Analysis of New, Draft TGA (Australia) M1 CTD Guidance (Part 2)

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My last analysis of the new TGA (Australia) Draft Module 1 Administrative Information and Prescribing Information left off at section 1.5.5 before analysis paralysis set in… today I wrap up with an examination of the rest of the document.

  • In Section 1.6.1 Relevant external sources, as in most sections, example forms have been replaced with instructions to download forms from the TGA website. In this case, each referenced DMF, PMF or CEP requires a corresponding declaration form and proforma letter of access. Pertinent legislation is described. Section 1.7 Good manufacturing practice now has information about how to handle manufacturing sites are not licensed for the necessary steps of manufacture, and requires copies of each of the manufacturing sites licences in 1.7.1. Also, the following clarifications were provided for 1.7.1 and 1.7.2:
    • For biotechnology products, GMP licences or clearances are required for active drug substance manufacturing and testing sites unless otherwise agreed in the pre-submission phase.
    • Australian manufacturing sites and the steps of manufacture for which they are licensed can be accessed from the eBS website.
    • Licences or clearances can be restricted to specific dosage forms, classes of medicines, and active ingredients.
    • Licences are not required for manufacturers providing simple salts for use as active pharmaceutical ingredients.
    • Clearances for overseas manufacturing sites are specific to the sponsor.
    • Clearances can be restricted to specific dosage forms, classes of medicines, and active ingredients.
    • All manufacturers and finished product testing facilities involved in the product manufacture must have GMP licences or clearances or have an application lodged with OMQ.
    • For biotechnology products, GMP licences or clearances are required for active drug substance manufacturing and testing sites unless otherwise agreed in the pre-submission phase.
  • In section 1.7.3 Copies of applications for TGA GMP clearances, sponsors are now instructed to lodge applications for the new GMP clearance or renewal via eBS, print the relevant eBS screen showing the tracking number for the application and include the printout in 1.7.3. It is not necessary to include all the supporting documentation that is sent to the Office of Manufacturing Quality in Module 1.7.3.
  • In 1.8.1 Details of compliance with pre-submission meeting outcomes, sub-sections have changed, with much more detail given. In the area of additional data, an important note is “The TGA will only agree to the lodgement of additional data where the medicine is of critical importance to the Australian community to address emergency situations. This must be established at a pre-submission meeting prior to the lodgement of a submission.”
  • The new section 1.8.3 Declaration of compliance with pre-submission planning form and planning letter is now required when The submission is a Category 1 or Category 2 submission for which a pre-submission planning form was lodged with the TGA. Another important note here: “Any inconsistencies between the information provided on the pre-submission planning form and the resulting submission that are considered to be an increase in scope and/or complexity will result in the submission being deemed ineffective.”
  • In section 1.9 Individual patient data, TGA clarifies that although in many cases, it is not a requirement for IPD to be supplied in the submission dossier, IPD may be requested and must be available. Where a request for individual patient data is not met within 15 working days, the application may lapse.
  • Subsections under 1.10 Overseas regulatory status have changed, with the former sections 1.10.1 and 1.10.4 being combined. In section 1.10.3 Data set similarities and differences. Where significant differences exist, these should be identified and commented upon in general terms. For Category 2 submissions, if any significant, undisclosed differences are subsequently found by the TGA, the application may be rejected.
  • Under 1.11.1 Summary of a Bioavailability or Bioequivalence Study, a separate summary form must be completed for each study (this used to be “encouraged”.) Australia’s requirements for biopharmaceutic studies are aligned with the CHMP Note for Guidance of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98) which has been formally adopted in Australia (with amendment).
  • In 1.11.2 Justification for not providing appropriate biopharmaceutic studies, a justification must now be included in Module 1.11.2 where the biopharmaceutic data provided for a generic medicine were not generated against a reference product obtained from Australia. Significant additional details are provided on what to include in the justification.
  • Section 1.12 References to paediatric development program now requires a justification if there is no paediatric development program.
  • In Section 1.13 Information relating to pharmacovigilance, some points to note include:
    • An RMP must be submitted when requested by the TGA (both pre-and post-authorisation). This applies to medicines already registered in the ARTG.
    • An RMP may also be submitted on the initiative of a sponsor when they identify a safety concern with a medicinal product at any stage of its life cycle.
    • More information is available from the RMP Q&As.
  • The existing Annex I Environmental risk for non-GMOs (genetically modified organisms) containing medicines appears to have been dropped.
  • Annex I Antibiotic resistance data provides more detail on when this document is required and how to prepare it.
  • Annex II Overseas evaluation reports again stresses that “Any differences between the data set supplied to the TGA and the two acceptable countries must be clearly identified in Module 1.10.3”. The sponsor is encouraged to provide copies of evaluations from other regulatory agencies or authorisation (via the application form) for the TGA to obtain evaluations from other regulatory agencies, as this may expedite the evaluation process.
  • An entirely new Part C discusses Requests for confidentiality. This replaces former 1.0.2 Request for confidentiality (optional).  This should be reviewed in detail by concerned sponsors.

Finally, a very handy Part D – Dossier documents matrix maps all of the sections to all of the submission types and will serve as a terrific checklist as submission time approaches.

Of course, we’re all wondering what effect this will have on Australia’s eCTD program. No word as of yet, but at a minimum it will result in some changes to their (still draft) M1 specification for eCTD. It’s obvious that this overhaul was a very major effort at TGA, and perhaps now that it is largely done (although still draft) they may be able to turn their attentions in the eCTD direction.

Author: GS

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