Applications to register new biological medicines are:

• managed through the prescription medicines registration process
• to be submitted in Common Technical Document (CTD) format
• in the course of evaluation, risk-assessed (see Risk assessment) and assigned to a risk category

Variations to an ARTG entry use the normal Category 3 and self-assessable request processes.

Significant changes in the manufacturing process

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.

Requirements for batch/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.

Additional information which may be requested

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:

• a Certified Product Details (CPD) document
• pre-registration samples, standards and consumables for method development.

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.

On this page: Risk assessment tool for biological medicines | How the risk assessment tool works | Other factors we may consider | Calculating testing intervals

Risk assessment tool for biological medicines

To objectively assess the risk posed by a therapeutic good, we developed a risk assessment tool, which addresses the risks:

• inherent in the product and its use (consequence)
• posed by its manufacture, distribution and marketing (likelihood)

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'.

How the risk assessment tool works

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:

• Risk to the consumer (scheduling)
• Access to alternative medicines
• Vulnerability of the patient population
• Good manufacturing practice issues
• Risk of route of administration
• Adverse events, locally and overseas
• Volume of product used
• Testing failures, locally and overseas
• Type of use (acute or chronic)
• Possibility of counterfeiting
• Complexity of product structure
• Length of registration and product record
• Complexity of manufacturing process and testing
• Recalls of the product, locally and overseas
• Stability of product
• Issues raised by premarket evaluator(s)

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.

Other factors we may consider

We may consider other mitigating or exacerbating factors, such as:

• the corrective actions established by the sponsor
• the severity or pervasiveness of reported adverse events
• stakeholder sensitivity to adverse events.

These factors are recorded in both the review of the calculated risk group, and the final risk group.

Calculating testing intervals

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:

• any reports of critical GMP deviations, testing failures, severe adverse event and recalls to be used in subsequent risk assessments, or
• to explain the reason for any immediate risk assessment updates and/or actions taken in respect of any of these problems.

Example of the ongoing monitoring program calculations and records

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.

On this page: The five risk groups assigned by the risk assessment tool | 1. Pre-registration assessment and testing | 2. Initial batch release | 3. Ongoing batch release | 4. Protocol release | 5. Post market monitoring program

The five risk groups assigned by the risk assessment tool

The five (5) risk groups in the risk assessment tool (and the quick-reference colours used for each) are:

1. Pre-registration assessment and testing (grey)
2. Initial batch release (orange)
3. Ongoing batch release (red)
4. Protocol release (yellow)
5. Post market monitoring program (green)

1. Pre-registration assessment and testing

Samples submitted before registration for method development and validation are placed in this risk group.

• The batches may be unlabelled, or carry overseas labels.
• No regulatory action is taken on the testing results.

As testing methods have to be validated (see Validating a method for use) when products are placed in Risk Group 1, we then request*:

• a CPD document
• pre-registration samples
• standards
• consumables.

*usually after we complete the second round of evaluation.

2. Initial batch release

This risk group aims to demonstrate batch consistency of new, or significantly modified, biological prescription medicines:

• All new biological medicines are placed on batch release as a condition of registration (either in the approval letter, or in a separate section 28 letter).
• Variations to the manufacturing process of already registered products assessed as:
  • posing sufficient risk, or
  • deemed to be sufficiently different to the original product (e.g. transfection of a new cell-line with a different genetic construct)
  may also be placed on batch or protocol release conditions, even if they have demonstrated batch consistency at registration. (Sponsors will be informed either in the Category 3 approval letter or in a subsequent section 28 letter)

In this section: Requirements for batch release (both initial and ongoing) | Requirements for testing samples | Timeframe for testing | Time a product will remain under these conditions | If the medicine is urgently needed

Requirements for batch release (both initial and ongoing)

We require:

• full Certificates of Analysis of the drug product and drug substance batches
• evidence of maintenance of approved temperature storage conditions during shipment to Australia for the drug product
• samples of the drug product
• relevant reference standards, controls, cell lines, and other proprietary material required for the testing to be performed

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:

• gel photographs
• chromatography traces
• statistical analysis

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.

Requirements for testing samples

• Batches of drug product should be from different, independently manufactured, drug substance batches.
• When drug product batches are made from the same drug substance batch, you only need to provide samples for the first drug product batch.
• For subsequent batches of drug product from the same drug substance lot, you only need to supply:
  • a statement detailing the drug substance identity
  • the Certificate of Analysis of the drug product lot(s)
  • evidence of maintenance of approved temperature storage conditions during shipment.

Arrangement for the delivery of the requested items can be made by contacting Biochemistry.Testing@tga.gov.au.

Timeframe for testing

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:

• samples involving in vivo assays may take several weeks
• samples involving only a single physicochemical test may be as short as 5 working days.

