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While the last issue of the GMP Journal covered the changes in the GMP area in the previous year, now the focus is on the changes in the current year1. The most important and comprehensive change will take place in the area of investigational medicinal products.

Let's start with the GCP requirements. The current Clinical Trial Directive 2001/20/EC on the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use will be withdrawn. It will be replaced by Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use, and for repealing Directive 2001/20/EC (published on 16 April 2014).

The aim is the establishment of a harmonised procedure with a coordinated assessment throughout Europe. The different national implementations of Directive 2001/20/EC are regarded as a barrier for multinational studies within Europe. Therefore the restructuring was not carried out in the form of a Directive which gives the Member States certain freedoms when transposing the directive into national law but as a Regulation. Regulations do not need to be transposed into national law, they come into effect immediately. This means that all respective national guidance and laws will become obsolete.

Although they have been published already in 2014 the new regulations have not yet entered into force. The EMA still has to set up a single electronic submission portal for the submission of clinical trials (the application dossiers for clinical trials carried out in a single Member State should also be submitted through that single portal). EMA's Management Board will discuss a time frame for the submission portal in October 2017, depending on the progress of the IT system. The EU Clinical Trial Regulation will then come into force in 2019 instead of October 2018, as previously planned.

This also concerns the area of GMP. Based on Article 62 of Regulation (EU) No 536/2014 the GMP requirements on investigational medicinal products also have to be adjusted. For this, Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines of GMP in respect of medicinal products for human use and investigational medicinal products for human use will be withdrawn and replaced by two separate new documents. One of these two documents pursuant to the first subparagraph of Article 63(1) of Regulation (EU) No 536/2014 is a new Commission Delegated Act "…on principles and guidelines on good manufacturing practice for investigational medicinal products for human use and inspection procedures." The concept paper was published in August 2015.

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Subsequently, Annex 13 of the EU Guidelines to Good Manufacturing Practice "Manufacture of investigational medicinal products" will also be withdrawn. Pursuant to the fi rst subparagraph of Article 63(1) of Regulation (EU) No 536/2014 it will be replaced by detailed Commission Guidelines "…on principles and guidelines on good manufacturing practice for investigational medicinal products for human use and inspection procedures". The relevant concept paper was also published in August 2015. Stakeholders were asked for feedback.

They were also asked to answer some questions. The feedback was published in March 2016. One of the 26 stakeholdes who sent feedback is the IMP Working Group of the European QP Association. This working group welcomes the actual revision of the GMP Guidelines for investigational medicinal products but also has further comments. The group recommends in general that the requirements concerning investigational medicinal products and commercial medicinal products are described clearly, as laid down in Annex 16, e.g. by adding clear provisions concerning the supply chain requirements. Furthermore it recommends to put special focus on the quality assurance of IRT systems used by sponsors and to use a harmonised and consistent terminology in the complete IMP relevant Directive. It also proposed some changed wordings and gave the relevant justifications.

Water for Injections (WFI)

Monograph 0169 of the European Pharmacopeia (Ph. Eur.), Water for Injections (WFI) has been revised. The requirements have become effective in April 2017.

What will change? The revision means that the production of WFI will not be limited to distillation any more (distillation was deemed to be required in order to prevent biofilm formation). The revision allows for production of WFI by means of a process equivalent to distillation such as reverse osmosis, coupled with other techniques.

In the case of a change from distillation to an alternative technology notice must be given to the competent supervisory authority. The new method must demonstrate to give results equivalent in quality to distillation. Equivalence in quality can not only be proven by compliance with the Ph.Eur. specifications, but the robustness of the production method must also be demonstrated. This means that monitoring data must show over a certain running time that the formation of a biofilm can be ruled out.

The new requirements on the technology for the production of water for injections will also be included in the Annex 1 EU GMP Guidelines at the same time.

The fact that the GMP/GDP Inspectors Working Group of the European Medicines Agency (EMA) has developed a corresponding Q&A document ("Questions and answers on production of water for injections by non-distillation methods - reverse osmosis and biofilms and control strategies") is very interesting for a monograph of a Pharmacopeia. The draft was published in August 2016 and consultation ended in November. The document shall ensure that all critical points of non-distillation technologies are known when the new WFI monograph is introduced. It consists of a set of 6 questions and answers and summarizes all concerns of the European inspectors. All things considered, the document rather has the character of a Guideline.

