CMDh and other updates – March 2022

Last updated: 29 March 2022

Report from the CMDh meeting held on 22-23 February 2022

Included in the report and minutes from the above meeting are the following items:

CMDh position on PASS results according to Art. 107q of Directive 2001/83/EC concerning hydroxyethyl-starch solutions for infusion

The CMDh, having considered the PRAC recommendation and the PRAC assessment report and also taking into consideration additional information from the marketing authorisation holders and external parties, agreed by a majority that the marketing authorisations for hydroxyethyl-starch (HES) solutions for infusion should be suspended across the European Union. These products were authorised as an addition to other treatments for plasma volume replacement following acute (sudden) blood loss.

As the CMDh position was adopted by majority vote, it will now be sent to the European Commission, which will take an EU-wide legally binding decision in due course.

Alprazolam containing products – Impurity G in alprazolam confirmed positive in bacterial mutagenicity test

The CMDh agreed to publish a letter addressed to MAHs of alprazolam-containing medicinal products to inform them that an Ames test (bacterial mutagenicity test) performed on the alprazolam Impurity G (7-chloro-1-methyl-5-phenyl[1,2,4]triazolo[4,3-a]quinolin-4-amine) was found positive and this implies that it is a Class 2 impurity according to ICH M7.

In the absence of additional information from in vitro or in vivo studies and pending the outcome of further investigations, it is required to ensure that Alprazolam Impurity G is controlled at an appropriate acceptable limit, as outlined in ICH M7 for known mutagens with unknown carcinogenic potential (class 2) via a suitable control strategy.

Further information on the establishment of the specifications and of an appropriate control strategy is included in the letter published on the CMDh website under “Advice from CMDh”.

Safety Working Party (SWP) response to CMDh questions regarding genotoxic medicinal products and contraception duration period

With reference to the CMDh press releases of April and July 2021 and following variations submitted by MAHs, the CMDh has asked SWP for a clarification of the scope of their previous recommendations regarding genotoxic medicinal products and contraception duration period.

  • SWP clarified that the recommendations should apply to any genotoxic active substance regardless of its therapeutic indication. However, the recommendations should not apply to active substances whose mechanism of genotoxicity is known to have a threshold which is not expected to be attained in patients.
  • The published SWP recommendation will be updated in due course. MAHs should take the updated recommendation into account when reviewing the need to update their product information.
  • Additionally, , the CMDh has now agreed that for cases, where a calculation of the duration of contraception is submitted, an assessment is needed and such cases should therefore also be submitted as type II variations. If the calculation is taken over from another product and no new calculation is required, a type IB variation is sufficient.

Whilst no link has been provided in the CMDh report, to the updated SWP recommendation mentioned above, it is possible that this could the updated document on the basis that it is dated 24 Feb 2022 and concerns an update of section 3.3 to clarify to which type of products the recommendations apply. It should be stressed that it has not been possible to verify if this is indeed the updated document.

Applicant’s response during DC procedures – new template and update of guidance

The CMDh has agreed a new template for applicants to provide their responses during DC procedures.

  • The new template allows the applicant to provide responses to clinical, nonclinical, quality and Module 1 issues in one joint document or as separate documents per Module.
  • The response document(s) should be provided both in pdf format in Module 1 and in current Word format in the working doc folder.
  • Guidance on the use of the new template has been included in the document.
  • The CMDh guidance document “Applicant’s response document in MRP and DCP for MAAs” has also been updated to reflect the use of the document.
  • It is foreseen that the use of the new template will facilitate the work of applicants and of the RMS.

The new template has been published on the CMDh website under “Templates > Assessment Reports > DCP”. You can accesss it from this page. The updated guidance document is now available. Here, you can view the track changed and clean versions of the document.

The use of the template will become mandatory as of 1 April 2022 for all upcoming responses and also for ongoing procedures, but it can be used before that date on a voluntary basis.

Regulation (EC) No 1234/2008 on variations
i) Recommendation for the classification of an unforeseen variation submitted to the EMA for a centrally authorised product

The CMDh discussed a recommendation for the classification of an unforeseen variation submitted to the EMA for a centrally authorised product.

  • The CMDh agreed with the EMA that the proposed change (“Deletion of one manufacturing process of a non-pharmacopoeial excipient (when described in the dossier) or a novel excipient”) should be submitted as a type IA variation under B.II.c.4.z (certain conditions apply).
  • The outcome has now been included in the CMDh list of Art. 5 recommendations and published on the CMDh website under “Procedural Guidance > Variation > Article 5 recommendations”. You can view it here.
ii) Update of the Best Practice Guide on CMDh Recommendations on Unforeseen Variations (Chapter 8 of the BPGs for the Submission and Processing of Variations in MRP)

The CMDh also agreed an update of the Best Practice Guide on CMDh Recommendations on Unforeseen Variations (Chapter 8 of the BPGs for the Submission and Processing of Variations in MRP). The update takes into account that under the Veterinary Medicinal Products Regulation (Regulation (EU) 2019/6) the CMDv is no longer actively involved in Article 5 recommendations on unforeseen variations. The outcome of such recommendations will be shared with CMDv for information. The updated document has now been published on the CMDh website under “Procedural Guidance > Variations”. Here, you can view the track changed and clean versions of the document.

iii) Update of RMS Validation Checklist for Human Medicinal Products in DCP

The CMDh agreed an update of the RMS Validation Checklist in DCP.

