At a glance and always at hand – the most relevant regulatory developments of 2019.
The European Medicines Agency (EMA) revised its four-page Q&A document on the EU-US Mutual Recognition Agreement (MRA) on marketing authorisation applications and variations.
Updated question 1: How does the EU-USA Mutual Recognition Agreement (MRA) affect marketing authorisation applications or variations?
The corresponding answer lists all available documents that have to be submitted as proof of GMP compliance for US manufacturing sites that have previously been inspected by the US FDA.
End of December 2019, the EMA has updated the Q&A document regarding information on nitrosamines for marketing authorisation holders who are currently reviewing their medicines for the possible presence of nitrosamines and testing products at risk.
It should support companies in their ongoing review of their manufacturing processes. The 10-page updated document lists potential sources of nitrosamine contamination that have been identified so far and includes four new Q&As.
The Q&A contains track changes making it easier to find the updated information.
Due to repeated cases of nitrosamine contamination in sartans new strict limits apply for the contamination of sartans with nitrosamines since 1 January 2020.
As N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) are classified as possible carcinogens for humans, manufacturers must ensure that these impurities do not occur in their manufacturing processes and must develop appropriate control strategies. To allow them to make the necessary changes to their processes, a two-year transitional period was agreed and strict provisional limits for the content of these impurities, which are included in the section "testing for purity". The corresponding Sartan monographs are:
This step is in accordance with the European Commission’s decision on limit values for valsartan, candesartan, irbesartan, losartan and olmesartan. These sartans have a tetrazole group in common which is responsible for the risk of contamination with nitrosamines.
On 4 December 2019, the European Commission published eight documents containing technical specifications for unique device identifiers (UDIs).
Four documents of
deal with Basic UDI-DI. These are required for the upcoming Eudamed database and consist of an 18-character string reflecting the manufacturing facility, the type of product and the product description code. The four other documents address UDI human readable interpretation (HRI) formats.
On 25 November 2019, the European Commission published the second corrigendum to the EU Medical Devices Regulation (MDR). The corrections mainly concern Class I medical devices.
The timetable for these products will be adjusted, thus giving manucfacturers of class I products additional four years to meet MDR requirements.
"[…] a device which is a class I device pursuant to Directive 93/42/EEC, for which the declaration of conformity was drawn up prior to 26 May 2020 and for which the conformity assessment procedure pursuant to this Regulation requires the involvement of a notified body, or which has a certificate that was issued in accordance with Directive 90/385/EEC or Directive 93/42/EEC and that is valid by virtue of paragraph 2 of this Article, may be placed on the market or put into service until 26 May 2024, provided that from 26 May 2020 it continues […]“
The new ICH guideline provides guidance on a framework to facilitate the management of post-approval chemistry, manufacturing and controls (CMC) changes in a more predictable and efficient manner across the product lifecycle.
Objectives and potential benefits of ICH Q12 i.e. include:
Two of the main tools that are presented for this purpose are:
ICH Q12 should be seen in line with ICH Q8 to Q11 and complements this series of ICH quality guidelines. It is an optional document and the introduced tools and concepts can be adopted, if appropriate. Under step 5 ICH Q12 is to be implemented in the ICH regions.
Please note: The document is fully in line with the US regulatory framework. In the EU legal adjustments will be necessary to achieve full compatibility with ICH Q12.
Please note: A new version of the Aide-Mèmoire was released on 22 January 2020.
On 18 November 2019, the European Commission published the Aide-Mémoire for GDP inspection of wholesalers compliance with commission delegated regulation (EU) 2016/161 for safety features. As a checklist, the six-page document is intended to assist wholesalers in complying with the relevant GDP regulations on safety features.
The Aide-Mémoire lists questions to be asked during an inspection as well as the documents that should be ready at hand during the inspection. The questions range from general information such as
but also includes specific questions about the
An additional column lists various references to corresponding text passages within suitable regulations.
