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Mandatory requirements for an effective application

Applicable for applications lodged from 9 February 2018

21 February 2018

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Appendix A - Specific mandatory requirements

General
Section Issue Requirement
All Language See General dossier requirements - Part A
All Measurements See General dossier requirements - Part A
All Provision of Module 1 All application dossiers must include Module 1. The required content of the Module 1 is described in CTD Module 1: Administrative information and prescribing information for Australia.
All Electronic data

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.

All Applications that have previously been rejected by the TGA or withdrawn by the applicant before a decision by the TGA Delegate.

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.

Module 1: Administrative information and prescribing information for Australia
Section Issue Requirement
All Requirements in CTD Module 1 - Administrative information and prescribing information for Australia The application must meet all the relevant administrative and Module 1 requirements described in CTD Module 1: Administrative information and prescribing information for Australia.
1.0 Letter of authorisation
  • 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.
1.2.1 Evidence of Good Manufacturing Practice (GMP)
  • 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.
1.5.1 Determination/Designation
  • 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.
1.8 Information relating to pharmacovigilance

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.

1.8.3 Declaration of compliance with PPF and planning letter
  • 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.
1.11.2 Justification for not providing appropriate biopharmaceutic studies (overseas reference product)

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.

1.11.2 Justification for not providing appropriate biopharmaceutic studies (studies not provided for some or all products)

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:

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

Module 2 - CTD summaries
Section Issue Requirement
2.4 Generic applications

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.

2.5 Generic applications Module 2.5 must be supplied for all new generic applications.
2.7 Generic applications Module 2.7 must be supplied for new generic applications where biopharmaceutic studies have been provided in support of the application.
Module 3 - Quality
Section Issue Requirement
3.2.S Drug substance (name, manufacturer)

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).

3.2.S If a DMF is submitted
  • 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.
3.2.S If a CEP is submitted Documentation detailed in the TGA Drug master file guideline and Module 1.6 of the CTD must be provided.
3.2.S If all aspects of a drug substance manufacture (including sterile manufacture, if applicable) and control has been previously approved by the TGA
  • 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.
3.2.S If the drug substance is fully described in Module 3.2.S
  • 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.
3.2.S If any raw material or excipient is plasma derived
  • The epidemiological data for the previous calendar year must be provided.
3.2.S.4.3 Validation of test methods
  • 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.
3.2.P Drug product (name, dosage form)
  • 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).
3.2.P.5 Control of drug product
  • 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.
3.2.P.5.2 Analytical procedures Detailed description of all in-house test methods must be provided.
3.2.P.5.3 Validation of test methods

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.

3.2.P.7 Container closure system

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.
3.2.P.8 Stability

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.

3.2.A.2 Adventitious Agent Safety

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.

Module 4 - Safety (nonclinical study reports)
Section Issue Requirement
4

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)
Nonclinical data or a scientific justification for the absence of nonclinical data must be provided.
4 Excipients If the medicine contains an excipient used for the first time in a therapeutic product in Australia, an assessment of the information relating to safety must be provided in the nonclinical overview (Module 2.4). Nonclinical data must be provided for a new excipient, an excipient with a new route of administration or an increased daily dose or a justification for not providing data must be included in the application. Also see 3.2.P.
4 Impurity qualification Toxicology data (Module 4) or a scientific justification (Module 2.4 and/or Module 4) for impurities that are above the ICH qualification threshold must be provided. An assessment of this information must be provided in the nonclinical overview (Module 2.4).
Module 5 - Efficacy (clinical study reports)
Section Issue Requirement
5.3.1 Generic medicine: Establishing clinical equivalence

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:

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.

5.3.1 Generic medicine: Immediate release oral dosage forms

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:

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.

5.3.1 Generic medicine: Modified release oral dosage forms

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.
5.3.1 Generic Medicine: Clinical Usability and Safety

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).

5.3.1 Reports of biopharmaceutic studies using overseas reference product

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.
5.3.1 New chemical entity/biological entity: Immediate release oral dosage forms

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.
5.3.1 New chemical entity/biological entity: Modified release oral dosage forms

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.
5.3.1 Individual comparative bioavailability 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.
5.3.1.1 New chemical entities, new routes of administration: Bioavailability study

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.

5.3.4, 5.3.5 Pharmacodynamics and dose ranging, efficacy and safety studies

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.

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