  • The checklist has been amended to take into account the updated application form concerning a section on medical devices and companion diagnostics and to include the latest information with regard to Brexit in line with Commission Notice 2021/C 524/02.
  • The updated document has now been published on the CMDh website under “Procedural Guidance > Application for MA”. You can view it on this page under the heading ‘Validation Procedure’.
iv) Working Party on Variation Regulation – Should manufacturing sites responsible for physical importation of intermediates products which undergo further processing should be recorded in the dossier?
  • The WP discussed whether manufacturing sites responsible for physical importation of intermediates products which undergo further processing should be recorded in the dossier. The CMDh agreed that MSs shall ensure that the import of intermediates which undergo further processing (referred to as “importation of intermediates”) and/or the import of finished medicinal products (referred to as “physical importation”) into their territory are subject to authorisations in accordance with Article 40(3) of Directive 2001/83/EC. Of note, that physical importation and batch certification of imported products are different operations that can take place at the same or different authorised manufacturing sites located in the in Union (EEA).
  • It is not a requirement to register in the dossier of the Marketing Authorisation, the manufacturer(s) responsible for importation of intermediate and/or the physical importation of the finished product, hence no variations applications are required for changes in intermediate importation sites and/or physical importation sites.
  • The Manufacturing and Importation Authorisation (MIA) holder responsible for batch certification of medicinal products manufactured from imported intermediates and/or imported medicinal products should ensure that the site(s) importation are appropriately authorised for this operation. The importer of the intermediate and/or physical importer needs to hold MIAs with entries in section 2.3.2 and/or 2.3.1 according to the Union Format for MIAs.
  • Technical agreements between the different manufacturers involved with importing the intermediate for further processing, the finished product manufacturer, the physical importer and the batch release site, as appropriate, shall be in place.
  • For more information on the certification by a QP and on batch release in the EU, also with regards to importation, see GMP annex 16.
  • In addition, the CMDh noted that in case these sites are already part of the dossier and the MAH intends to delete them a type IA variation A.7 is necessary.
Medical device regulation and transdermal patches

The CMDh agreed with a response to a question from a MAH (prepared by the EMA/CMDhsmall group) that transdermal patches do not fall under the second subparagraphs of Article 1(8) or (9) of the Medical Devices Regulation and therefore do not need to comply with Section 3.2., point 12, of Annex I of Directive 2001/83/EC, as amended by Article 117 MDR. To understand this better, you can read this post.

Applicability of Article 10(3) procedure for abridged application for which bioequivalence cannot be shown in fasted state

The CMDh discussed comments received during a Repeat Use Procedure for an Article 10(3) (of Directive 2001/83/EC) application (i.e. a hybrid medicinal prioduct application. .

The salient points of this particular case are:

  • The product was shown to be bioequivalent under fed conditions but failed to demonstrate bioequivalence under fasting conditions. Due to this difference in food effect, between the test and the reference products, the dossier was submitted under the legal basis of Article 10(3).
  • Additionally, SmPC changes are proposed to mitigate any risk associated with the difference of bioavailability under fasting conditions. The RMS considered this approach to be in line with the Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms (EMA/CHMP/EWP/280/96 Rev1).
  • The approach was not considered acceptable by a CMS during the Repeat Use Procedure, which is of the opinion that the relevant part of the guideline is intended for products which demonstrate a lesser food effect compared to the reference product, in order to stimulate availability of better formulated products which would lead to a lower risk to the patient with erroneous drug intake.
  • It was further noted that Article 10(3) is not acceptable for products for which bioequivalence could not be demonstrated, as described in the NtA Vol. 2A (chapter
  • The CMDh agreed to send a question to the Pharmacokinetics Working Party(PKWP) to ask for the right interpretation of the guidance in this case and if PKWP agrees with the RMS assessment.
Requests from MHRA to MAHs for PI updates following safety reviews

With reference to the discussion in September 2021 about the handling of variations toupdate the PI following safety reviews by the MHRA, the CMDh discussed an updated proposal on how to handle these variations, specifically for the MHRA safety review on anti-epileptic medicines.

The CMDh agreed that proposals for changes to SmPC section 5 (with the exception of section 5.3) or for changes to the PL only, can be handled by the RMS in consultation with the CMS in the procedure (no PRAC advice needs to be requested). Only variations that propose clinically relevant changes to SmPC section 4 and/or section 5.3 should be brought to the attention of the CMDh for discussion if a request for PRAC advice is applicable.

Generics are advised to await the update of the Reference Medicinal Product (RefMP) and to follow the wording implemented for the RefMP.