Time a product will remain under these conditions

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:

• update the risk assessment for the medicine
• assign it to the appropriate risk category
• inform the sponsor of the changes to conditions of registration (with a section 28 letter).

If the medicine is urgently needed

You may request early release based on the data you supplied on the understanding that:

• this approach is required because of special circumstances
• it does not set a precedent for the early release of any other products
• if subsequent testing shows non-compliance with specification, a recall of the batch may be necessary.

3. Ongoing batch release

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).

4. Protocol release

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:

• GMP
• adverse events
• repeated testing failures and/or product recalls.

Monitoring of the data may continue until there is adequate resolution of the original problems, even where:

• ongoing batch release testing is completed, and
• the analytical data have been demonstrated as reliable.

In other cases, the problems are sufficient to:

• require close monitoring of the product, but
• do not warrant physical testing of samples (e.g. recalls for labelling problems which don't affect the quality or safety of the product, or when significant manufacturing problems have been reported but adequate corrective actions have been taken).

Requirements for protocol release

We require:

• full Certificates of Analysis of the drug product and, where specifically requested, drug substance batches, and
• evidence that approved temperature storage conditions have been maintained during shipment to Australia.

We will email you a letter changing the conditions of registration (under section 28 of the Act) when all problems have been resolved.

How long protocol release takes

We will usually assess the data within 5 working days.

5. Post market monitoring program

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:

• submission of an Annual Report
• periodic testing (usually by product surveys)

In this section: Annual Reports | Product surveys | Periodic risk assessments and changes to risk group | Testing methods and handling of results | Certified Product Details (CPD)

Annual Reports

The format of the Annual Report is in the template available on our website. It requires the number of:

• batches, and the number of units, distributed in each year
• deviations from approved storage conditions (during shipping) for that year (See Temperature excursions). If there are unapproved temperature excursions, ensure you attach the deviation reports.

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.

Deadline for annual reports

The timing is flexible, and you can negotiate this by contacting us via email at: Biochemistry.Testing@tga.gov.au.

Product surveys

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:

• with similar drug substances, or
• used for similar indications.

For example, all:

• insulin preparations (whether short or long acting), or
• erythropoiesis stimulating agents (even though the drug substances are different).

Testing results

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.

Periodic risk assessments and changes to risk group

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:

• batch consistency is demonstrated, and
• the initial batch release is ended by a change of conditions of registration (under section 28 of the Act).

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 significant or severe problems

If there are local or overseas reports of significant or severe problems with:

• GMP
• adverse events
• repeated testing failures and/or product recalls

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.

Changes to risk group

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.

Testing methods and handling of results

Where available, we use pharmacopoeial methodologies to test products, however we will apply the approved specifications if they differ from the pharmacopoeial standards.

Where pharmacopoeial methods aren't available

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.

Validating a method for use

Before we use any method, we validate their use according to the following standards:

• Current Good Manufacturing Practice for Finished Pharmaceuticals, section 194 (a)(2), US Code of Federal Regulation - Part 211
• General Requirements For The Competence Of Testing And Calibration Laboratories, ISO/IEC 17025, Part 5.4.2
• Guidelines for the validation and verification of quantitative and qualitative test methods. NATA technical Note 17 – October 2013
• Validation of Analytical Procedures: Text and Methodology Q2(R1), ICH Harmonised Tripartite Guideline.

Because methods need to be validated before use in batch release, products are placed in Risk Group 1 before registration, and we then request*:

• a CPD document
• pre-registration samples
• standards
• consumables.

*usually after we complete the second round of evaluation.

General methodologies which are neither pharmacopoeial nor CPD

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).

If deviation from specification is detected

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:

• For marginal failures, this may be a simple information letter, a warning and/or possible request for further samples (for testing).
• For significant failures (or failures which may have safety implications), the batch may be recalled and you may be required to send 'Dear Doctor' letters.

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.

Certified Product Details (CPD)

The Certified Product Details (CPD) of a biological medicine specifies its:

• formulation
• manufacturing process
• test methods
• specifications.

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).

Approved changes to existing ARTG entries

Ensure you provide an updated CPD when we approve changes* to the:

• drug substance
• product specifications and/or test methods

*via a Category 3 application, or a self-assessable change

Treatment of confidential information

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.

Temperature excursions

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.

Evaluation and registration of all new biological medicines:

• section 25 of the Therapeutic Goods Act 1989 (the Act)
• with reference to subregulations 16C and 16D of the Therapeutic Goods Regulations 1990 (the Regulations)

Variation of the entry of the ARTG:

• section 9D of the Act

Conditions of registration:

• section 28 of the Act

Example: biological medicine risk assessment tool

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.