Mandatory requirements for an effective application

Applicants should consult this guideline to ascertain:

• whether or not biopharmaceutic studies will be required to support their application in Australia.
• minimal issues to be addressed if providing a justification for not submitting biopharmaceutic data.
• issues to consider concerning the choice of reference product.

If it is unclear whether a medicine is of the category Prescription medicines which do not require biopharmaceutic data, the applicant should contact us prior to lodging the PPF.

While this guidance suggests that the design and conduct of the study should follow EU regulations on Good Clinical Practice, applicants should note that the EU Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) has been adopted in Australia with TGA annotations.

The procedure for abridged applications claiming essential similarity to a reference product (i.e. generics), which allows applications to be made to numerous Member States of the EU, based on bioequivalence with a reference product from one Member State, does not apply in Australia.

A bioequivalence study to support the registration of a generic product in Australia should use a reference product obtained in Australia. Where an overseas reference product is used, the applicant must be able to demonstrate the overseas and Australian reference products are identical (see TGA guideline Biopharmaceutic studies).

Locally applied products that do not act at the immediate site of application (skin, cornea etc.) are not covered by this guideline.

For example, eye drops that exert their effect beyond the cornea (i.e. the deeper tissues of the eye). Examples of such eye drops include eye drops for the treatment of glaucoma.

Requirements for establishing the bioequivalence of such products to a reference product are set out in the adopted EU Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1).

Products applied in a transdermal dosage form are not covered by this guideline – refer to the Note for Guidance on Modified Release Oral and Transdermal Dosage Forms.
Section II (Pharmacokinetic and Clinical Evaluation) (CPMP/EWP/280/96)

For multiple strengths of generic transdermal and modified release oral dosage forms, bioequivalence studies should be performed at least on the lowest and highest strengths versus the corresponding reference products.

If an applicant considers that this is unnecessary in a particular case, a justification for not submitting bioequivalence data should be submitted in accordance with the TGA guideline Biopharmaceutic studies (Justification for not submitting biopharmaceutic data).

Some clinical guidelines provide additional information about the studies needed to demonstrate therapeutic equivalence for specific therapeutic products or use. However, applicants must ensure the guidelines are relevant to their particular application/product.

For example, the guideline: Clinical Investigation of corticosteroids intended for use on the skin refers to the use of a vasoconstriction assay. This is an example of a pharmacodynamic endpoint that is not related to the therapeutic effect of the medicinal product. When using a pharmacodynamic model to replace clinical data, applicants must ensure the model chosen is internally valid. In the case of the vasoconstriction assay this endpoint may not be externally valid where the composition of the generic product differs to that of the reference product.

The use of pharmacodynamic endpoints should be justified in terms of their direct relevance to the intended therapeutic effect of the active component of the medicinal product.

See General dossier requirements – Part B

Applications must be submitted in eCTD format to be eligible for Priority review or the COR report-based process.

Applicants must identify in the letter of application how the deficiencies identified in the previous application have been addressed. To ensure that the data to be evaluated by the TGA are the current data relevant to that application, the applicant must provide:

A complete, up-to-date electronic data set for each new application.

A complete new Module 1 plus replacement for those volumes that have changed, plus any additional volumes. The letter of application must specify which modules and data volumes from the previous application should be used for the current application.

Data previously submitted to us must be clearly identified in the Table of Contents of the dossier.

• If an applicant is acting on behalf of another applicant, a letter of authorisation must be provided.
• Where the applicant is using another company's name and/or livery on labels, a letter of authorisation from the company owning the name/livery must be provided.

• The application must meet GMP requirements outlined in Manufacturing principles for medicinal products
• Under the COR report-based process:
  • COR-A applications must include evidence of compliance with GMP (a current GMP licence or clearance number for all relevant manufacturing sites)
  • COR-B applications must include evidence that the applicant has applied for a GMP clearance, licence or certification and paid the associated fee(s) for each manufacturing site.
• To be eligible for Priority review, applicants must:
  • provide evidence of compliance with GMP (a current GMP licence or clearance number for all relevant manufacturing sites); or
  • demonstrate they have applied for a GMP clearance, licence or certification and paid the associated fees for each manufacturing site.

