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Mandatory requirements for an effective over-the-counter medicines application

Applicable for applications lodged from 1 March 2016

29 February 2016

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Appendix A - Specific technical data requirements

Where an application meets the description of more than one of the application types listed in this appendix, data must be provided in accordance with the requirements for each application type that is relevant to the application. Where these tables refer to the data requirements described in European Union (EU) guidelines that have been adopted by the TGA, the guidance should be read in conjunction with any applicable TGA annotation.

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Module 2 - CTD Summaries

Quality overall summary

CTD Module: 2.3
Table ref. number: 1.a
Application level: N5 (new active ingredients only)

Provide Module 2.3 completed in accordance with ICH M4Q Common technical document for the registration of pharmaceuticals for human use - Quality (CPMP/ICH/2887/99 Rev 1 Quality).

Module 2.3 is not required for other N5 level applications.

Nonclinical overview

CTD Module: 2.4
Table ref. number: 1.b
Application level: N4, N5, C3, C4

For all applications that include Module 4, provide Module 2.4 completed in accordance with ICH M4S Common technical document for the registration of pharmaceuticals for human use - Safety (CPMP/ICH/2887/99 Rev 1 Safety).

Also provide Module 2.4 for applications where the levels of impurities and degradants lie outside the levels permitted in Guidelines on quality aspects of OTC applications (these applications require Module 4 data in support of the proposed limits or a justification for the absence of Module 4 data).

Clinical overview

CTD Module: 2.5
Table ref. number: 1.c
Application level: N4, N5, C3, C4

For all applications that include Module 5, provide Module 2.5 completed in accordance with ICH M4E Common technical document for the registration of pharmaceuticals for human use - Efficacy (CPMP/ICH/2887/99 Rev 1 Efficacy) to the extent that it is applicable.

For example, for a generic medicine application where Module 5 only consists of a bioequivalence study (Module 5.3.1), Module 2.5 would consist of a clinical overview of the findings from the bioequivalence study together with any other relevant information, as appropriate.

Nonclinical summary

CTD Module: 2.6
Table ref. number: 1.d
Application level: N4, N5, C3, C4

For all applications that include Module 4, provide Module 2.6 completed in accordance with ICH M4S Common technical document for the registration of pharmaceuticals for human use - Safety (CPMP/ICH/2887/99 Rev 1 Safety).

Clinical summary

CTD Module: 2.7
Table ref. number: 1.e
Application level: N4, N5, C3, C4

For all applications that include Module 5, provide Module 2.7 completed in accordance with ICH M4E Common technical document for the registration of pharmaceuticals for human use - Efficacy (CPMP/ICH/2887/99 Rev 1 Efficacy) to the extent that it is applicable.

For example, for a generic medicine application where Module 5 only consists of a bioequivalence study (Module 5.3.1), Module 2.7 would consist of a clinical summary of the bioequivalence study.

Module 3 - Quality

The table below describes the minimum data that must be submitted in Module 3 for an application to be considered effective. For further guidance refer to the Guidelines on quality aspects of OTC medicines.

Drug substance

CTD Module: 3.2.S
Table ref. number: 2.a
Application level: N5 - new active ingredient

For an application to register a medicine containing a new chemical entity that is an active ingredient, provide Module 3.2.S data in accordance with the Mandatory requirements for an effective application for prescription medicines.

Drug substance (Control)

CTD Module: 3.2.S.4
Table ref. number: 2.b
Application level: N3, N4, N5 - excluding new active ingredients and premixes

For a drug substance that is the subject of a default standard monograph provide, either:

  • Confirmation that the full specifications (test methods and limits) detailed in the relevant monograph in the default standard (BP/Ph.Eur or USP) are applied and no additional critical control parameter tests are necessary to ensure the quality of the medicine, e.g. particle size of the active for inclusion in a suspension, or
  • The proposed drug substance specifications and:
    • a justification for any non-pharmacopeial tests and limits
    • details of non-pharmacopeial test methods.

For a drug substance that is not the subject of a default standard monograph, provide:

  • The proposed drug substance specifications and:
    • a justification for the tests and limits.
    • details of the test methods.

