The Regulatory Times

March 2018

Your monthly round-up of Life Sciences regulatory news from around the globe


Final Guidance for Industry M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk

This guidance aims to provide a framework for the identification, categorization, qualification, and control of mutagenic impurities. While ICH Q3A Impurities in New Drug Substances (Revision 2) (Q3A) and Q3B(R2) Impurities in New Drug Products (Q3B) provide guidance for qualification and control for the majority of the impurities, the guidance acknowledges that there was limited guidance available for those impurities that are DNA reactive. The guidance is applicable to new drug substances and new drug products during their clinical development and subsequent applications for marketing. It also applies to post-approval submissions of marketed products, and to new marketing applications for products with a drug substance that is present in a previously approved product if any of the following criteria apply:

  • Changes to the drug substance synthesis result in new impurities or increased acceptance criteria for existing impurities;
  • Changes in the formulation, composition or manufacturing process result in new degradation products or increased acceptance criteria for existing degradation products;
  • Changes in indication or dosing regimen are made which significantly affect the acceptable cancer risk level.

Assessment of the mutagenic potential of impurities as described in this guidance is not intended for the following types of drug substances and drug products: Drug substances and drug products derived from the following sources are out of scope of the guidance document: biological/biotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation, herbal, and crude products of animal or plant origin.

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Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities) Questions and Answers

Since the ICH guidance Q11 Development and Manufacture of Drug Substances (ICH Q11) was finalized, worldwide experience with implementation of the recommendations on the development and manufacture of drug substances has given rise to requests for clarification relating to the selection and justification of starting materials for chemical entity drug substances. The referenced document was originally published by ICH in August 2017. The document has now been republished by FDA.

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Additional Data requested for New Applications in the Mutual Recognition and Decentralised Procedures

The additional data request for EU member states during New Applications during MRP/DCP has been updated with deletion of requirement “Sample of the finished product and API before day 0“.  Links to clean and tracked change version of the document are at the links below:

Clean PDF

Tracked change PDF

CMDh Best Practice Guide on the processing of renewals in the MRP/DCP 

The CMDh best practice guide document has been updated to include clarity on certain requirements such as date of next renewal from RMS, document required as per Annex 3 for products authorized under Article 10(1) and RMP. Please refer below links for detailed information on updates on best practice guide.

Clean PDF

Tracked change PDF

EU eCTD Validation Criteria updated to v7.1 & EU NeeS Validation Criteria updated to v4.3

Both eCTD and NeeS validation criteria will come into force from 1st September 2018.

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Flow chart of the Decentralised Procedure

The flow chart of DCP has been updated to include Day 160 at Assessment Step II “Applicant sends the response document to CMSs and RMS”. Additionally, there is more clarity provided for Day 210 activities during Assessment Step II. Please refer to links below (clean and tracked change version):

Clean PDF

Tracked change PDF

Update of procedural advice on validation of MRP/RUP/DCP

The CMDh has updated its procedural advice on validation to remove reference to the pilot on the use of the DCP validation check-lists, as these are now part of the standard procedure. The updated document will be published on the CMDh website under “Procedural guidance, Application for MA”.

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Template for RMS switches and update of the CMDh procedural advice on changing the RMS

In the anticipation of a high number of RMS switches due to Brexit, the CMDh has agreed a new template for RMS switches. The template should be used for all requests for switches to a new RMS.

In parallel the CMDh procedural advice on changing the RMS has been updated to include nformation on the use of the template.  Further procedural information is also provided to support applicants.  The updated document will be published on the CMDh website under “Procedural guidance, General information”.

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South Africa

Six Monthly Progress Report Form For Clinical Trials

The templated form, which became effective in January 2018, is to be completed six monthly from the date of approval of a clinical trial by the Medicines Control Council (now South African Health Products Regulatory Agency, SAHPRA).

The form can be found at the following link:

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Permitted indications for listed medicines – V1.0, March 2018

Listed medicines in Australia are defined as ‘low risk’ medicines.  They are not individually assessed before entry into the Australian Register of Therapeutic Goods (ARTG).  All medicines supplied to Australian market require an entry in the ARTG.

Listed medicines must only use pre-approved ‘permitted indications’ and must comply with any additionally stated requirements. The Permitted Indications for Listed Medicines guideline provides the following information for sponsors on:

  • What are permitted indications?
  • How to use permitted indications
  • How to apply for new indications for listed medicines

The new regulatory requirements for permitted indications commenced on 6 March 2018. There is a three year transition period for existing listed medicines to comply with the new legislative requirements.   At the end of the transition period (6 March 2021), listed medicines that do not meet the legislative requirements for permitted indications, will be cancelled from the ARTG. Medicines that are cancelled from the ARTG cannot be supplied to the Australian market.

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Australian regulatory guidelines for biologicals (ARGB) – March 2018

The Australian Regulatory Guidelines for Biologicals (ARGB) Appendices 1, 2 and 3 have been updated to indicate that eCTD is acceptable for biological application.

Refer to below links for Details:

Appendix 1 – Guidelines on Class 2 Biological dossier requirements

Appendix 2 – Guidelines on Class 3 Biological dossier requirements

Appendix 3 – Guidelines on Class 4 Biological dossier requirements

Biosimilar medicines regulation – Version 2.1, February 2018

Updates in this new version of the regulation include a renaming of the ‘TGA proposed biosimilar naming convention’ to ‘Active ingredient names’.  Hyperlinks have been updated.  The updated regulation can be found at the link below:

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Permitted indications for listed medicines – V1.0, March 2018

CTD Module 1 – Administrative information and prescribing information for Australia – Version 4.0, February 2018

This guidance:

  • Explains the format and content for Module 1 of a dossier
  • Describes each document in Module 1
  • Outlines when each document needs to be provided
  • Details any other requirements relating to the documents.
  • The updated version to include requirements for the Comparable Overseas Regulator (COR) report-based process, Priority review registration process, remove Category 2 application requirements and align with version 3.1 of the eCTD regional specifications. This update will be applicable to applications received by the TGA from 9 February 2018.

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