Batch Testing And Brexit: 4 Things You Need To Know

By Tom Schiavon

Following the referendum¹ on June 23, 2016 that resulted in a vote to leave the European Union (EU), the United Kingdom entered a period of uncertainty regarding international agreements. Of paramount importance is the effect this will have on the conduct of clinical trials, specifically when dealing with batch testing of new medicines. As part of the EU, the U.K. enjoyed reciprocity with other countries under the jurisdiction of the European Medicines Agency (EMA), including those countries that had an agreement with the agency.

As part of the Article 50 injunction, the U.K. has until March 29, 2019 to negotiate a deal with the EU to remain a member of the EMA. If no agreement is reached, the U.K.’s regulatory body, the Medicines and Healthcare products Regulatory Agency (MHRA), has set forth the principles that will be in place on March 30, 2019 in case of a “no deal” scenario.

MHRA recently introduced new guidelines² for the batch testing of medicines entering or leaving the United Kingdom. The following sections describe four important takeaways from those guidelines.

1. The U.K. is committed to minimizing disruptions.

The MHRA realizes how vital it is to maintain the regular and predictable flow of human medicines and investigational medicinal products (IMPs). Many clinical trials are carried out in the United Kingdom, and the U.K. is also an important hub for the manufacture and shipping of IMPs, as well as many human medicines. To this effect, the MHRA will not drastically change the operational component of manufacturing or shipping medicines.

The United Kingdom's current presence in the EU makes batch testing more straightforward. Prior to March 30, 2019, the reciprocity of the EU, European Economic Area (EEA), and countries under the Mutual Recognition Agreement (MRA) means that medicines manufactured within the area can be sold or supplied without further certification in any of the member countries. This includes human medicines produced in the U.K., as long as a U.K.-based qualified person (QP) certifies compliance with Market Authorization (MA) and GMP guidelines. Human medicines made in a third country outside of the EU or EEA still require batch testing and QP certification, but once certified it meets MA standards in the U.K., EU, or EEA, it can be sold anywhere within those areas without additional certification.

The government of the U.K. has declared³ in the past its desire to continue working closely with EU regulatory agencies. The MHRA has also confirmed that drug products labeled before Brexit will not require relabeling, a move that provides continuity and will reduce operational impact. Given these statements, it appears the government of the U.K. Is committed to cooperating with the EU regarding human medicines and IMPs in the interest of public health and safety.

2. Changes to the EMA drug approval process will depend on the country.

As a member of the EMA, the U.K. was part of an organization that pooled resources to make the authorization of medicines more streamlined, reducing the burden of gaining approval in each country. The process will change depending on the country in which the medicines were manufactured, but the process remains nearly the same, except for third countries that are not exempt from the new requirements.

The guidelines define three groups of countries: the U.K., the EU/EEA, and "third countries." Third countries are those outside of the EU, but that can act within the EEA: Norway, Iceland, Liechtenstein, and Switzerland. The MHRA attitude toward each group of countries will follow the principles outlined below:

• Human medicines manufactured in EU and EEA⁴ states will continue to be accepted, as they are now, along with any third countries with which the EU has an MRA.
• IMPs manufactured and batch tested in the EU or EEA will continue to be accepted, and any agreements currently in place for third countries remain unchanged.
• Human medicines and IMPs manufactured in the U.K. will continue to require a U.K.-based QP to certify batch testing meets MA⁵ and GMP guidelines to be sold or supplied in the U.K.
• A U.K.-based QP will also need to certify human medicines and IMPs meet MA and GMP guidelines if the medicines are manufactured in a third country and directly imported into the U.K.
• The MHRA will maintain a list of countries that are exempt from the previous two conditions. On exit day, this list will include EU and EEA countries recognizing MA and GMP certification, release, and assurance of compliance carried out by a QP in the listed countries, including those that already have relevant QP certification.

One additional change is that if an application for which the centralized procedure would end after March 30, 2019, the U.K. will not be able to serve⁶ as one of the two members of a committee or working party that leads the evaluation of an application, known as a "co-rapporteur." As a result, any of the 370 "centrally authorized products" (CAPs) in the U.K.'s portfolio have been reassigned to eligible rapporteurs and co-rapporteurs still operating within the EMA.

The responsibilities of the U.K. government toward Northern Ireland are also a special consideration. As of the time the guidance was published, no definite plan was in place. As the guidance states, "[t]he Irish government have indicated they would need to discuss arrangements in the event of no deal with the European Commission and the EU Member States. The U.K. would stand ready in this scenario to engage constructively to meet our commitments and act in the best interests of the people of Northern Ireland."

