GMP Update - what's new in the EU?

The GMP world was turning a bit slower in 2016 - now, it's picking up speed again. Currently, several crucial changes are being made with consequences even for national legislation. There may not be a great amount of guidelines being changed or revised at the moment, but some of the changes that are being made do have significant impact (e.g. for manufacturers of IMPs, parenterals or ATMPs).

The changes will also entail a restructuring within the EU GMP guidelines - but let us start at be beginning.

IMPs

The reorganisation of the guidelines on clinical trials in the EU was decided upon in May 2014, already. The reason for this was the so far different implementation of Directive 2001/20/EG in the individual member states. The objective of Regulation (EU) No 536/2014 "… on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC" of 16 April, 2014 is therefore to establish standardised regulations for the execution of clinical trials in the EU.

To prevent future deviations, the restructuring won't be in the form of a directive, but a regulation (the Clinical Trial Regulation = CTR), which is directly applicable without needing to be transformed into national law.

Therefore, the GMP requirements for IMPs must be revised, as well. For 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practice in respect of medicinal products for human use and investigational medicinal products for human use" will be withdrawn and replaced by two individual directives; one specifically for commercial products and one for investigational medicinal products. At the same time, specific GMP guidelines for IMPs will be issued. This entails the following new documents:

• Commission Directive (EU) 2017/1572 of 15 September 2017 "supplementing Directive 2001/83/EC of the European Parliament and of the Council as regards the principles and guidelines of good manufacturing practice for medicinal products for human use"
• Commission Delegated Regulation (EU) 2017/1569 of 23 May 2017 "specifying principles and guidelines for good manufacturing practice for investigational medicinal products for human use and arrangements for inspections"
• 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" (replaces Annex 13 of the GMP Guidelines)

All this will come into force as soon as the EU's new submission portal for clinical trials has been implemented. A transitional period of three years will follow. However, there are some delays at the moment (probably until 2019).

New GMP rules for ATMPs

Similar to the new IMP guidelines structure, advanced therapy medicinal products (ATMPs) are to be defined in separate guidelines in the future, as well. To that end, the European Commission has issued the "New Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products" on 22 November 2017. ATMP manufacturers should implement the guideline's requirements by 22 May 2018.

New Structure of EU specifications

The aforementioned changes ultimately lead to a new structure of EU specifications. While it is difficult to describe in writing, the following diagrams show it quite clearly.

Structure of EU specifications so far:

Future structure of EU GMP specifications (without GDP - they remain the same):

Revision of Annex 1 of the EU GMP Guidelines (sterile medicinal products)

The long awaited draft of Annex 1 (Manufacture of Sterile Medicinal Products; Targeted stakeholders consultation) was published on 20 December 2017. What's special about it is that the revised Annex 1 won't be an independent EU document. Instead, it will also apply for the PIC/S guidelines. Even though it is still just a draft (comments can be submitted until 20 March 2018), the pharmaceutical industry will have to prepare for several changes, like:

• The revised and significantly larger Annex includes a new paragraph on Barrier Technologies (RABS and isolators). Before, only the isolator technology was mentioned. It differs between routine particle measurements and limits for initial clean room classification.
• The section on viable and non-viable Environment and Process monitoring was restructured and considerably expanded.
• In manufacturing, almost all the previous points have been expanded, e.g. the requirement for validated downtimes and process times.
• The new requirements for 100% visual inspection reflect the current state of the art. Trending is expected here, too.
• The sections on sterilisation have been expanded as far as text is concerned; there are no identifiable new requirements, though.
• The part on Aseptic Process Simulation (APS, also: Media Fill) has been restructured and considerably extended. Deviation assessments and the subsequent correctional measures will be redesigned here, especially. The goal is "zero growth".

What will become of the MRA?

The new Mutual Recognition Agreement (MRA) with the USA came into force on 01 November, 2017. Since then, the competent authorities of the EU have not conducted any inspections in the USA. In return, the FDA approved eight European authorities, so far: Croatia, France, Italy, Malta, Spain, Austria, Sweden and the United Kingdom. Other EU member states will be added as soon as their evaluation by the USA is complete; by 15 July, 2019, all authorities resp. countries are supposed to be evaluated and approved.

Challenges: the MRA is not 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. If and how EU authorities will inspect IMP manufacturers in the US 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 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 is necessary.

ICH Q12 Lifecycle Management

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

ICH Q3D Elemental Impurities: It's getting serious

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 apply since 01 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.