Having supported the commercial launch of 12 orphan and niche products into the EU in the last 4 years, Almac have witnessed a steady increase in the number of U.S. companies taking advantage of European market opportunities and expect this trend to increase. 

However, with its 28 member states, the European marketplace presents a variety of challenges from numerous official working languages to a complex regulatory framework. Consequently, U.S. companies are engaging with experienced one-stop-shop service providers for guidance on launch strategy, Named Patient Supply, pack design and artwork, including market-specific requirements for packaging and end-user distribution. Some common challenges to be aware of are discussed below.

Regulatory Filings & Market Access
For a U.S. company the Marketing Authorization Application (MAA) submission strategy in Europe can present challenges, given the different filing routes—centralized and decentralized—and the various options to be considered, depending on the type of product and therapeutic indication.

One of the most common pitfalls of companies moving into the EU from the U.S. is the assumption that complying with FDA requirements will lead to European product approval. Often this is not the case and, given that in terms of population the EU is a far larger market than the U.S., it is worth considering a development program that meets the combined needs of both regions.

Knowing the differences up front can help avoid unpleasant surprises at product approval stage, and more importantly can make all the difference to the type of approach that is taken with regulatory authorities when seeking scientific advice.

One method is to provide pre-launch access to drug products via Named Patient Supply program, which enable physicians and patients in Europe to access drug products that have been approved by the EMA, but have yet to be launched commercially in the individual member states, or drugs that have been approved outside of Europe, but not yet in the member state.

While pre-launch access is permitted by EU legislation, Named Patient Programs are governed by the individual member states, which have their own regulations regarding access and specific requirements for supply. Navigating the logistical and regulatory pathways is often a challenge faced by non-EU companies, so working with an experienced EU service provider helps alleviate some of the unknowns and speeds up the supply process. 

PTC Therapeutics, a leading biotechnology company engaged with Almac to provide launch support for their innovative Duchenne muscular dystrophy therapy, Translarna (ataluren). PTC recently received marketing authorization for Translarna in the EU for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD) in ambulatory patients aged five years and older.

Preceding the marketing authorization, PTC established Named Patient Programs in several countries. Though timelines were tight, Almac was able to supply Translarna for PTC’s Named Patient Programs in Spain and France, with additional countries to follow. The drug product was assembled into country specific packaging to meet individual member state requirements and distributed from Almac within 4 weeks, meeting an important product milestone timeline. 

With the initiation of PTC Therapeutics’ Expanded Access Program and subsequent conditional approval for its first product, Translarna (ataluren), the biotech firm needed a company it could depend on for distribution. It was important that the company have broad European experience and the ability to reach small patient populations efficiently.

Quality Assurance & Product Release
Europe also presents different quality requirements to the U.S. For instance, all products manufactured outside of Europe must undergo EU Import Testing according to Directive 2001/83/EC: Article 51, to ensure they are compliant with the specifications provided in the MAA. Within Europe all drug products must be QP released onto the market to confirm that the product is fit for purpose and has been processed to cGMP standards. These two requirements are unique to Europe hence the need for client companies to ensure they select a CMO with significant quality resources, extensive knowledge and experience.

Impact of Multiple Languages on Packaging Requirements
One of the biggest challenges to entering the European market is the multitude of languages, resulting in a large number of associated country-specific pack formats. Within the 28 member states of the EU there are more than 150 regional and minority languages, of which 24 are recognized working languages. Labeling and packaging needs to be in the member state language, requiring design, generation and management of all packaging components, including labels, Patient Information Leaflets (PILs), cartons etc. The use of regional (multilingual) packs, coupled to a blue box (country-specific detail) late-stage labeling operation, has proved a success for Almac’s clients when dealing with niche or orphan drug products, where product flexibility is key.

Complexity of the Supply Chain in the EU
Another challenge faced by client companies is defining their distribution strategy and associated product requirements throughout the distribution process. When distributing product to the selected target markets the drug product will face varying temperature ranges, transit times etc., so careful consideration needs to be given to the product packaging and distribution configurations.

Adding to this complexity, depending on the composition of the pharmaceutical drug product, importation duties and taxes can vary significantly therefore adding to the overall supply chain cost. By assessing the drug product and the manufacturing processes of the product, it may be possible to apply a specific customs procedure to minimize tax and duties payable.

With the increasing problem of counterfeit, misbranded, adulterated and diverted drugs entering the supply chain, it is essential to ensure the full traceability of the drug product by seeking advice on the country-specific requirements which vary between EU markets and then implementing an anti-counterfeiting strategy. For example, the French market requires drug products to have a 2D matrix barcode, incorporating the CIP code and batch and expiry details. Each individual saleable unit of drug product entering the Turkish market must also have a unique serial number, printed both in human readable format and incorporated in a 2D code. Working with a European CMO with experience and an established serialization solution will prove invaluable to ensure country-specific requirements are met.

All of the above can seem daunting for U.S. companies that are unfamiliar with the European marketplace and the various requirements. Therefore, engaging with an experienced European CMO as early in the process as possible is a key determinant in success, helping to build a strong relationship of trust and a long-term partnership for a successful product launch.

For example, NPS Pharma is a global biopharmaceutical company headquartered in New Jersey that engaged Almac to support the launch of their lead product, teduglutide [rDNA origin]) in Europe, which was first approved in the EU in August 2012, under the brand name Revestive, for adult short bowel syndrome (SBS).

NPS Pharma engaged Almac across a suite of services including artwork design, Compassionate Use Product Supply, commercial labeling and packaging, QP finished product release to market, end-user distribution and product invoicing. Almac’s integrated solution facilitated communication, connectivity and, ultimately, a successful set up to launch NPS’ first product in Europe.

Almac has built and expanded this service over the last five years to meet the requirements of its client partners. Providing an end-to-end service to companies launching high value, low volume, orphan drug products, who have limited experience in the EU marketplace, provides for a very strong value proposition. 

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David Downey joined Almac’s Pharma Services business unit in March 2008. Prior to joining Almac, he worked for Patheon EU as business director, Patheon UK/France having joined Patheon in 2002 as business manager, Monza Operations, bringing more than a decade of Pharma experience to the role in QA, validation, production and project management.