3. EMA is relocating but remains involved in the batch testing process.

EMA will be moving from its current London location to Amsterdam. To minimize disruption during the move, a business continuity plan⁶ has been developed and is being implemented in phases. However, with the logistics of the physical move and an expected 30 percent staff loss, some disruption is expected as the stated plan "enables EMA to deliver its highest priority activities and to temporarily scale back or temporarily suspend lower priority activities if required." EMA's focus will be on the "evaluation and supervision of medicines," and scaled-back activities will include:

• international collaboration
• the development and revision of scientific guidelines
• the reduction of specialized consulting teams for non-product-related guidelines
• publishing clinical data⁷

In addition to the guidelines published by the MHRA, EMA has also published operational guidelines⁸ and an FAQ.⁹ The U.K. has assumed an open attitude toward medicines batch tested in the EU or EEA, but EMA guidance requires batch testing to be done at an authorized importation site if an MRA is not in place.¹⁰ Given that EMA has stated the importance of continuity concerning evaluating and supervising medicines, support for batch testing-related activities should not be affected.

EMA has published a website¹¹ with guidance to assist companies with planning and navigating throughout the transition, which is updated as conditions evolve as the talks process.

4. Any changes will come via a two-year transition period.

Per the MHRA guidelines, these arrangements “will continue until the government considers any further change is necessary." This would seem to make the guidelines arbitrary, but the statement is qualified that “any changes will entail a two-year notice period.” The notice period is intended to minimize impact and give affected supply chains and manufacturing processes time to plan and act to meet new guidelines.

Even with the guarantee, the uncertainty will affect companies' long-term plans to continue operations within the U.K. One primary reason is that EU law requires batch testing be performed within a member state. It may make more sense for pharmaceutical companies operating in Europe to have their primary manufacturing and release facilities within the EU to reduce redundancies. This is especially critical when Brexit may cause supply disruptions¹³ for dozens of products.

References:

1. Hunt, Alex & Wheeler, Brian. Brexit: All you need to know about the UK leaving the EU. Retrieved from BBC News: https://www.bbc.com/news/uk-politics-32810887
2. 0Batch testing medicines if there’s no Brexit deal. Retrieved from Medicines and Healthcare products Regulatory Agency: https://www.gov.uk/government/publications/batch-testing-medicines-if-theres-no-brexit-deal/batch-testing-medicines-if-theres-no-brexit-deal
3. Hunt, Jeremy & Clark, Greg. The UK wants to continue to work with the EU on medicines. Retrieved from Financial Times: https://www.ft.com/content/a94326ac-5dbd-11e7-9bc8-8055f264aa8b
4. Countries in the EU and EEA. Retrieved from Gov.UK:  https://www.gov.uk/eu-eea
5. Marketing authorization. Retrieved from European Medicines Agency: https://www.ema.europa.eu/human-regulatory/marketing-authorisation
6. United Kingdom's withdrawal from the European Union ('Brexit'). Retrieved from European Medicines Agency: https://www.ema.europa.eu/about-us/united-kingdoms-withdrawal-european-union-brexit
7. Clinical Data Publication. Retrieved from European Medicines Agency: https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/clinical-data-publication
8. Practical guidance for procedures related to Brexit for medicinal products for human and veterinary use within the framework of the centralised procedure. Retrieved from European Medicines Agency: https://www.ema.europa.eu/documents/regulatory-procedural-guideline/practical-guidance-procedures-related-brexit-medicinal-products-human-veterinary-use-within_en.pdf
9. Questions and Answers related to the United Kingdom's withdrawal from the European Union with regard to the medicinal products for human and veterinary use within the framework of the Centralised Procedure. Retrieved from European Medicines Agency: https://www.ema.europa.eu/documents/other/questions-answers-related-united-kingdoms-withdrawal-european-union-regard-medicinal-products-human_en.pdf
10. Concept paper on new guidance for importers of medicinal products. Retrieved from European Medicines Agency: https://www.ema.europa.eu/documents/scientific-guideline/concept-paper-new-guidance-importers-medicinal-products_en.pdf, 2. 
11. Brexit-related guidance for companies. Retrieved from European Medicines Agency:  https://www.ema.europa.eu/en/about-us/uks-withdrawal-eu/brexit-related-guidance-companies

About The Author:

Tom Schiavon, M.A. is an experienced project manager who enjoys exploring the intersection of theory and practice to innovate or improve processes. He gained an understanding of supplies management while serving as an IRT project manager and manager of technical support and data management teams. He obtained his M.A. in English from Florida Gulf Coast University, where he also graduated summa cum laude as an undergraduate. A humanities wonk by nature, he enjoys contributing to the development of novel medications aimed at easing human suffering. As part of KoCreation Design, he helps tell the story of the company’s unique mission and approach.