February 2021

· 9 min read

EU, ICH and Brexit Pharma Regulatory Update - July 2020 to January 2021

Read the latest information on all things Brexit, nitrosamines and the implementation of the clinical trials regulation from regulatory expert Pete Gough.

EU News

New Head of EMA

Emer Cooke is the new Executive Director of the European Medicines Agency. Emer took over as head of the EMA on November 16, 2020. Emer said her priorities for the Agency would be the access and affordability of medicines.

Clinical Trial Regulation Implementation

The Clinical Trials (CT) Regulation 536/2014 published on May 28, 2014 has yet to be implemented as it requires a new portal, the Clinical Trials Information System (CTIS), to be operational for new processes to be functional. At its Management Board meeting on June 11, the EMA proposed December 2021 as the go-live date for the CTIS and CT regulation implementation.

Once the CTIS goes live, a three-year transition period to the new system will commence. In the first year of this transition, sponsors of clinical trials will be allowed to submit applications using either the existing EudraCT system or the CTIS. In years two and three, new CTA applications must be done via the CTIS. Trials authorized via EudraCT can continue but must be transferred to the CTIS by end of the three-year transition period.

Nitrosamine Contamination

On June 25, 2020, a Committee for Medicinal Products for Human Use (CHMP) Assessment Report recommended extending the requirement to conduct a risk assessment to consider the possibility of the presence of nitrosamine contamination to biological medicinal products. This requirement applies to both new marketing authorization applications and all existing products.

In August 2020, the EMA provided a deadline for the completion of the risk assessments and report of the outcome for biological products and, at the same time, further extended the deadline for products with chemically produced APIs to:

  • March 31, 2021 for chemical medicines
  • July 1, 2021 for biological medicines

In December 2020, the European Pharmacopoeia (Ph. Eur.) Commission adopted a new general chapter on the analysis of N-nitrosamine impurities in active substances (2.5.42, previously listed as 2.4.36).

Water Quality Guideline

In July 2020, the EMA issued an update to the “Guideline on the quality of water for pharmaceutical use,” which becomes effective on February 1, 2021. This revision is the first in 18 years.

The guidance lists the four types of water that can be used for manufacturing drug substances and finished drug products:

  • Water for injection, which is mainly used for sterile products
  • Purified water, which is used for non-sterile products and certain active substances
  • Potable water, which can be used for manufacturing active substances and the early stages of cleaning equipment
  • Water for the preparation of extracts, which is a new category for herbal products

This new guidance permits the use of potable water for producing the fermentation media and cell culture media in making active substances for biological products, whereas the preceding draft called for using higher-grade purified water for producing such media.

Brexit

On December 24, 2020, the EU and UK finally agreed to a trade deal. Annex TBT-2 of this trade deal contains the agreed provisions for medicinal products. The agreement applies to the following medicinal products for human and veterinary use:

  • Marketed medicinal products for human or veterinary use, including marketed biological and immunological products for human and veterinary use
  • Advanced therapy medicinal products
  • Active pharmaceutical ingredients for human or veterinary use
  • Investigational medicinal products

The agreement includes the following:

  • Mutual recognition of GMP inspections. Unfortunately, this agreement is not a mutual recognition agreement (MRA) and does not include removing the requirement for re-testing of product made in the UK on importation into the EU, and vice versa. For political reasons this requirement may not be removed for several years, if ever.
  • Regulatory cooperation

Notable absences from the trade agreement include any mention of herbal medicinal products or medical devices. Also absent is any arrangement for a two-way alert system or pharmacovigilance information sharing.

From January 1, 2021, the MHRA has published a library of new guidance that applied as the transition period came to an end. This guidance covers the following areas:

  • Clinical trials
  • Devices
  • Importing and exporting
  • IT systems
  • Legislation
  • Licensing
  • Pharmacovigilance
  • Pediatrics

Brexit Impact Summary

Northern Ireland effectively remains within the EU so many changes only impact the UK.
Impact Area
New marketing authorisations, centrally authorised products (CAPs)
EU Position
Must have marketing authorisation holder (MAH) in the EU/EEA
UK Position
Must apply for separate UK authorisation using the same information as for EU authorisation
Impact Area
New marketing authorisations, mutual recognition procedure (MRP)/decentralised procedure (DCP)
EU Position
UK cannot be a Reference Member State (RMS) or Concerned Member State (CMS)
UK Position
Need separate UK application
Impact Area
Existing marketing authorisations
EU Position
CAPs must have an MAH in the EU

Where UK was (co-)rapporteur this has been reassigned to other EU/EEA Member States

If MRP/DCP, then RMS/CMS cannot be the UK. If UK is the RMS, need to transfer to an RMS in the EU, usually to one of the CMSs

MAH must be located in the EU/EEA
UK Position
CAPs automatically granted a UK authorisation: one year to provide MHRA with baseline data.

MAH must be located in UK by end 2022.

Need a contact in the UK from 1 Feb. 2021
Impact Area
Batch testing and QP certification
EU Position
Batch testing must be within the EU/EEA or mutual recognition agreement (MRA) country (no MRA with UK)

QP certification must be within the EU/EEA

From 1 Jan. 2022 product exported to Northern Ireland will need re-testing and QP certification in Northern Ireland
UK Position
Testing must be within the EU/EEA, MRA country or UK

No additional QP certification required in UK if certified by a QP in the EU/EEA but wholesalers importing from EU/EEA need to name an RPi on WDA by 1 Jan. 2023
Impact Area
Batch testing, product manufactured in EU/EEA
EU Position
Testing must be performed within the EU/EEA
UK Position
No additional testing is required on import to UK until 1 Jan. 2023
Impact Area
Batch testing site, product manufactured in a third country and no MRA in place with the EU
EU Position
Testing must be within the EU/EEA
UK Position
Testing may be in the EU/EEA or UK

No additional testing required in UK if tested in EU/EEA until 1 Jan. 2023
Impact Area
Access to EU Medicines Agency’s IT systems such as EudraVigilance
EU Position
UK will no longer have access to EudraVigilance
UK Position
UK has own system; ADRs to be reported to MHRA
Impact Area
Good Manufacturing Practice and Good Distribution Practice
EU Position
EU Regulations and guidance apply
UK Position
UK will continue to follow EU guidance at least until 1 Jan. 2023

ICH News

The 2020 ICH biannual meetings, scheduled to be held in Canada in May and Greece in November, were both converted to virtual meetings due to the COVID-19 pandemic and the resulting global travel restrictions. The next ICH meeting is scheduled for June 2021 in South Korea.

In October 2020, the assembly endorsed the concept paper for the revision of Q9, Quality Risk Management. The concept paper for Q9 (R1) lists four areas for improvement with the current application of QRM:

  • High levels of subjectivity in risk assessments and in QRM outputs
  • Product availability risks
  • Lack of understanding as to what constitutes formality in QRM work
  • Lack of clarity on risk-based decision-making

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