• To be eligible for Priority review, applicants must provide a copy of the Priority review determination letter that was issued by the TGA. The determination must be in force at the time of making the application.
• To be eligible for a waiver of the section 23 application fees (for Priority or standard pathways), applicants must provide a copy of the Orphan drug designation letter that was issued by the TGA. The designation must be in force at the time of making the application.
   

The risk management plan (if required) is to comply with requirements as set out in TGA guidance: Risk management plans for medicines and biologicals.

The Risk Management Plan should be the current, unaltered EU-RMP (if available) and an Australian Specific Annex should be included. An alternative to the EU RMP is acceptable only if there is no current EU-RMP (see Risk management plans). All attachments, annexes and appendices referred to in the RMP should be in English and included in full in electronic form.
 

• In Module 1.8.3, applicants must provide a declaration of compliance with the information provided about the application(s) in the PPF (including attachments) and planning letter.
• The declaration must also address any issues that we raised in the planning letter, and identify how the issues were resolved in the application.

A justification for not providing biopharmaceutic studies against an Australian sourced reference product must be provided where the biopharmaceutic data provided have been generated against an overseas reference product.

_{Note: See Module 5 section in this document for further information and requirements about when this document must be provided.}

A justification for not providing appropriate biopharmaceutic studies must be provided where biopharmaceutic data are required (TGA guideline Biopharmaceutic studies - Medicines that require biopharmaceutic data) but have not been provided for one or more products.

Such a justification must consist of a document that:

• provides an accurate, robust and scientific response to each point/heading listed in Biopharmaceutic studies - Justification for not submitting biopharmaceutic data
• provides any other information relevant to the justification in separate section/s, and
• addresses any other aspects from relevant EU guidelines adopted in Australia (for example, Guideline on the investigation of bioequivalence CPMP/QWP/EWP/1401/98 Rev 1).

_{Note: See Module 5 section in this document for further information and requirements about when this document must be provided.}

A Module 2.4 must be supplied for all new generic applications where the active ingredient is a different salt/ester from the Australian reference product’s active ingredient.

A Module 2.4 must also be supplied where the levels of impurities and degradants lie outside the levels permitted in ICH guidelines. Except for biotechnology-derived products, an assessment of the impurities and degradants present in the drug substance and product should be included along with what is known of their potential pharmacologic and toxicologic effects. This assessment should form part of the justification for proposed impurity limits in the drug substance and product, and be appropriately cross-referenced to the quality documentation.

There are four options for providing the supporting data for the drug substances (active ingredients) in a product. One of these options MUST be used:

• drug master file (DMF) submitted
• certificate of suitability (CEP) submitted
• confirmation that all aspects of drug substance manufacture (including sterile manufacture, if applicable) and control has been previously approved by the TGA
• drug substance is fully described in Module 3.2.S.

_{Note: If the drug substance is sterile and is not subjected to further sterilisation during finished product manufacture, a CEP alone does not provide sufficient information for evaluation of sterility aspects. It may be submitted in conjunction with one of the other options (TGA Drug master file guideline).}
 

• The full quality control specifications applied to the drug substance by the drug product manufacturer must be provided in Module 3.2.S.
• If the drug substance is sterile and not subjected to further sterilisation, then full details of sterile manufacture, its validation and associated microbiological validation of container integrity and transportation, if applicable, must be provided as per guidance in 3.2.P and 3.2.P.7.
• Batch analytical data generated by both the drug substance and the drug product manufacturer(s) must be supplied for typical batches of drug substance from each supplier.
• If a DMF for a biotechnological drug substance is submitted, it should contain the data required under 'If the drug substance is fully described in Module 3.2.S.

• Details and scientific justifications must be provided of any additional tests and requirements (e.g. for particle size distribution, polymorphic form) applied to the bulk drug substance before use in the manufacture of the drug product(s) covered by the current application.
• Detailed validation data must be provided for these additional tests.
• Representative batch analytical data must be provided.