Drug substance (control)

CTD Module: 3.2.S.4
Table ref. number: 2.c
Application level: N3, N4, N5 - premixes (ingredient blends)

For a drug substance that is purchased already manufactured as part of an ingredient blend or premix, provide:

  • The finished product manufacturer's acceptance specifications for the ingredient blend or premix.
  • A justification for the tests and limits
  • Confirmation that all components of the blend or premix are of appropriate pharmaceutical grade and comply with any relevant default standards.

Drug product (description, composition, and pharmaceutical development)

CTD Module: 3.2.P.1 and 3.2.P.2
Table ref. number: 2.d
Application level: N3, N4, N5
  • Define the composition of the medicine and role of the ingredients.
  • Provide details and a justification for any overage applied during manufacture.
  • If tablets are scored, provide data to confirm that splitting is clean and the portions produced comply with pharmacopoeial limits for uniformity of weight/content.
  • Provide full details of pharmaceutical development for:
    • Modified release dosage forms
    • N5 applications for new strengths, new dosage forms, new fixed combination medicines or new chemical entities.

Drug product (manufacture)

CTD Module: 3.2.P.3
Table ref. number: 2.e
Application level: N3, N4, N5

Include a brief outline of the method of manufacture and batch formula.

Provide an assurance that the manufacturing process will be validated (or has been validated) according to the requirements of the Code of Good Manufacturing Practice [the Therapeutic Goods (Manufacturing Principles) Determination No. 1 2013 contains a definition of 'the Code'], and that the manufacturer's validation report and related information will be available for review, on request, by the TGA within 3 months of release for supply of the first production batch.

Additional manufacturing validation information is required for the following specific medicine types:

  • For oral dosage forms where the active ingredient is present at less than 2 mg or 2% w/w (microdose) the full manufacturer's process validation report must be provided.
  • For metered dose inhalers, novel dosage forms, sustained release medicines (excluding enteric coated medicines) and nasal corticosteroids, provide the manufacturer's process validation report (or a summary of the report) including the critical steps in the manufacturing process and the manufacturer's analysis and conclusions.
  • For sterile medicines, provide validation data that covers the following:
    • for all sterile medicines, 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: the TGA has the expectation 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.

  • For medicines that are sterilised by filtration and aseptically filled or aseptically manufactured the following validation data (as applicable):
    • containers/closures:
      • parameters of the sterilisation processes and confirmation that these have been physically and microbiologically validated to a 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 medicines 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).

Control of excipients

CTD Module: 3.2.P.4
Table ref. number: 2.f
Application level: N1 (flavour/fragrance/colour variants only)
C2 (change code GPI - addition of flavour/fragrance/printing ink or colouring)

Provide the proposed specifications, and details of the test methods, for the new flavour/fragrance/colours(s).

Control of excipients

CTD Module: 3.2.P.4
Table ref. number: 2.g
Application level: N3, N4, N5

State which excipients comply fully with the applicable monograph in the default standard (BP/Ph.Eur. or USP).

For excipients that are the subject of a default standard monograph, provide either:

  • Confirmation that the full specifications (test methods and limits) detailed in the relevant monograph in the default standard (BP/Ph.Eur or USP) are applied and no additional critical control parameter tests are necessary to ensure the quality of the medicine; or
  • The proposed specifications and:
    • a justification for any non-pharmacopoeial tests and limits
    • details of non-pharmacopoeial test methods.

For excipients that are not the subject of a default standard monograph, provide:

  • The proposed specifications and:
    • a justification for the tests and limits
    • details of the test methods.

For excipients that are purchased already manufactured as part of a premix (ingredient blend), provide:

  • The finished product manufacturer's acceptance specifications.
  • A justification for the tests and limits.
  • Confirmation that all components of the blend or premix are of appropriate pharmaceutical grade and comply with any relevant default standards.

Control of drug product

CTD Module: 3.2.P.5.1
Table ref. number: 2.h
Application level:N2, N3, N4, N5

Provide the proposed expiry and release specifications for the finished product.

Note: Finished product specifications must be provided for all N2, N3, N4 and N5 applications, including those where a justification is made for providing an abridged Module 3 (for example, when all quality aspects are identical to a fully evaluated 'parent' medicine, whose sponsor has given the TGA authorisation to access the parent files for the purpose of the application).

Analytical procedures

CTD Module: 3.2.P.5.2
Table ref. number: 2.i
Application level: N3, N4, N5

Provide a detailed description of all in-house test methods, in accordance with the requirements of the Guidelines on quality aspects of OTC medicines - Analytical procedures and validation.

