14/15 February 2023
The new EU Directive 2011/62/EU and its delegated acts keep on changing the pharmaceutical supply chain. The directive introduced numerous Delegated Acts with different time schedules and had some impact on revisions of several chapters of the EU-GMP Guidelines.
Here is the status quo of the Directive and the delegated acts:
Already in 2011, the European Commission published Directive 2011/62/EC, the so called Falsified Medicines Directive (or FMD).The main goal was the fight against counterfeit medicines. In 2014 the technical characteristics of one key requirement were defined, the unique identifier delivering the possibility of verification of the authenticity of single folding boxes. This will be a 2D barcode (data matrix). As this new requirement will become active in 2018, it is time to start defining strategies for both technical implementation and change control strategy.
The new EU GDP Guidelines have been effective since 2013 (2013/C343/01). These requirements highlighted the need for an effective quality management system supported by risk assessment and appropriate controls in the distribution chain.
The new GDP Guidelines apply not only to the wholesalers and manufacturers of pharmaceuticals; they also incorporate the specific requirements for the Brokers dealing with pharmaceutical products. The responsibility for the product during storage and distribution will remain with the manufacturers up to the point of sale, where wholesale dealers will take ownership of the products. It is clear that those playing a role in the pharmaceutical supply chain now have to comply with these requirements, therefore the service providers such as transportation companies and logistic service providers need to gain good understanding of what is required to be able to provide appropriate service to their clients.
In 2014, the Pharmaceutical Inspection Co-operation Scheme PIC/S has published a PIC/S Guide to Good Distribution Practice for Medicinal Products (PE 011-1). This Guide is based on the EU GDP-Guidelines (2013/C 343/01) and quotes the EU Guide almost completely.
However, EU specific references have been deleted and the term "must" is often replaced by the term "should". A dedicated Responsible Person is not introduced by the PIC/S document. It talks about "designated responsible person(s)" or "designated person(s)". Chapter 2.2 "Responsible person" of the EU GDP Guide is not quoted in the PIC/S document.
GDPs for APIs are still on their way. The "Guidelines on the principles of good distribution practices for active substances for medicinal products for human use" were published for consultation by the EU early 2013. The new guidelines address distribution organisations and distributors involved in procuring, importing, exporting, holding or supplying active substances.
GMPs for APIs: Whereas for medicinal products a GMP Directive (Directive 2003/94/EG from 8 October 2003) and detailed guidelines (Part I of the EU GMP Guide) have been existing for many years, there has been no equally binding act in all the EU members states for APIs. Only the detailed guidelines as Part II of the EU GMP Guidelines are in place. This has now been caught up on. On 25 November 2014, the "Commission Delegated Regulation (EU) No 1252/2014" was published in the Official Journal of the European Union. As the subtitle shows, this regulation is to be seen as "supplementing Directive 2001/83/EC... with regard to principles and guidelines of good manufacturing practice for active substances for medicinal products for human use".
Now, the set of rules for APIs is complete: the new regulation provides the necessary legal framework of GMP principles for APIs; the long existing Part II of the EU GMP Guide delivers further concretisation of these principles.
EMA has published a template for the QP's declaration concerning GMP compliance of the API used as starting material and verification of its supply chain called "The QP declaration template":
The QP Declaration should be provided in support of an application for a new marketing authorisation, variation or renewal of a medicinal product(s) authorised in the Community, using EU or national procedures within the scope of the respective Directives.
With this document, the Qualified Person confirms that an API used in manufacture of a Medicinal Product submitted for approval meets EU GMP standards. It includes all sites of full or partial manufacture of the API and the confirmation has to be based upon an audit of the API manufacturer(s).
In 2013, hardly any other topic was as extensively discussed in the pharmaceutical environment as the so called Written Confirmation (confirming the GMP compliance of an API / of the API manufacturer). Since 2 July 2013, all APIs manufactured outside the EU have to be accompanied by a Written Confirmation, issued by the Competent Authority of the exporting country. Without this confirmation there is almost no possibility to import an API into the EU. However, one alternative to a Written Confirmation is the admission to the list of "Third Countries" with comparable inspection standards. Authorities from countries on that list do not have to issue Written Confirmations. Countries currently on the list are Australia, Japan, Switzerland and the USA. Countries under assessment are Brazil, Israel, Singapore and New Zealand.