Appendix A - Specific mandatory requirements

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 Quality data for complementary medicines (these applications require Module 4 data in support of the proposed limits or a justification for the absence of Module 4 data).

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.

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.

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.

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.

3.2.P.1 & 3.2.P.2 Drug product

(description, composition and pharmaceutical development)

• 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
  • RCM5 applications for new strengths, new dosage forms, new fixed combination medicines or new chemical entities.

3.2.P.3

Drug product (manufacture)

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 2018 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 (micro dose) the full manufacturer's process validation report must be provided
• for novel dosage forms and sustained release medicines (excluding enteric coated medicines) 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.

3.2.P.4

Control of excipients

RCM1 (flavour/fragrance/colour variants only)

C2-RCM change code GPI - addition of flavour/fragrance/colour.

3.2.P.4

Control of excipients

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.

3.2.P.5.1

Control of drug product

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

Note: Finished product specifications must be provided for all RCM2, RCM3, RCM4, RCM5 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).

3.2.P.5.2

Analytical procedures

3.2.P.5.3

Validation of test methods

Provide analytical validation reports for critical assay methods, in accordance with the requirements of theQuality data for complementary medicines - Analytical procedures.

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

3.2.P.5.4

Batch analysis

3.2.P.5.6

Control of drug product

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 Quality data for complementary 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.

3.2.P.7

Container closure system

3.2.P.7

Container closure system

• 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.
• UP TO HERE
• 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 TGO 80.
• 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.

3.2.P.8

Stability

Provide information regarding stability trials in accordance with the requirements of the Quality data for complementary 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.

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.

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 listed complementary medicines
• at a higher concentration or daily dose than has been approved for that route of administration; and/or
• is proposed for a new route of administration.

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

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

• Safety and efficacy information for complementary medicines

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

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).

Provide information in accordance with the TGA guidance:

• Literature based submissions
• Safety and efficacy information for complementary medicines

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

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

• a new chemical entity that is an active ingredient new salt or ester
• a new combination of active ingredients
• a new route of administration of the active ingredient
• higher dosages (strength) of the active ingredient or use over a longer period of time
• a different patient population

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

• Module 4: Safety (non-clinical study reports)
• Safety and efficacy information for complementary medicines

Provide an assessment of the information relating to safety in the nonclinical overview (Module 2.4) or nonclinical summary (Module 2.6).

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

• Guidance 15: Biopharmaceutical Studies

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 1.9.1

Provide information in accordance with the TGA guidance:

• Literature based submissions
• Safety and efficacy information for complementary medicines

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

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

• Generic registered complementary medicines
• Safety and efficacy information for complementary medicines
• Guidance 15: Biopharmaceutic Studies

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

• Guidance 15: Biopharmaceutic Studies
• Guideline in the investigation of bioequivalence (pdf,233kb)
• Safety and efficacy information for complementary medicines
• Guidance on the pharmacokinetic and clinical evaluation of modified release dosage forms (EMA/CPMP/EWP/280/96 Corr 1)

5.3.4

5.3.5

Provide data demonstrating therapeutic equivalence with a corresponding Australian originator medicine, in accordance with the requirements detailed in:

• Generic registered complementary medicines
• Safety and efficacy information for complementary medicines

Generic antiseptic for:

• First aid
• Use in the mouth

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

• the in vitro test described in the FDA Tentative Final Monograph for first aid antiseptic products
• TGA disinfectant test (option D) for antiseptics modified to make it a quantitative method and supported by adequate validation data
• FDA Tentative Final Monograph for oral antiseptic drug products
• FDA proposed monograph for antigingivitis /antiplaque drug products

Generic antiseptic:

• Handwashes or handrubs

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

• The European Standard EN13727 for chemical disinfectants and antiseptics
• FDA Tentative Final Monograph for health-care antiseptic drug products
• The European Standard EN 1499 for hygienic handwashes
• The European Standard EN 1500 for hygienic handrubs
• The European standard EN 12791 for surgical hand disinfectants

Provide data in accordance with:

• Guidelines on OTC applications for specific substances - Headlice treatments
• Safety and efficacy information for complementary medicines

Provide data demonstrating therapeutic equivalence with a corresponding Australian originator medicine, in accordance with the requirements detailed in:

• Generic registered complementary medicines
• Safety and efficacy information for complementary medicines

• For medicines that are systemically absorbed (e.g. oral tablets), provide comparative bioavailability/bioequivalence study reports in accordance with Guidance 15: Biopharmaceutic Studies.
• For locally applied, locally acting medicines, provide data in accordance with the EU document Clinical requirements for locally applied, locally acting products containing known constituents.

Provide data in accordance with:

• the guidance Safety and efficacy information for complementary medicines
• any other specific Australian or EU guidelines relevant to the medicine.

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

Provide data in accordance with:

• the guidance Safety and efficacy information for complementary medicines
• any other specific Australian or European Union (EU) guidelines relevant to the medicine, including the Guidance on the pharmacokinetic and clinical evaluation of modified release dosage forms (EMA/CPMP/EWP/280/96 Corr 1)

Provide data in accordance with:

• the guidance Safety and efficacy information for complementary medicines
• any other specific Australian or EU guidelines relevant to the medicine.

Provide data in accordance with:

• the guidance Safety and efficacy information for complementary medicines
• any other specific Australian or EU guidelines relevant to the medicine.

Provide data in accordance with:

• the guidance Safety and efficacy information for complementary medicines
• Complementary medicines presented as composite packs or kits
• any other specific Australian or European Union (EU) guidelines relevant to the medicine, including the Guideline on Clinical Development of Fixed Combination Medicinal Products (CPMP/EWP/240/95 Rev 1), adopted by the TGA.

Provide data in accordance with:

• the guidance Safety and efficacy information for complementary medicines
• any other specific Australian or European Union (EU) guidelines relevant to the medicine, including the guideline Clinical requirements for locally applied, locally acting products containing known constituents

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

• The in vitro test described in the FDA Tentative Final Monograph for first aid antiseptic products
• The TGA disinfectant test (option D) for antiseptics modified to make it a quantitative method and supported by adequate validation data
• The FDA Proposed Rule for oral antiseptic drug products
• FDA proposed monograph for antigingivitis /antiplaque drug products
• The European Standard EN13727 for chemical disinfectants and antiseptics
• FDA Tentative Final Monograph for health-care antiseptic drug products
• The European Standard EN 1499 for hygienic handwashes
• The European Standard EN 1500 for hygienic handrubs

Provide data in accordance with:

• Guidelines on OTC applications for specific substances - Head lice treatments

Provide data in accordance with the following studies (or a robust scientific justification for not including such studies):

• absolute bioavailability study (the extent of the absorption of a non-intravenous dose compared to intravenous administration of the same substance)
• 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 (if applicable)
• a food effect study; and
• any other specific Australian or European Union (EU) guidelines relevant to the medicine, including:
  • for topical medicines provide safety and efficacy data in accordance with the EU guidance Clinical requirements for locally applied, locally acting products containing known constituents
  • for modified release medicines provide safety and efficacy data in accordance with the EU Note for guidance on modified release and transdermal dosage forms: Section II (Pharmacokinetics and clinical evaluation) (CPMP/EWP/280/96)
  • for fixed combination medicines or composite packs provide safety and efficacy data in accordance with the EU Guideline on Clinical Development of Fixed Combination Medicinal Products (CPMP/EWP/240/95 Rev 1), adopted by the TGA.