure you provide an updated CPD when we approve changes* to the:
*via a Category 3 application, or a self-assessable change
As laboratory protocols and Reference Standards may be subject to Intellectual Property protection, all information supplied in the CPD will be treated as official information as detailed in Treatment of information provided to the TGA.
Deviations from approved storage conditions may cause a biological medicine to be of unacceptable quality and therefore not suitable for supply.
There are ways you can gain permanent approval of temperature excursions (of specified and validated magnitude and duration) to allow you to manage them under GMP. See Temperature excursions of biological medicines.
V1.0 December 2015
Evaluation and registration of all new biological medicines:
Variation of the entry of the ARTG:
Conditions of registration:
V1.0 December 2015
This image represents a screenshot of the report page of TGA's biological medicine risk assessment tool.
It displays the sponsor name, each product which was entered (including its ARTG number).
Below this, it displays scores for both consequence and likelihood of risks, and the total score which results from multiplying the consequence and likelihood scores.
Where this total score sits within a range determines the risk level of a product for the purpose of testing.
The report also displays a calculated risk rating; calculated risk group; a description field for the review of the risk assessment; and a final risk group rating.