GMP UPDATE - WHAT IS NEW IN THE EU - PART II

In the first part of this article in the January/February issue of the GMP Journal, you could read about the regulatory changes that manufacturers of investigational medicinal products, Advanced Therapy Medicines (ATMPs - for example gene therapeutics, somatic cell therapeutics, or biotechnologically engineered tissue products) are facing.

In the second part you can read about changes in other Annexes to the EUGMP Guidelines and the consequences these changes will have. In addition, you will learn more about the MRA agreement between the EU and the US FDA as well as about the latest developments concerning the ICH Guidelines Q12 and Q3.

Other Annexes to the EU-GMP Guidelines

The revised Annex 17 ("Real Time Release Testing", so far "Parametric Release") has not been published yet. The public consultation on the revised draft of Annex 17 started on 15 September 2015 already. Deadline for comments was 11 December 2015. The feedback of the different interest groups was published in September 2016.

The completely new Annex 21 ("Importers of Medicinal Products") hasn't been published yet, either. The concept paper was already published on 13 May 2015 (EMA/238299/2015) and the consultation phase ended in August 2015. The actual problem is the discussion on how to react in the case of a merely financial change of ownership ("financial import and export") where the goods remain in the EU but the change of ownership takes place in a third country (such as Switzerland).

Recommendation

Berlin, Germany4/5 December 2024

Root Cause Analysis

What will become of the MRA?

A Mutual Recognition Agreement (MRA) with the USA has a c t u a l l y been existing since 1998 already. But the "Sectorial Annex on for Pharmaceutical Good Manufacturing Practices" has never been fully implemented and there only was a Joint Audit Programme, established in 2014. The Sectoral Annex has now been renegotiated and entered into force on 1 November 2017. The European Commission informed some weeks before that the FDA has the capability, capacity and the appropriate procedures to carry out inspections on the same level as the EU. Since 1 November 2017 the regulatory authorities of the EU have not conducted any inspections in the USA. In return, the FDA approved 14 European authorities, so far, as being suitable to carry out inspections of facilities that are equivalent to FDA standards: Croatia, France, Italy, Malta, Spain, Austria, Sweden and the United Kingdom. In March the Czech Republic, Greece, Hungary and Romania were added, and more recently Lithuania and Ireland. This list might seem to be a little short or even strange but this is due to the time when the single authorities were evaluated. It doesn't mean necessarily that the other countries did not successfully complete this evaluation process. Other EU member states will be added as soon as their evaluation by the USA is complete; by 15 July, 2019, all authorities respectively countries are supposed to be evaluated and approved.

Challenges

Not everything is as simple as it sounds. For example, the FDA does not perform routine inspections of IMP manufacturers. After the implementation of Delegated Regulation 2017/1569 however, IMP manufacturing in third countries is to always be inspected by national EU authorities (see part one of the article). If and to what extent EU authorities will inspect IMP manufacturers in the USA in spite of the MRA is still not clear (the regulation has not come into force, yet, after all).

Another problem is the non-issuing of GMP certificates. Currently, authorisation applications submitted to an EU authority listing drug manufacturers in the USA must prove the ownership of a licence issued by the FDA [Articles 8 (3) (k) and 12 (3) (m) Directive 2001/ 83/EC] as well as an EU-GMP certificate issued to the site by an EU authority. However, after the implementation of the MRA, these EU-GMP certificates are not issued anymore. And the FDA usually does not issue GMP certificates. Therefore, an alternative approach will be necessary.

What about the audits by the pharmaceutical manufacturer?

The manufacturing authorisation holder is responsible for an adequate supplier qualification. This means that audits will continue to be a fundamental part of this process. Another main part of the qualification of suppliers is the verification of available GMP certificates. Here, a Qualified Person (QP) must check what will be available in the future and which information can be used if no EU-GMP certificate is available. It might be possible to use the FDA establishment inspection report.

ICH Q12 Lifecycle Management

The new ICH Q12 Guideline "Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle" was published for a consultation phase (Step 2) in December 2017.

ICH Q12 was mainly intended to provide concepts for a scientific, risk-based approach to evaluate changes over the complete lifecycle of medicinal products. It was supposed to allow a more efficient regulatory evaluation, e.g. by reducing the required level of detail and the information in the dossier and by a risk-based change system.

Unfortunately, there seem to arise problems as concerns the future implementation. It cannot be implemented without a modification of the regulatory framework in the EU. For instance the regulation on variations would need to be revised. Eventually, the European Commission will take the implementation of ICH Q12 only into consideration after the variation guideline has been reviewed.

ICH published a declaration that the ICH Q12 Guideline is not always compatible with the existing legal framework in certain ICH regions as concerns the use of explicit established conditions (ECs) and the product lifecycle management (PLCM) described in the guideline. According to ICH the concepts have to be observed whenever they are compatible with the legal framework. In the meantime the Guideline should be implemented as far as possible in the framework of the applicable regulations (such as EU's Variations Regulation) in the relevant ICH regions.

ICH Q3D Elemental Impurities: It's getting serious

The ICH Q3D Guideline on Elemental Impurities and the relevant papers of other authorities have accompanied us for quite a while now. EMA published the Guideline "Elemental impurities in marketed products. Recommendations for implementation" (EMA/CHMP/QWP/109127/2015) already in February 2015. These recommendations address manufacturers of medicinal products and the national regulatory authorities. The EMA Guideline "ICH Q3D on Elemental Impurities" (EMA/CHMP/ICH/353369/2013) was published on 25 July 2016. New marketing authorisations were affected immediately and the effective date for medicinal products for human use with existing authorisation was December 2017. But in this case no notice of variation is necessary if risk assessment shows that neither further controls, replacement nor change of quality of materials used or change of the manufacturing process are needed.

Recommendation

22/23 January 2025

HPLC Data Integrity - Live Online Training

The requirements and revisions resulting from the ICH Q3 Guideline have been implemented in various chapters and monographs of the European Pharmacopoeia (Ph. Eur.). These changes were published in Supplement 9.3 and have been applying since 1 January 2018:

• General chapter 5.20 "Elemental impurities" (ICH Q3D)
• General monograph "Pharmaceutical preparations" (2619), refers to chapter 5.20
• General monograph "Substances for pharmaceutical use" (2034) includes procedures to monitor elemental impurities
• General method 2.4.20 "Determination of elemental impurities" describes, amongst other things, method development and validation
• The now obsolete heavy metal test (2.4.8) will be removed from over 500 monographs (exceptions are substances of natural origin or pure veterinary products, for example)

Soon-to-be necessary change control procedures must be considered here, as well.

 

Author:
Wolfgang Schmitt
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the areas QA, GMP and GDP.

Source:
¹ A recording of this and further webinars is available at www.gmp-compliance.org/training/recorded-gmp-webinars.