Validation of test methods

CTD Module: 3.2.P.5.3
Table ref. number: 2.j
Application level: N3, N4, N5

Provide analytical validation reports for critical assay methods, in accordance with the requirements of the Guidelines on quality aspects of OTC medicines - Analytical procedures and validation.

All raw data supplied (e.g. HPLC traces) must be clear and legible.

Batch analysis

CTD Module: 3.2.P.5.4
Table ref. number: 2.k
Application level: N2, N3, N4, N5

Provide certificates of analysis for at least two batches.

Control of drug product

CTD Module: 3.2.P.5.6
Table ref. number: 2.l
Application level: N3, N4, N5

Provide a justification for the finished product specifications including:

  • a justification in terms of safety for any impurity limits that are above those specified in the Guidelines on quality aspects of OTC medicines (refer to Table 1 and Table 3 for the relevant Module 2.4 and Module 4 requirements).

Note: The finished product specifications must ensure compliance with all applicable default standard requirements and Therapeutic Goods Orders.

Container closure system

CTD Module: 3.2.P.7
Table ref. number: 2.m
Application level: N2 - where a measuring device is supplied with the medicine.

Provide details of the calibrations on the measuring device.

Container closure system

CTD Module: 3.2.P.7
Table ref. number: 2.n
Application level: Application level: N3, N4, N5
  • Provide details of the container and measuring or dose delivery devices, including:
    • details of the materials and specifications
    • technical drawings of dose delivery/measuring device, where design, composition and performance of the device is not clearly described in the submitted specifications (including details of the calibrations).
      • For plastic and rubber packaging components of the primary packaging provide evidence that the components comply with relevant BP/Ph. Eur and/or USP/NF requirements for polymeric materials used in packaging medicines or, if appropriate, are approved for use with foodstuffs.
      • If the medicine is subject to the Therapeutic Goods Order No 80 Child-resistant Packaging Requirements for Medicines (TGO 80) provide an assurance that the container closure system complies with the Therapeutic Goods Order No 80 Child-resistant Packaging Requirements for Medicines.
      • For medicines supplied with a measuring device, provide an assurance that it complies with the requirements for Uniformity of Weight (Mass) of Delivered Doses from Multidose Containers in the BP/Ph.Eur Appendix XII C. Consistency of Formulated Preparations.

Stability

CTD Module: 3.2.P.8
Table ref. number: 2.o
Application level: N3, N4, N5

Provide information regarding stability trials in accordance with the requirements of the Guidelines on quality aspects of OTC medicines, including:

  • A tabular stability summary and conclusions in regard to the storage conditions and shelf-life.
  • A statement of which batches are identical to those intended for marketing in terms of formulation, container, and manufacture. Provide details and justification for any differences between the stability batches and the proposed medicine.
  • A post-approval stability commitment to conduct full term stability testing on at least two production batches (if required).
  • Full details of stability testing conducted on each individual strength, container type and size of the medicine (unless bracketing or matrixing is applied), in accordance with the relevant CPMP/ICH guidelines and associated TGA annotations.
    • Results must be in tabular format.
    • Confirm that the test methods used in the stability study are the same as those provided in 3.2.P.5 Control of the Drug Product or, if this is not the case, provide detailed stability study test methods and analytical validation data.
    • If there were any changes in test procedures during the course of the trials, provide comparison and correlation of results generated by the alternative methods.
    • For conventional dosage forms where the active ingredient is known to be stable, provide no less than 6 months long term and accelerated stability data on a minimum of two batches of at least pilot scale.
    • For unconventional dosage forms (including modified release) or for medicines that are likely to be unstable or contain a new active ingredient, provide no less than 12 months long term and 6 month accelerated stability data on a minimum of three batches, of which two must be at least pilot scale.
    • Provide results of microbiological contamination testing or, where relevant, sterility testing.
    • For solid dosage forms in potentially moisture-permeable packaging, provide high humidity stability data.
    • For non-solid dosage forms in potentially moisture-permeable packaging, provide low humidity stability data.
    • For multi-dose liquid or semi-solid medicines provide:
      • antimicrobial preservative efficacy data at the beginning and end of the closed shelf life, as specified in TGO 77 Microbiological Standards for Medicines
      • information to support the in-use period, e.g. microbiological challenge testing/simulated use testing.
    • For oral solid dosage forms or suspensions that make 'fast' or 'rapid' claims on the labels, provide dissolution data in accordance with the Guideline on presentation aspects of OTC applications - Fast or rapid claims.

