Euro Roundup: EMA answers questions on the shelf-life of sterile products after opening or reconstitution

The European Medicines Agency (EMA) has answered questions raised by its 26-year-old guidance on the maximum shelf-life of sterile products for human use after first opening or following reconstitution.

EMA finalized the note for guidance early in 1998 and brought it into effect later that year. The one-page document explains that it “is difficult to predict all the possible conditions under which the product will be opened, diluted, reconstituted and stored” and “the user is responsible for maintaining the quality of the product that is administered to the patient.” Applicants should help users meet that responsibility by running “appropriate studies” and providing the relevant information to users.

The 1998 guidance features a brief overview of the type of information developers of unpreserved and aqueous preserved sterile products should provide. The new Q&A, which is longer than the guidance, expands on the older text to support the provision of consistent in-use storage details.

In its first answer, EMA explains that the “proposed in-use shelf life should preferably be covered by the results of chemical and physical in-use stability tests” but “other scientific rationale could be acceptable.” At the minimum, companies should assess stability at room and refrigerator temperatures. The length of the studies depends on how the product will be used in the real world.

“Companies should provide data that support product specific scenarios which could be anticipated in actual practice such as time needed between first opening/reconstitution in the hospital pharmacy and administration to the patient. The applied in-use shelf-life requested to be included in the SPC should not be longer than what is needed in actual practice,” EMA wrote.

Another question covers the wording used to communicate the shelf-life. Only the text provided in the guidance should be used in the product information “in principle,” EMA wrote. The information should “clearly and unequivocally” state the in-use shelf-life and “highlight that in-use storage times and conditions are the responsibility of the user.”

Other answers address when to use the “general” wording, “specific text for preparations for infusion or injection,” and the wording for aqueous preserved products from the note for guidance. EMA has also provided a flow chart to help companies to determine which wording is right for their product.

EMA Q&A

Pharma trade group sends political leaders a to-do list for integrating Ukraine into the EU

Off-patent pharmaceutical trade group Medicines for Europe has written to political leaders to set out priority areas for pharmaceutical cooperation between the European Union and Ukraine. The proposed steps are intended to help Ukraine meet the requirements for becoming part of the EU single market.

Ukraine applied for EU membership in February 2022 and received unanimous support from the existing member states several months later. The European Commission listed seven steps Ukraine needs to take to advance toward membership but those were high-level actions, such as the implementation of a law on how judges are selected, and the strengthening of legislation against money laundering. Integrating Ukraine into the EU will also require industry-specific changes, including in pharma.

Working with the European Business Association, Medicines for Europe listed the actions it sees as the most important priorities in a letter to leaders including the director-general of the Commission's health and food safety group and the minister of health for Ukraine.

The letter lists seven priorities, including the “complete re-evaluation of the regulation and strategy of Ukraine’s pharmaceutical market.” Medicines for Europe wants to see “the development of a vision for Ukraine's place within the EU healthcare ecosystem and the Pharmaceutical Strategy for Europe.” The trade group is also pushing for the reform of Ukraine’s pharmaceutical regulatory agencies.

“The initial step should be the development and finalization of the concept of the new agency guided by principles of transparency, efficiency and profound consideration for Ukraine's future EU membership conditions. This will enable the selection of the most suitable EU member state agency as an operational example to follow within the technical support project,” the trade group wrote.

Medicines for Europe listed the alignment of regulatory requirements to enable mutual recognition of good manufacturing practices (GMPs) as its third priority area. The trade group “would welcome more engagement and dialogue between” inspection bodies in the EU and Ukraine to facilitate alignment. In Medicines for Europe’s view, involving bodies in the EU and Ukraine could accelerate the process.

The other priorities cover digitalization, counterfeit drugs, healthcare access, and intellectual property rights (IPR). Medicines for Europe spent the most time discussing IPR, setting out areas that Ukraine will need to align its legislation with the EU.

Open Letter

EMA’s safety committee proposes measures to minimize the risk of valproate medicines

EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has recommended actions intended to cut the risk of neurodevelopmental disorders in children born to men taking valproate medicines.

Valproate is used to treat epilepsy, bipolar disorder, and migraines but evidence of a risk of malformations and developmental problems has mounted in recent years. PRAC previously made recommendations for the drug in 2014 and 2018. A retrospective observational study run in response to the 2018 assessment led PRAC to look at the risks once again.

The latest recommendations center on the treatment of male patients. The observational study suggests babies born to men taking valproate in the three months before conception may be at an increased risk of neurodevelopmental disorders such as autism spectrum disorders, intellectual disability, and communication disorders. It is unclear if valproate is responsible for the increased risk of the disorders.

To mitigate that potential risk, PRAC is recommending that the treatment of male patients is started and supervised by a specialist. Doctors should tell patients about the possible risk, discuss the need to use contraception, and review the treatment plan regularly to consider if valproate remains appropriate, particularly when the patient is planning to conceive a child.

PRAC made the recommendations at a meeting last week. The committee also used the meeting to start a review of the safety of CAR-T medicines. Like its counterpart in the US, EMA is assessing the data on secondary malignancies related to T-cells, such as T-cell lymphoma, in recipients of the six CAR-T cell therapies approved for use in the EU.

Press Release, More

Other News:

The Medicines and Healthcare products Regulatory Agency (MHRA) has updated guidance on applying for a license to market a medicine in the UK. The update adds information about the three types of product license numbers — PL, PLNI and PLGB — that describe whether a license covers all or part of the UK. MHRA Guidance

The European Commission wants to connect with organizations that are interested in joining the Critical Medicines Alliance. Officials are setting up the alliance to provide recommendations and advice on how to address shortages of critical medicines and have put out an open call for expressions of interest to join the initiative. Press Release

The Big Data Steering Group (BDSG) has released its report for last year. BDSG, a collaboration between EMA and the Heads of Medicines Agency, used the report to outline the progress it made on its priority areas in 2023. The steering group also published an updated plan covering the work it aims to complete in 2024 and 2025. BDSG Report, More

Euro Roundup: EMA answers questions on the shelf-life of sterile products after opening or reconstitution

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