New EU good manufacturing practice legislations for “investigational medicinal products” & arrangements for inspections

After public consultation conducted by the EU Commission in 2015 that allowed stakeholders to comment on whether the regulations regarding the “good manufacturing practice” (GMP) guidelines for medicinal products for human use and “investigational medicinal products” (IMPs) should be divided, the EU Commission published two documents in the Official Journal of the European Union:

• Directive 2017/1572 (“GMP Directive”) 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 (for advanced therapy medicinal products (ATMPs) the guidelines of Article 5 of EC Regulation 1394/2007 apply).
• Delegated Regulation 2017/1569 (“GMP Regulation”) supplementing Regulation (EU) No 536/2014 (“EU Clinical Trials Regulation 536/2014”) of the European Parliament and of the Council by specifying principles of and guidelines for good manufacturing practice for investigational medicinal products for human use and arrangements for inspections.

Both subsections are currently part of Directive 2003/94 (8 October 2003) for determining the principles and guidelines of good manufacturing practice governing medicinal products for human use and investigational medicinal products for human use. According to Article 15 of the GMP Directive on medicinal products for human use, Directive 2003/94 is then to be suspended (see below).
GMP Regulation was developed by the EU Commission based on Article 63(1) (Manufacturing and import) of the EU Clinical Trials Regulation 536/2014 and is made of 4 Chapters & 27 Articles with the following details:

• Chapter I: General Provisions. 2 Articles.
• Chapter II: Good Manufacturing Practice. 14 Articles.
• Chapter III: Inspections. 9 Articles.
• Chapter IV: Final Provisions. 2 Articles.

The following two articles need to be highlighted:
1. Article 5 on “Pharmaceutical Quality System” links with the ICH Q10 Guideline, although Q10 is not mentioned in this Regulation;
2. Article 12 on the “Responsibilities of the qualified person.” Under article 12 of the GMP Regulation, the responsibilities of “Qualified Persons” (QPs) in the context of EU Clinical Trials Regulation 536/2014 are:
i. For IMPs manufactured in the Member State, a QP verifies that each batch has been manufactured and checked in compliance with the GMP requirements for investigational medicinal products laid down in the GMP Regulation as well as the information set under Article 25 of the EU Clinical Trials Regulation 536/2014;
ii. For IMPs manufactured in a third country, the QP verifies that each batch has been manufactured and checked by quality standards at least equivalent to those laid down in this GMP Regulation as well as the information set under Article 25 of the EU Clinical Trials Regulation 536/2014, considering the guidelines referred to in Article 63(1) of the EU Clinical Trials Regulation 536/2014 on manufacturing and import;
iii. The QP must certify in a register or equivalent document provided for that purpose that each production batch complies with the requirements mentioned above. The register or equivalent document must be kept up to date as operations are carried out and must remain available to the authorities for at least five years after the completion of or formal discontinuation of the last clinical trial in which the product batch was used.

Also, Chapter III of the GMP Regulation 2017/1569 regulates inspections in accordance with the EU Clinical Trials Regulation 536/2014
By means of regular GCP inspections as referred to in Article 63(4) of the EU Clinical Trials Regulation 536/2014, the Member State must ensure that holders of an authorization as referred to in Article 61(1) of that Regulation comply with the principles of GMP laid down in this Regulation (2017/1569) and take into account the guidelines referred in second subparagraph of Article 63(1) of the EU Clinical Trials Regulation 536/2014.

Regarding the effective date of the new provisions, both GMP documents relate to the initial application of the EU Clinical Trials Regulation 536/2014 (according to the EMA, this will be in 2019; an exact date is supposed to be set in October 2017):
• Directive 2003/94/EG will be suspended with the initial application of the EU Clinical Trials Regulation or as of April 1, 2018, whichever date is later. References to the repealed Directive must be construed as references to GMP Directive and GMP Regulation and read in accordance with the correlation table in the Annex of GMP Directive.
• Since GMP Directive must be converted into national law, Article 16 of this Directive asks member states to adopt and publish, by 31 March 2018 at the latest, the laws, regulations, and administrative provisions necessary to comply with this Directive
• GMP Directive and GMP Regulation shall enter into force on the twentieth day following that of their publication (i.e., on October 6, 2017). They shall apply from the date of applicability of the EU Clinical Trials Regulation or as of 1 April 2018, whichever date is later.

Stratulat Albulescu - Attorneys at law