Process Validation for biotechnology products

The EMA Guideline on process validation for the manufacture of biotechnology- derived active substances and data to be provided in the regulatory submission (EMA/CHMP/BWP/187338/ 2014) was published in April 2015 and has entered into force already on 1 November 2016. It is intended to support and promote the implementation of QbD concepts and principles. Hence it is in line with Annex 15 EU GMP Guidelines and the corresponding Guideline on classical medicinal products.

The focus is put on recombinant proteins and recombinant polypeptides, their derivatives, and products of which they are components (e.g. conjugates). The principles may also apply to vaccines or plasma-derived products or to other biological products. To determine applicability, manufacturers should consult with the local competent authority.

Advanced Therapy Medicinal Products (ATMPs)

Another topic intensively debated among manufacturers concerned and authorities are the plans to combine the GMP requirements for ATMPs (such as gene therapy medicinal products, somatic cell therapy medicinal products, tissue engineered products) in a stand alone document and to separate them from the other EU-GMP requirements. A first draft was published in July 2016 whose consultation period ended in September 2016.

On the face of it, the Commission's idea to combine specific GMP requirements in a consolidated way in one document is a good one because ATMPs have some special features the classical medicinal products don't have. Worth mentioning are for example the following aspects:

  • quantitatively limited starting materials (such as cells and tissues) with a high degree of variability
  • extremely small batch sizes
  • limited shelf-life (in many cases analytical results will not be available at time of administration)
  • difficult quality control procedures.

Nevertheless, the plan met with the opposition of the GMP/GDP Inspectors Working Group of the European Medicines Agency (EMA) and the Member States. All rules regulated in other chapters or Annexes of the EU Guidelines to Good manufacturing Practice would need to be reformulated for a stand alone document and kept up to date (harmonised). The terminology in the Guidelines is problematic already now. A further document could lead to even more terminological confusion and contradictions. Instead it would be preferable for instance to summarize the specific features of ATMPs in an additional, separate Annex (22) to the EU GMP Guidelines with cross-references to relevant parts in the EU GMP Guidelines as is already done in the case of radiopharmaceuticals in Annex 3.

USA and EU adopt Mutual Recognition Agreement (MRA)

On 2nd March 2017, the US FDA and the EU (EMA) informed that they concluded a so-called MRA (Mutual Recognition Agreement). Such agreements are intended to mutually recognize GMP inspection systems. As a consequence, the GMP Compliance of a site is reviewed by the respective inspection authority. Afterwards, the FDA can use EU inspection results and vice-versa. FDA inspections in the EU or EU inspections in the USA should be only performed in exceptional cases.

The EU has already concluded MRAs with other countries like Australia, Canada, Japan, Switzerland and New Zealand. The MRA with the USA has already been under discussion since the nineties. In 1998, a contract was made but never put into practice, though, because of the two very different legal systems. The question of communicating detailed inspection results has been a recurring subject of discussions. Moreover, the FDA had doubts about the consistent quality of inspections in Europe. Equivalent systems had been recognised for some countries but it had also been noticed that some EU countries couldn't show an inspection system comparable to that of the FDA. Yet, the EU has consistently made clear that the agreement could only be concluded with the EU and not with individual EU member states.

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In the context of negotiations over the last years, progress has been made with regard to those points. Since 2014, cooperation has been intensified. Thereby, a Joint Audit Programme has been established. So far, the FDA has participated as an observer in 13 audits performed among EU countries. During the first audit of this kind, inspectors from England and Norway audited the Swedish GMP inspectorate under FDA supervision.

It will be interesting to see how the procedural rules are concretely applied in case of suspension of recognition of an authority - e.g. when the FDA refuses to recognise the inspection authority of an EU country and vice-versa. Article 13 specifies that. According to it, "Each Party has the right to suspend recognition of a recognized authority of the other Party. This right shall be exercised in an objective and reasoned manner and communicated in writing to the other Party and the recognized authority." [...] Furthermore: "Upon the suspension of an authority previously listed as a recognized authority, a Party is no longer obligated to accept official GMP documents of the suspended authority."

The agreement which has been made shall cover both medicinal products and APIs. Human blood, human plasma, human tissues and organs, and veterinary immunologicals are excluded from the scope of the agreement. The new agreement should come into force on 1st November 2017. Until then, the FDA wants to review the authorities of further EU countries. Similarly, the EU wants to check the regulatory authorities in the different US Federal States.


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.

1 This summary is based on the webinar "GMP Update" in December 2016. A recording of this as well as of other webinars is available at webinars.

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