• For biotechnology products:
  • a flow diagram of the synthetic process(es) must be provided.
  • protein and DNA sequences of the drug substance must be provided.
  • characterisation data, including post- translational modifications and functional characteristics of product-related substances as detailed in The EU guideline 3AB1a “Production and Quality Control of Medicinal Products derived by recombinant DNA Technology” Section 7, must be included.
  • a complete description of the manufacturing process including fermentation, modification reactions and purification should also be included.
  • full data describing development genetics, generation of cell substrate, cell banking and cell bank stability, including diagrams and sequence(s) of the vector(s), must be provided (see ICH Topic Q5E: Comparability of biotechnological/biological products).
  • full batch release specifications and validation of test methods used must be provided.
  • detailed validation data for all critical steps.
• For similar biological medicinal products, additional characterisation studies consistent with ICH Topic Q 5 E: "Comparability of Biotechnological/ Biological Products Note for Guidance on Biotechnological/Biological Products Subject to Changes in their Manufacturing Process" must be provided to demonstrate comparability with reference product.
• If the drug substance is sterile and not subjected to further sterilisation, then full details of sterile manufacture, its validation and associated microbiological validation of container integrity and transportation, if applicable, must be provided as per guidance in 3.2.P and 3.2.P.7.
   

• Detailed validation reports for each test method must be provided. If a PMF is submitted, these reports should be within the PMF.
• All raw data supplied (e.g. SDS-PAGE photos or HPLC traces) must be clear and legible.

• The composition of each product and strength must be clearly defined.
• All proprietary and non-proprietary ingredients must be listed as Australian Approved Names (AANs), Australian Biological Names (ABNs) Australian Herbal Names (AHN), or appropriate documentation submitted to the TGA for a new AAN/ABN/AHN to be created (also see 1.2.2 and Module 4).
• Safety data (nonclinical and/or clinical) must be provided for:
  • any new ingredient which has not been included in the ARTG previously
  • any ingredient administered via a new route of administration or intended to be used for a different purpose.
• If tablets are scored, data must be provided to confirm that splitting is clean and the portions produced comply with pharmacopoeial limits for uniformity of weight/content.
• For modified release dosage forms, investigation of the effect of ethanol on in vitro dissolution/release must be included.
• Detailed validation data must be provided for all critical steps in the manufacturing process (including any cleaning and/or sterilisation steps).

For sterile drug products, validation data must be included and must cover the following:

• For all drug products, bioburden information including presterilisation bioburden limits and for extended processing times (including hold times), evidence to show that sterility or microbiological quality (as applicable) is not compromised.
  
  _{Note: we expect that bioburden information including a specification for pre-sterilisation bioburden limits will be provided for all applications for market authorisation, not just for those with certain sterilisation procedures.}
• Drug products that are sterilised by filtration and
  aseptically filled or aseptically manufactured (as applicable):
  • Containers/closures:
    • parameters of the sterilisation processes and confirmation that these have been physically and microbiologically validated to a sterility assurance level (SAL) of 10-6
    • statement that processes to remove endotoxin have been validated to demonstrate a reduction in endotoxin units of > 3-log.
  • Sterilising filter:
    • confirmation that the membrane filter is tested for integrity before and after use
    • validation of the bacterial retention capabilities of the filter conducted in the presence of the product.
  • Statements of maximum permitted processing (holding, storage and filling times) during manufacture.
  • Media fill studies to validate the aseptic manufacturing process. Media fill studies should be conducted under worst case conditions including maximum processing and filling times, and should include simulation of all aseptic manufacturing processes, including those using previously sterilised components.
  • For terminally sterilised drug products or sterilised drug substances or excipients not subjected to further sterilisation:
    • physical and microbiological performance qualification studies and confirmation that these studies show that a SAL of 10^-6 is achieved throughout the maximum and minimum loads.
• Statements of processing times (e.g. from start of compounding until terminal sterilisation).

• The proposed specifications for the finished product must be provided.
• Impurity limits that are above the ICH threshold(s) must be qualified by toxicology data or by reference to an appropriate pharmacopoeial monograph. For generic medicine applications, limits above the ICH threshold may also be qualified by comparison with the Australian reference product near or just past expiry date.
• For endotoxin testing, the applicant must provide the bacterial endotoxin specification, based on either the monograph limit or on the maximum human dose per kg.
• For sterility testing, the applicant must provide a statement that sterility testing is performed according to the current version of the harmonised pharmacopoeial (USP/BP/ Ph Eur) method.