If the stability data package does not meet any or all of the above requirements, this must be identified in the application cover letter and a justification must be included that meets the requirements detailed above in Justification for not complying with technical data requirements.

Module 4 - Safety (nonclinical study reports)

Application for a medicine that contains an excipient that is one or more of:

  • a new chemical entity (i.e. not on the TGA Ingredient tables)
  • not approved for use in OTC medicines
  • a new route of administration
  • at a higher concentration or daily dose than has been approved for that route of administration.
CTD Module: 4
Table ref. number: 3.a
Application level: N4, N5, C3

Provide nonclinical data or a justification for not providing data, in accordance with the:

An assessment of the information relating to safety must be provided in the nonclinical overview (Module 2.4).

Note: If you are unsure whether the excipient has been assessed for the proposed route of administration, concentration or OTC use, contact otc.medicines@tga.gov.au.

Application for a medicine that has impurities that are above those allowed without justification in the Guidelines on quality aspects of OTC Medicines

CTD Module: 4
Table ref. number: 3.b
Application level: N4, N5

Provide safety data (Module 4) or a scientific justification (Module 2.4 and/or Module 4) to support the proposed impurity limits.

Provide an assessment of this information in the nonclinical overview (Module 2.4).

Applications that are fully or partly literature based (literature based submissions)

CTD Module: 4.3
Table ref. number: 3.c
Application level: N4, N5, C3, C4

Provide information in accordance with the TGA guidance:

Note: Modules 1.5.1, 2.4 and 2.6 (as applicable) are also required.

Applications for a topical medicine that includes a 'hypoallergenic' claim

CTD Module: 4
Table ref. number: 3.d
Application level: N4, N5
Provide data in accordance with the requirements detailed in the Guidelines on OTC applications for specific substances - Hypoallergenicity of topical preparations.

Application for a non-generic medicine that has one or more of:

  • a new chemical entity that is an active ingredient including:
    • new salt or ester
    • new isomer/ mixture of isomers
  • a new combination of active ingredients
  • a new route of administration of the active ingredient
  • higher dosages of the active ingredient or use over a longer period of time
  • a new strength
  • a different patient population
CTD Module: 4
Table ref. number: 3.e
Application level: N5, C4

Provide nonclinical data or a scientific justification for the absence of nonclinical data, in accordance with:

Provide an assessment of the information relating to safety in the nonclinical overview (Module 2.4).

Module 5: Efficacy (Clinical study reports)

General application requirements

In addition to the requirements in this table, the specific Module 5 requirements for generic medicine applications are described in Table 5, and for non-generic medicine applications in Table 6.

Applications that include comparative bioavailability / bioequivalence reports

CTD Module: 5.3.1
Table ref. number: 4.a
Application level: N4, N5, C4

Provide bioavailability/bioequivalence study reports in accordance with requirements detailed in:

Note:.

  • The Australian originator reference medicine used in the studies must have been registered on the basis of a full dossier, which may include chemical, biological, pharmaceutical, pharmacological-toxicological and clinical data.
  • The bioavailability/bioequivalence summary is placed in Module 1.11

Applications that include reports of biopharmaceutic studies using overseas reference product

CTD Module: 5.3.1
Table ref. number: 4.b
Application level: N4, N5, C4

For a biopharmaceutic study using an overseas reference product, provide data in accordance with requirements detailed in Guideline 15: Biopharmaceutic studies - Choice of the reference product for bioequivalence of generic medicines.

Applications that are fully or partly literature based (literature based submission)

CTD Module: 5.4
Table ref. number: 4.c
Application level: N4, N5, C4

Provide information in accordance with the TGA guidance:

Note: Module 1.5.1, 2.5, and Module 2.7 and copies of all references will need to be provided.

Applications for locally acting, locally applied medicines that include studies using pharmacodynamic endpoints

CTD Module: 5
Table ref. number: 4.d
Application level: N4, N5, C4

Provide data demonstrating that the pharmacodynamic model is internally and externally valid. The use of pharmacodynamic endpoints must be justified in terms of their direct relevance to the intended therapeutic effect of the active ingredient in the medicine.

