13/14 December 2023
What is the year holding in store for us in GMP matters? In Part one of our GMP Update we already looked at a number of GMP trends. Further developments will be covered in this article:
The biggest and most comprehensive change will be in the area of investigational medicinal products (IMPs):
Let's begin with the GCP guidelines. The currently valid directive 2001/20/E.G., "The Clinical Trials Directive", on good clinical practice will be withdrawn and replaced by regulation (EU) No 536/2014 on clinical trials on medicinal products for human use (published on 16 April 2014).
The aim is to establish a harmonized European procedure with a coordinated evaluation. National regulations will become obsolete, which will also lead to changes in the local law of the Member States.
Although they were already published in 2014, the new regulations are not effective yet. For their implementation, a central submission portal for clinical investigations has yet to be established at the EMA. Application dossiers for clinical investigations in only one Member State must also be submitted there. The regulation will come into force after the central submission portal has been implemented (with a transition period of 3 years).
However, the GMP area is affected as well. Based on Article 62 of Regulation 536/2014, the GMP requirements for investigational medicinal products (IMPs) must also be revised. To that purpose, Directive 2003/94 laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use will be withdrawn and replaced by two separate regulations. One of them is a new delegated act by the commission "… on principles and guidelines on good manufacturing practice for investigational medicinal products for human use and inspection procedures, pursuant to the first subparagraph of Article 63(1) of Regulation (EU) No 536/2014". The concept paper was published in August 2015.
Annex 13 of the EU GMP Guideline on IMPs shall also be withdrawn subsequently. It will be replaced by detailed guidelines "… on Good Manufacturing Practice for Investigational Medicinal Products for human use, pursuant to the second subparagraph of Article 63(1) of Regulation (EU) No 536/2014". This concept paper was also published in August 2015. Interest groups were asked for their feedback on this. They were also asked to answer a few questions. Their feedback was published in March 2016. The IMP Working Group of the European QP Association was also among the 26 feedback providers.
Annex 1 of the EU GMP Guideline (Manufacture of Sterile Medicinal Products)
A concept paper on Annex 1 of the EU GMP Guideline (Manufacture of Sterile Medicinal Products) was published in 2015 (the consultation phase ended in March 2015). So far however, there was no first draft of a revised annex for comments and there were already rumours that this draft would never come. The development is not that drastic though. The disclosure was delayed mainly because of the change in the ISO standard in question and the draft is already being discussed internally at the EMA.
Basically the following changes and amendments are in the focus:
New Annex 21 - Importers of Medicinal Products
With regard to the publication of the completely new Annex 21 on the import of medicinal products, it was also rumoured that it would disappear into oblivion. The concept paper (EMA/238299/2015) was published on 13 May 2015 after all, and the consultation phase ended in August 2015. But the annex is still alive! Currently, the critical point is the discussion on the procedure regarding a purely financial change of ownership ("financial import and export") where the product stays within the EU, but the ownership changes to a third country (e.g. Switzerland).
Water for Injection (WFI)
Monograph 0169 of the European Pharmacopoeia (Pharm. Eur.), water for injection (WFI), was revised. The requirements are supposed to come into force in April 2017.
What will change?
The revision is a renunciation of the strict demand for distillation as the only way to generate WFI (in order to avoid biofilms). It allows the production of WFI with equivalent methods such as reverse osmosis in combination with other techniques.
The change from distillation to an alternative technology must be indicated to the competent authority though. The new method must deliver the same good results as distillation. This can be proven through adherence to the measurement specifications according to the Ph. Eur. monograph, but the robustness of the manufacturing process must also be verified. This means that, over a certain period of time, any development of biofilms can be excluded with the help of appropriate monitoring data.
It's interesting to note that the GMP/GDP Inspectors Working Group of the European Medicines Agency (EMA) has developed a Questions and Answers paper ("Questions and answers on production of water for injections by non-distillation methods - reverse osmosis and biofilms and control strategies"). The draft was published in August 2016 and the consultation phase ended in November. The document shall guarantee that when the new WFI monograph will be introduced, any critical points regarding non-distillation techniques are known. It consists of a set of 6 questions and the associated answers and comprises all issues that the European inspectors are worried about. As a consequence, the document rather qualifies as a guideline.
Advanced Therapy Medicinal Products (ATMPs)
The plans to summarize the GMP requirements for ATMPs (e.g. gene therapy or somatic cell therapy medicinal products and tissue engineered products) in an individual document - and remove them from other EU GMP guidelines - are currently an emotional topic for the manufacturers and authorities concerned. A first draft was published in July 2016 and its consultation phase ended in September.
The EU Commission's idea to summarize specific GMP requirements in one consolidated document is not bad per se. After all, ATMPs have some particularities that we do not find in classical medicinal products. Nevertheless, the GMP/GDP Inspectors Working Group of the European Medicines Agency (EMA) and also the member states were opposed to it. All regulations that are laid down in other chapters or annexes of the EU GMP Guidelines have to be restated and updated ("harmonized") for a "stand-alone" document. There are already terminology issues within the guideline. An additional document could lead to even more conceptual confusion and possible contradictions. A summary of specific ATMP aspects in a separate Annex (22) to the EU GMP Guideline with references to other parts of the EU GMP Guideline for instance, as it is already done with radiopharmaceuticals in Annex 3, might be preferable.