Detailed validation reports for each test method must be provided, except for pharmacopoeial test methods.

For Bacterial Endotoxin testing, this validation should follow Ph. Eur. 5.1.10. Guidelines for using the test for Bacterial Endotoxins, particularly noting 13-2 requiring the test for interfering factors to be performed on 3 production batches.

All raw data supplied (e.g. SDS-PAGE photos or HPLC traces) must be clear and legible.

The immediate and outer packaging and packaging materials (e.g. type of glass or plastic), pack sizes, any dosing device, any induction seals and any desiccant or cotton wool contained in the package must be defined and described – samples are not required.

Details of the stopper formulation and appropriate leaching studies provided.

The full specifications and routine tests on the proposed marketing containers and closures must be provided.

If the drug product is packaged in a child-resistant container, an assurance must be provided of the tests that have been performed to ensure that the child-resistant properties of the packaging are not affected by the contents and are retained throughout the product shelf- life, including during routine use. An assurance must be provided that full details of compliance are held by the applicant and are available for submission to the TGA upon request.

For sterile injectable drug products, the following must be provided:

• for containers closed by fusion (i.e. ampoules), confirmation that containers are subjected to 100% integrity testing
• for containers closed by other means (i.e. vials, syringes), information on container/closure integrity tests such as dye penetration or microbial ingress tests
• for multi-dose injectables, confirmation that additional integrity tests are as per Ph Eur 3.2.9.

In the case of liquid drug products in a stoppered container, stability trials carried out on the product stored in the inverted position must be provided.

If there were any changes in test procedures during the course of the trials, comparison and correlation of results generated by the alternative methods must be provided.

For multi-dose products, the following must be provided:

• information on antimicrobial preservative efficacy data at the beginning and end of the closed shelf life, as specified in TGO 77 Microbiological Standards for Medicines
• information on microbiological challenge testing/simulated use testing as applicable, to support the open shelf life (in-use) period.

In the case of biological products, no less than 6 months real-time stability data should be supplied and the shelf- life allowed will be no more than the amount of real-time data supplied.

In the case of chemical entities, no less than 6 months real-time and accelerated stability data must be provided.

For non-conventional, including modified release, dosage forms, no less than 12 months real-time and 6 month accelerated stability data must be provided.

Non-viral adventitious agents (e.g. transmissible spongiform encephalopathy agents and mycoplasma):

• detailed information should be provided on the avoidance and control of these agents
• this information could include, for example, certification and/or testing of raw materials and excipients, and control of the production process as appropriate for the specific material.

The applicant should refer to European Pharmocopeia (Ph.Eur.) – 5.2.8, EMA/410/01 and TGA Guidance 10: Adventitious agent safety of medicine for further guidance.

Viral Adventitious Agents:

Detailed information for the following aspects of viral safety of the product should be provided in relation to all stages of product development and production:

• Materials of biological origin – related to information in Sections 3.2.S.2.3 and 3.2.P.4.5. Cell line qualification should be included in this assessment.
• Testing at appropriate stages of production and viral testing of unprocessed bulk – details and results of testing during manufacturing to demonstrate that the product is free from viral contamination at appropriate stages of manufacture. Related to information provided in Sections 3.2.S.2.4 and 3.2.P.3.4.
• Viral clearance studies – rationale and action plan for assessing viral clearance, and results and evaluation of viral clearance studies. Related to Sections 3.2.S.2.5 and 3.2.P.3.5.

The applicant should refer to ICH Guidelines Q5A, Q5D,
Q6B and TGA Guidance 10: Adventitious agent safety of medicine for further Guidance.

