15.6 Choice of the reference product for bioequivalence of generic medicines

Reference products

To register a new generic medicine in Australia, you must demonstrate bioequivalence against the Australian reference product.

A bioequivalence study using an overseas reference product may be acceptable, provided you can demonstrate identicality between the Australian and overseas reference products.

An overseas reference product can be used for:

• solid oral, immediate and modified release tablets and capsules
• oral suspensions

For inhalation products see guidance on inhalation and nasal spray registered medicines.

The Australian reference product should be used for other dosage forms that require a bioequivalence study (see Guidance 15.4). Please contact streamlinedsubmission@tga.gov.au at the TGA for specific advice.

Conditions for using an overseas reference product

If you intend to use an overseas reference product, you must ensure it meets both the following conditions:

• registered in, and obtained from, a country or jurisdiction with a regulatory system comparable to Australia
• marketed in the country of origin by the same company as the Australian reference product, or by a corporate entity that has a licensing arrangement with the company.

If the reference product does not meet the conditions listed above, you must submit a bioequivalence study using the Australian reference product.

Demonstrating the overseas and Australian reference products are identical

You need to provide evidence that the overseas reference product is identical to the Australian reference product.

The level of evidence required varies depending on several factors. Use the evidence requirement decision tree below to determine which scenario you meet and what evidence you are required to submit. You can also use the checklist table to help determine the evidence required for each scenario.

Evidence requirement decision tree

Scenario 1

The following evidence is required:

• a declaration from the innovator company that the overseas and Australian reference products are identical in all respects including formulation and method of manufacture.

Scenario 2

The following evidence is required:

• Evidence that the overseas and Australian reference products:
  • have the same size, shape, weight, colour and markings
  • contain the same nominal quantity of drug substance
  • have the same qualitative formulation (e.g. as detailed in product information documents)
• Copies of the labels and product information (or equivalent document) for both the overseas and Australian reference products.
• Certificates of analysis for both the overseas and Australian reference products analysed using the specifications proposed in the application for the generic medicine.
• Comparative dissolution profiles (see Guidance 15.2) of the overseas and the Australian reference products. The profiles should be determined across the physiological pH range (pH 1.2-6.8), including the Quality Control method.

For Scenario 2, the same evidence is required for immediate and modified release tablets and capsules.

Scenario 3

The following evidence is required:

• Evidence that the overseas and Australian reference products:
  • have the same size, shape, weight
  • do not have a narrow therapeutic index
  • contain the same nominal quantity of drug substance
  • have the same qualitative formulation, other than differences attributable to colours and/or markings (e.g. as detailed in product information documents).
• Copies of the labels and product information (or equivalent document) for both the overseas and Australian reference products.
• Certificates of analysis for both the overseas and Australian reference products analysed using the specifications proposed in the application for the generic medicine.
• Comparative dissolution profiles (see Guidance 15.2) of the overseas and the Australian reference products. The profiles should be determined across the physiological pH range (pH 1.2-6.8), including the Quality Control method.
• Evidence that the drug substance has a well-described dose-response curve and does not exhibit:
  • a steep dose-response relationship
  • a risk of serious undesired effects
  • complicated or variable pharmacokinetics, such as:
    • nonlinear pharmacokinetics
    • variable or incomplete absorption
  • an absorption window (i.e. site-specific absorption) or substantial (> 40 per cent) first-pass metabolism.
• Physicochemical evidence generated by an accredited laboratory demonstrating the overseas and Australian reference products are quantitatively identical.
  • This may include Fourier transform infrared spectra, X-ray diffraction spectra, and full or partial quantitative chemical analyses (carried out in duplicate) of the excipients in those products.
  • If a tablet is coated, provide spectroscopic and chemical analytical data for both the core and the coating, wherever possible.
  • Provide data for at least two batches of each of the Australian and overseas reference products.

The precision and accuracy of the analytical methods and the inter-batch variability are critical to determining if the formulations are identical. The analytical methods and analytical method validation reports used to generate the physicochemical data are typically provided to satisfy this requirement.
As part of the validation of the test methods used, three batches of the proposed product should be tested with the test methods to demonstrate that the results obtained are both accurate and precise.

For modified release products:

Evidence is required to demonstrate that the Australian and overseas reference products have the same method of manufacture.

Scenario 4

The following evidence is required:

• Evidence to demonstrate that the overseas and Australian reference products:
  • have the same appearance
  • do not have a narrow therapeutic index
  • contain the same nominal quantity of drug substance
  • have the same qualitative formulation (e.g. as detailed in product information documents).
• Copies of the labels and product information (or equivalent document) for both the overseas and Australian reference products.
• Certificates of analysis for both the overseas and Australian reference products analysed using the specifications proposed in the application for the generic medicine.
• Comparative dissolution profiles (see Guidance 15.2) of the overseas and the Australian reference products. The profiles should be determined across the physiological pH range (pH 1.2-6.8), including the Quality Control method.
• Evidence that the overseas reference product has the same particle size distribution of suspended drug substance as the Australian reference product.
• Evidence that the overseas reference product has comparable re-suspension times to the Australian reference product.
• Physicochemical evidence. This might include, but not be limited to pH, buffer capacity, viscosity, surface tension and refractive index. Seek advice on relevant guidelines prior to submission if required.

Checklist table

The checklist table below may be used as a checklist for the evidence required for each scenario.

Grey boxes indicate that evidence is not required for the scenario. Further detail regarding these requirements can be found in the relevant scenarios detailed above.

Checklist table

Evidence required	Scenario 1	Scenario 2	Scenario 3	Scenario 4
Declaration from the innovator company	Yes	No	No	No
Dosage form size, shape, weight, colour and markings	No	Yes	No	No
Dosage form size, shape and weight	No	Yes	No	No
Quantity of drug substance	No	Yes	Yes	Yes
Qualitative formulation	No	Yes	Yes	Yes
Labels and PI	No	Yes	Yes	Yes
Certificate of analysis	No	Yes	Yes	Yes
Dissolution profile	No	Yes	Yes	Yes
Drug substance is not narrow therapeutic index	No	No	Yes	Yes
The drug substance has a well-described dose-response curve	No	No	Yes	Yes
Physicochemical evidence	No	No	Yes	Yes
Method of manufacture (modified release products only)	No	No	Yes	No
Physical appearance	No	No	No	Yes
Particle size distribution of suspended drug substance	No	No	No	Yes
Re-suspension times	No	No	No	Yes