Real Generics’ Regulatory News Digest For Generics – 24 November 2015

Planned changes to intellectual property protection in Europe

Towards the end of October 2015, the European Commission published a working document entitled A Single Market Strategy for Europe – Analysis and Evidence.

The document suggests a number of changes in intellectual property protection that would have a positive and significant impact on manufacturers of existing active substances and generic pharmaceuticals if implemented (section 3.3.3, pages 74-76.)

Three issues have been identified and solutions proposed:

  • Supplementary protection certificates, which extend patent protection by up to five years, are granted nationally, resulting in market fragmentation. Solution: SPC harmonisation.
  • The R&D exemption is implemented in different ways by different Member States. In the extreme case, some countries do not even allow supply of APIs to EU-based generic manufacturers for the purpose of MA applications. Solution: R&D exemption harmonisation.
  • Because EU-based manufacturers cannot manufacture – even for export – during the period of SPC protection, generic products from other countries (e.g. the BRIC countries) flood unprotected markets years earlier than generics from the EU. This advantage may also give a head start to non-EU manufacturers when launching generics in the EU market following patent expiry. Solution: SPC manufacturing waiver for export purposes.


A new edition of the technical guide for the elaboration of European Pharmacopoeia monographs

The 7th edition of the EDQM Technical Guide for the Elaboration of Monographs has been published recently. It can be downloaded here (free).

The guide is an invaluable reference when using and/or contributing to EP monographs, but also for those responsible for creating in-house specifications and monographs for drug substances and excipients.


Revised guideline on the dossier for certification of suitability

EDQM’s Certification Policy Document on the content of the dossier for chemical purity and microbiological quality was revised in August 2015 and implemented in September. The document should be consulted when preparing an application for a Certificate of Suitability (CEP).


Water for pharmaceutical use

EMA’s note for guidance on quality of water for pharmaceutical use (CPMP/QWP/158/01 Revision) specifies the different grades of water that should be used in various situations: manufacture of drug substances, manufacture of drug products, as an excipient (or for reconstitution), and for cleaning.

Four grades of water are considered: potable, purified, highly purified, and water for injections.

In the manufacture of drug substances, potable water normally suffices unless there are technical requirements for greater chemical purity, or the drug substance is claimed to be sterile, or it is intended as a component of a sterile drug product.

EDQM has issued a useful clarification: because the CEP procedure does not consider the final use of a substance, whenever water is mentioned on a CEP (implying that it is used in the final stages of manufacture of the drug substance) it must be assumed that this refers to potable water unless stated otherwise. Supplementary information from the drug substance manufacturer may therefore be required for submission in a marketing authorisation application in certain cases.


EMA product-specific bioequivalence guidance

EMA has released draft product-specific bioequivalence guidance for consultation, for the following products:

Rivaroxaban 2.5, 10, 15 and 20 mg film-coated tablets

Ticagrelor 90 mg film-coated tablets

Tacrolimus 0.2 and 1 mg granules for oral suspension

Lenalidomide 2.5, 5, 7.5, 10, 15 and 25 mg hard gelatin capsules

Entecavir 0.5 and 1 mg film-coated tablets and 0.05 mg/ml oral solution

The consultation end date is 1 January 2016.


Methyl- and propylparaben as excipients in human medicinal products for oral use

When parabens are used as preservatives in products administered orally, the current European Commission guideline on Excipients in the label and package leaflet of medicinal products for human use requires a warning in the package leaflet about possible allergic reactions.

A reflection paper was issued in October to consider the need for additional warnings, in view of the possible endocrine-disrupting effects of these preservatives. It was concluded that no additional warnings are necessary.

The evaluation focused on methylparaben and propylparaben, which are the most widely used parabens in oral formulations. Methylparaben was not found to be associated with any adverse endocrine effects, so its use at a concentration of up to 0.2 % is not a concern, even in paediatrics. Propylparaben does have some oestrogenic effect, so a permitted daily intake (PDE) of 3 mg/kg/day was proposed.

The overview of comments received on the reflection paper may also be of interest.


Photograph: The EPO by Dirk Loop, CC BY 2.0


Real Generics Ltd is a member of the Real Regulatory Group. The partner company, Real Regulatory Ltd, is a consultancy firm specialising in European Regulatory Affairs, Quality Management Systems and Supply Chain Operations Compliance for the pharmaceutical, medical device and aligned industries.

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