Note: An example of a pharmacodynamic endpoint that is not related to therapeutic effect of the medicine is the vasoconstrictor assay referred to in the guideline Clinical Investigation of corticosteroids intended for use on the skin. The vasoconstrictor assay endpoint may not be externally valid when the composition of the generic medicine differs from the reference.

Applications to include a 'fast' or 'rapid' claim as part of the medicine name or a 'fast / faster absorption' claim

CTD Module: 5
Table ref. number: 4.e
Application level: N4, N5, C3, C4

Provide supporting clinical efficacy data or pharmacokinetic data in accordance with the Guideline on presentation aspects of OTC applications - Fast or rapid claims.

N4 application requirements (generic medicines)

Generic OTC oral medicines, other than those specifically excluded from requiring bioequivalence data in the guidance: OTC medicines - Safety and efficacy data (When bioequivalence data (or justification) are not required)

CTD Module: 5.3.1
Table ref. number: 5.a
Application level: N4

Provide bioavailability/bioequivalence study reports in accordance with the requirements for generic medicines detailed in:

Generic modified release oral medicine

CTD Module: 5.3.1
Table ref. number: 5.b
Application level: N4

Provide the bioavailability/bioequivalence study reports in accordance with the requirements detailed in:

Generic topical medicines

CTD Module: 5.3.4 and 5.3.5
Table ref. number: 5.c
Application level: N4
Provide data demonstrating therapeutic equivalence with a corresponding Australian originator medicine, in accordance with the requirements detailed in:

Generic nicotine replacement therapy

CTD Module: 5
Table ref. number: 5.d
Application level: N4

Provide data in accordance with the requirements detailed in:

Generic antiseptic for:

  • First aid
  • Use in the mouth
CTD Module: 5.3
Table ref. number: 5.e
Application level: N4

Provide in vitro data demonstrating the antimicrobial activity using the following suitable test methods (as relevant):

FDA proposed monograph for antigingivitis/antiplaque drug products

Generic antiseptic for:

  • Handwashes or handrubs
  • Patient preoperative skin preparations
  • Surgical hand disinfectants
CTD Module: 5.3
Table ref. number: 5.f
Application level: N4

Provide in vitro and in vivo data demonstrating the efficacy using the following suitable test methods (as relevant):

Generic head lice treatment

CTD Module: 5.3
Table ref. number: 5.g
Application level: N4

Provide data in accordance with the:

N5 and C4 application requirements (non-generic medicines)

New strength

CTD Module: 5.3.1
Table ref. number: 6.a
Application level: N5

If the new strength is associated with new indications, dosage, directions for use or target population, also provide data in accordance with the OTC medicines - Safety and efficacy data and any other specific Australian or EU guidelines relevant to the medicine.

New dosage form

CTD Module: 5.3.1
Table ref. number: 6.b
Application level: N5

Provide data in accordance with:

For example, for systemically absorbed dosage forms provide study reports in accordance with Guidance 15: Biopharmaceutic Studies.

New modified release dosage forms

CTD Module: 5
Table ref. number: 6.c
Application level: N5

Provide data in accordance with:

New route of administration

CTD Module: 5
Table ref. number: 6.d
Application level: N5

Provide data in accordance with:

New indications, dosage, directions for use, or target population

CTD Module: 5
Table ref. number: 6.e
Application level: N5, C4 (change code GID or GDD)

Provide data in accordance with:

New fixed combination medicine or composite packs containing multiple active ingredients that do not contain a new active ingredient (new chemical entity)

CTD Module: 5
Table ref. number: 6.f
Application level: N5

Provide data in accordance with the following:

Non-generic locally applied, locally acting medicine (e.g. topical medicine)

CTD Module: 5
Table ref. number: 6.g
Application level: N5

Provide data in accordance with the following:

Non-generic nicotine replacement therapy

CTD Module: 5
Table ref. number: 6.h
Application level: N5

Non-generic antiseptic

CTD Module: 5
Table ref. number: 6.i
Application level: N5

Provide in vitro and in vivo data demonstrating the efficacy using the following suitable test methods (as relevant):

Non-generic head lice teatment

CTD Module: 5
Table ref. number: 6.j
Application level: N5

New active ingredient (new chemical entity)

CTD Module: 5
Table ref. number: 6.k
Application level: N5

Provide data in accordance with all of the following:

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