CMDh updates – November 2021

CMDh meeting 9 – 11 November report

The report from the above meeting is available here. Items of note include the following:

1) Risk of azido-impurity in losartan-containing medicinal products
  • In September 2021 the CMDh published a letter addressed to MAHs of losartan-containing medicinal products to ask them to review if there is a risk of contamination of their product with an azido impurity (5-[4′ -[(5-(Azidomethyl)-2-butyl-4-chloro-1 H-imidazol-1-yl)methyl]-[1,1′-biphenyl]2-yl] -1H-tetrazole (CAS 727718-93-6)).
  • It was confirmed that this impurity has tested positive in abacterial mutagenicity (Ames) test and that therefore it should be ensured that the impurity is controlled at or below the Threshold of Toxicological Concern (TTC) as outlined in ICH M7 for known mutagens with unknown carcinogenic potential (class 2) via a suitable control strategy.
  • However, recently new information has become available that raises uncertainties regarding the validity of the Ames test and therefore the mutagenicity of losartan azide. CMDh will communicate once further information is available.
  • As a matter of precaution, until investigations are finalised, all MAHs of losartan containing medicinal products where a risk has been identified are requested to implement testing on this impurity for all new batches of finished product before release to the market.
  • Should confirmatory testing show that batches exceed the applicable TTC limit of 10 ppm, the relevant authority should be immediately informed of the result and the authorities shall decide on placing on the market of these batches.
2) New template for the End of Procedure in MRP/RUP
  • The CMDh agreed a new template for the End of Procedure in MRP/RUP.
  • Thus far, an End of Procedure template was only available for DCP procedures and it was considered useful to also develop a respective template for MRP/RUP to harmonise the information provided by the RMS at the end of the procedure.
  • The new template is based on the DCP template, amended with specific information applicable to MRP/RUP. The new template can be used by the RMSs from now on. The new template will be published on the CMDh website
3) Call for review for chemically synthesised and biological medicinal products regarding nitrosamine impurities

The CMDh agreed a minor update of its practical guidance for MAHs of nationally authorised products (incl. MRP/DCP) in relation to the Art. 5(3) Referral on Nitrosamines. Outdated reference to step 1 submissions has been replaced by information that these submissions should already have taken place.
The updated document will be published on the CMDh website.

CMDh meeting 12 – 14 October minutes and report

The minutes for the above meeting are now available. The document is packed with information. The report from the same meeting is available here.

Some of the items of note from the minutes include the following:

1) Multilingual packaging Working Group (pages 6 and 9)

The CMDh discussed the following:

  • an update of the BPG on multilingual packaging. The update takes into account the experience from discussions on issues arising, feedback from MSs collected in a survey earlier this year, concerns raised by IPs and requests from MSs for clarification on practical aspects of the pilot on multilingual packaging
  • an update of the cover letter template for new MAAs submitted through MRP/DCP, which now includes the option for the applicant to inform about theirinterest to participate in the pilot on multilingual packaging as described in the BPG.

The CMDh adopted both documents that will be published on the CMDh website

2) Joint CMDh/CMDv Working Party on Variation Regulation (page 7)

The Working Party (WP) discussed:

  • a question from a MAH regarding the new section on harmonisation that was added in eAF in the variation form v1.25.0.0. “Has harmonisation of a section/some sections of the SmPC/PIL/labelling been achieved through a variation WS?” The WP discussed whether the section should be filled in also when only subsections/sentences/words have been harmonised and not complete sections. The WP agreed that in the case of former harmonisation of a subsection or single sentence “yes” should be ticked as it is foreseen in legislation that once harmonisation is achieved it should be kept in the future. A Q&A on thetopic will be drafted for the next VRWP meeting.
  • a query from a MAH on whether a type IA variation to change the name of an API manufacturing site concerning MRP/DCP and purely national products could be submitted in a Work Sharing (WS) procedure. The WP agreed that the WS could not be accepted as this is a type IA variation (B.III.1 with CEP or A.4 without CEP) and WS is not foreseen. The WP noted that a super-grouping will not be possible either, as it concerns purely national products. The MAH will be advised to submit a horizontal grouping for all purely national MAs in each member state (MS) concerned (i.e. one grouping per MS) for identical changes (B.III.1 with CEP or A.4 without CEP).
3) TiO2 (E171) used as excipient (page 10)
  • The EC gave a presentation on the main element of the draft Regulation related to the use of titanium dioxide in medicinal products. On the basis of the EMA scientific analysis, and in order to avoid shortages of medicinal products that could have impacts on public health, it is foreseen that titanium dioxide (E 171) should remain provisionally on the list of authorised additives to allow its use in medicinal products as a colour, pending the development of adequate alternatives to replace it, while ensuring the quality, safety and efficacy of the medicinal products concerned.
  • It is of critical importance that the pharmaceutical industry makes any possible efforts to accelerate the research and development of alternatives that would be used as a replacement for titanium dioxide in medicinal products, and to submit the necessary variation to the terms of the marketing authorisations concerned.
  • The EC will review the necessity to maintain titanium dioxide or otherwise delete it from the Union list of food additives for exclusive use as a colour in medicinal products within three years after the date of entering into force of the Regulation. The Regulation may come into force in early 2022, subject to the adoption procedure.
  • Further discussion in the EU regulatory network will follow on how to engage with industry to develop alternatives for new and existing MAs. The importance to start the development now was stressed.
4) Ph. Eur. finished product monographs (Pages 11-13)

The CMDh was informed about the Qualty Working Party (QWP) responses to the CMDh questions on Medicinal Product Monographs (MPMs). It is well worth reading the detailed responses from the QWP if only to understand the potential impact on registered product specifications.

5) Time limit for Eudralink data packages (page 20)

The CMDh was informed that often the default duration of validity of Eudralink data packages
of 5 days is used by applicants (although the published guidance recommends a period of two
months), which makes it challenging to retrieve/save the data package in time.
The CMDh agreed to request a change of the default setting of the duration of Eudralink data
packages from 5 days to the longest possible duration.

6) EU eCTD technical guidance (page 21)

The CMDh was informed that the Human Harmonisation Group (HHG) is about to finalise a
new draft of the EU eCTD technical guidance. The draft will be sent to the CMDh for
comments within two weeks.

Recommendations on submission dates in 2022 for Applicants of the Decentralised Procedure (DCP)

Rev.16 dated 1 October 2021 has now been published by the Coordination Group (CMDh) in order to facilitate planning of submission dates of new applications in 2022 going through the decentralised procedure.