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May 13, 2020 Life Science Consulting

United in Diversity: Six Tips for European Batch Release

Marc Stegeman Principal Consultant

Europe consists of 44 countries, and 21 supranational organizations and within the EU alone there are 24 official languages. So, how do you navigate the differences across Europe in the EU? And more specifically: how do you navigate the different regulatory landscapes if you want to export your drug product to Europe, for clinical study or commercial purposes. Or maybe you already have your product in one country, and you may want to extend to another. Here are six points to consider.

  1. The European Union unites 27 of those 44 countries, but within the EU there is always a backdoor of local legislation

The good news is that pharmaceutical legislation is arranged at EU level and the best example is the European Medicines Agency, now based in Amsterdam. One of the consequences is that governmental inspections are executed by the individual EU countries in such a way to avoid duplication of inspections by other EU countries. For example, if you set-up business in The Netherlands, you may trigger an inspection at your production facility outside of the EU. However, all other 26 EU countries accept this inspection, thus avoiding duplication of this inspection. These inspections are all based upon the same set of GMP legislation (Eudralex Vol 4). The local hurdle however remains that countries may have specific requirements or specific interpretations of this legislation. For example, Germany has specific requirements on gamma irradiation and a specific application process. And if your product is an opiate analogue, each country may have specific requirements and local application and approval processes. Nevertheless, while 90% is the same, you have to know the remaining 10% local details.

  1. EU legislation may apply to countries outside of the EU

We are all anxiously watching for the consequences of Brexit and hoping the impact will be limited. On the positive side, many other countries accept EU legislation as equivalent to their own. For example, the European Free Trade Association is a de facto acceptance of EU legislation in countries such as Norway. But again, be aware of the specifics. There are also Mutual Recognition Agreements in place with countries such as the United States, Canada, Israel, Australia, Japan, Switzerland, and New Zealand. Important elements are the recognition of mutual GMP standards, mutual GMP inspections, and no longer the need for retesting in the EU. This implies that retesting is a requirement for other countries!

  1. The regulations for batch release apply to any drug product and active substance

There may be specifics, but any drug product is within scope of this legislation. Of course, medical cannabis, cell- and gene therapies, radiopharmaceuticals or small molecules are completely different products and you must understand the specifics of each. It also applies to any active substance you import into the EU. The nice thing is that all those specifics come together in the role of Qualified Person. This person has a legal duty to release batches, independent from management. It implies that management may not overrule a decision to reject batches. The Qualified Person (QP) is authorized to do so by local health authorities, based upon specific education (sciences, pharmacy) and experience with specific products and processes. For example, if you are very experienced with radiopharmaceuticals, it does not necessarily mean that you may be qualified to release medical cannabis.

  1. You need a Manufacturing & Importation Authorization (MIA) and/or a Wholesale Distribution Authorization (WDA)

This is a typical example that we encounter often: Suppose you manufacture your active substance in the United States, you perform fill/finish in Canada, you ship the bulk product to The Netherlands, where it is packed, sent to a warehouse, and distributed all over the EU. The packer in The Netherlands releases the product. However, this may not be enough. Why? That is because the contract packer only releases the packaging step and not the entire batch production chain. This touches upon the principle of batch certification. To do so, you need a QP overseeing the entire chain. What does this oversight entail? Release of batches of course, considering every step of the chain, but there is more. The QP must ascertain the GMP status of each manufacturer in the USA and Canada and the packer in The Netherlands. This is normally done with on-site audits.

In addition, the QP-release needs be connected to a legal entity. You may need to set-up your own private limited company in The Netherlands, called a “BV”. This requires, as a minimum, a (part-time) General Manager and a QP. To perform release, the QP also needs a Quality Management System in place. With the audits executed and the QMS operational, you need to apply for the MIA with the Dutch Health Authorities (IGJ). This is followed by an inspection and granting the MIA. The whole process typically takes 6 – 9 months, and a well-established relationship with the local Health Authority is key.

We are well able to guide you through this process, including the QP support.

  1. GMP Certificate required in EU regulatory dossier

Upon submission of the Marketing Authorization dossier in some or all EU countries information on the GMP status and the MIA is required. The appropriate name and address information of the QP and valid Certificates of the manufacturing sites need to be included with initial submission. Any changes after approval of the marketing authorization may be included through variations to the dossier.  The role of the Qualified Person is to ascertain that batches are manufactured in line with the dossier.

  1. You may also need a Wholesale & Distribution Authorization (WDA)

Congratulations, you have just received your MIA. But why bother about a WDA? Well, a MIA also includes distribution and because of this broad scope an additional WDA is not necessary. This statement is true, if the distributer in our example is based in The Netherlands. But if you chose to have your distributor in Germany instead, you also moved to a different jurisdiction. In this case you need to apply for a WDA, locally. And this is another example of a local hurdle. Well, just one hurdle? No, 16! Each of the 16 states in Germany is responsible for WDA/MIA applications and GMP-inspections.

Understanding the complex and various regulations across multiple European regulatory agencies can be quite a challenge, but implementing these tips will get you well on your way to preparing for a successful EU batch release.

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