WHO published a 28-page draft guideline on data integrity. It clarifies basic aspects to ensure reliable data and information in the manufacture and control of medicinal products. A 7-page annex provides additional examples for the practical implementation of the requirements.
The document has been harmonised with existing DI guidelines, e. g. of the US FDA, as far as possible.
In terms of content, the wheel might not be reinvented in this draft, but a clear structure and language speak for the document. The examples of quality risk management and data integrity assessments are well worth mentioning, as well as the ten examples of good documentation practices in data integrity.
A final version can be expected for the end of the year.
On 22 October 2019, the European Medicines Agency released a revised MDR/IVDR Q&A including new sections on the basic requirements for combination products and the selection of a notified body.
Further topics consider
The Q&A contains track changes making it easier to find the added information.
Please note: EMA has also published a 26-page draft guideline on the subject of quality requirements for combination products of medicinal products and medical devices.
According to the ICH, the PDE value for ethylene glycol was reinstated to its previous PDE value of 6,2 mg/day and a concentration limit of 620 ppm.
This value was changed in October 2018 with the ICH Q3C(R7) version to a PDE of 3.1 mg/day and a concentration limit of 310 ppm. The process was then preceded by an error correction procedure.
In 2019 the ICH received a request to suspend the error correction for ethylene glycol. Based on archive documents and in-depth literature research, the 2018-decision was reversed by the Expert Working Group. As a consequence, the Q3C(R7) version has now been reverted back to the Q3C(R6) version.
On 25 September 2019, the European Commission published Version 16 of the document on safety features for medicinal products for human use with two new questions:
This EMA Q&A published on 28 August 2019 clarifies when exemptions from batch re-testing of imported advanced therapy medicinal products (ATMPs) are permitted.
Four questions and their answers clarify
As of 15 July 2019 the US FDA grants all 28 EU member states the ability to conduct GMP inspections at a level equivalent to that of the US. The competent authorities in the US and the EU no longer have to carry out their own inspections of manufacturing sites, but can rely on reliable inspection results from the other side.
EMA has published a Q&A paper on the key points of the MRA, which is updated continuously.
It deals, e.g., with inspections outside the EU and the USA, with American combination products that are medical devices in the EU or with post-import controls.
In response to changes in the European Pharmacopoeia, WHO has published a 10-page draft guideline on WFI production without the means of distillation. It is intended to be the guideline WHO Good Manufacturing Practices: Water for Pharmaceutical Use. A publication date of a final version is currently not known.
With the publication of the 53nd TRS No. 1019 two revised guidelines in the area of
“Quality Assurance – GMP” were adopted:
The Q&A points out how companies should handle OOS batches of authorized cell or tissue-based advanced therapy medicinal products (ATMPs). For manufacturers, importers and Marketing Authorisation Holders of ATMPs this 2-page document will be of good value.
Six pairs of questions and answers explain a possible pathway for the administration of such out-of-specification (OOS) batches that have already been granted a marketing authorisation. Answers are given, e.g., on the following questions:
The 25-page final version of the guideline "Sterilisation of the Medicinal Products, Active Substance, Excipient and Primary Container” has entered into force on 1 October 2019.
The selection of appropriate sterilsation methods for sterile products is explained. The document comprises the
The optimal selection of a suitable sterilisation process is supported by decision trees.
On 22 March 2019, ICH published a revision of the Guideline for Elemental Impurities Q3D (R1) with an adjustment of the PDE value for cadmium by inhalation.
Cadmium is now listed with a new inhalation PDE value of 3.4 µg/day. The original value published in 2014 was 1.7 µg/day. It did not agree with the oral and parenteral PDE calculations, which are also given. Obviously, a modifying factor was not taken into account.
The guidance is intended to provide a tool to support the risk based classification of GMP deficiencies from inspections and to establish consistency amongst Inspectorates. It lays down the principles used to classify GMP deficiencies and also provides examples of the classification of different types of deficiencies.
The guidance entered into force on 1 January 2019.
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