Nonclinical data for category 1 application type:

• new chemical entity (new salt ester)
• new chemical entity (new combination of active ingredients)
• major variation (new route of administration; change in dosage, dose regimen or maximum daily dose; change in patient group)
• generic application (new isomer, mixture of isomers, complex of, derivative of or salt of a registered substance)
   

For all new generic applications, applicants must provide appropriate information to demonstrate clinical equivalence of the proposed product with the corresponding Australian reference product, unless specifically precluded by listed in Biopharmaceutic studies – Medicines which do not require biopharmaceutic data. Clinical equivalence is to be demonstrated through:

• bioequivalence studies
• a Biopharmaceutics Classification System (BCS)- based biowaiver approach (see Guideline on the investigation of bioequivalence, CPMP/EWP/QWP/1401/98 Rev. 1/Corr),
• a robust scientific justification prepared in accordance with Biopharmaceutic studies - Justification for not submitting biopharmaceutic data  (and any other relevant guidelines) and included in Module 1.11.2
• or a combination of the above.

If bioequivalence studies are not appropriate (for example, topical products) then pharmacodynamic and/or clinical non-inferiority studies may be necessary.

_{Note: Additional specific requirements in relation to biopharmaceutic studies for a number of common scenarios are set out below.}

Comparative bioavailability data must be provided to establish the bioequivalence of the generic medicine and the corresponding reference product in Australia, unless the applicant either:

• Provides a robust, scientific justification prepared in accordance with Biopharmaceutic studies – Choice of the reference product for bioequivalence of generic medicines at Module 1.11.2; or
• Adopts a Biopharmaceutics Classification System (BCS)-based biowaiver approach (see Guideline on the investigation of bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr).

If the in vivo data do not cover all strengths of the product, a comprehensive scientific justification prepared in accordance with Biopharmaceutic studies - Justification for not submitting biopharmaceutic data must be provided in Module 1.11.2.

The following studies are required:

• fed and fasted
• steady state study versus the reference modified release reference product or an appropriate scientific justification must be included in the application.

Generic medicines should have comparable dosage forms and identical (or a subset of) indications, directions for use and strengths in comparison with the Australian reference product’s presentations.

Use of different tablet sizes or excipients that are not found in the Australian reference product presentations and that have clinical implications (e.g. gluten, sodium content) should be justified and addressed by risk management initiatives (for example, relevant information or warnings on label or in PI).

For a biopharmaceutic study using an overseas reference product, the following must be provided (in accordance with Biopharmaceutic studies – Choice of the reference product for bioequivalence of generic medicines):

• evidence to establish that the physical, physiochemical, qualitative and quantitative characteristics of the overseas reference product and the corresponding Australian reference product are identical
• detailed validation data for the procedures used in the quantitative analysis of the excipients
• data for at least two batches (including the batch used in the relevant study) from the overseas country concerned AND at least two batches from Australia.

The following studies (or a robust scientific justification for not including such studies) must be submitted:

• absolute bioavailability study
• study to establish that the proposed formulation is optimal (e.g. a study versus an oral solution of the drug)
• bioequivalence studies between the proposed registration formulation and pivotal clinical trial formulations
• bioequivalence studies amongst the various strengths proposed for registration
• food effect study.

In addition to the studies required for immediate release oral dosage forms, the following studies (or a robust scientific justification for not including such studies) must be submitted:

• steady-state versus an appropriate immediate release reference product
• in vitro-in vivo correlation studies.

• The source from which the batch of reference products was obtained must be provided.
• If the batch of reference product was obtained from outside Australia, evidence that it is identical to the corresponding product distributed in Australia must be provided.
• The individual calculated pharmacokinetic parameters (Tmax, Cmax, AUC, etc.) together with their means, standard deviations, etc. must be provided in tabular form.
• The statistical analyses (ANOVA, estimated ratios and 90% confidence intervals for the ratios) of Cmax and AUC (and Cmin and degree of fluctuation for a steady state study) must have been carried out using parametric analyses of log-transformed data and the results reported.

All applications to register a new:

• chemical entity
• route of administration

must be supported by an absolute bioavailability study (or a robust scientific justification for not including such studies). Any justification for not supplying such a study must be based on science (for example where it is not feasible to prepare an intravenous formulation or there is robust evidence to support lack of systemic absorption) and not a claimed lack of necessity.

The EU guidelines relevant to the specific product, as adopted by the TGA, must be taken into account. In particular there must be:

• adequate dose ranging studies to support the dose selected
• an appropriate pivotal study that relates explicitly to the indication proposed
• safety data that takes into account the proposed duration of use and includes information on stopping the drug.