Grace Period requirements in EU/ EEA

Marketing Authorisation Holders must plan regulatory procedure submissions and take into consideration several factors including impact on stock level. Stock level could be impacted by sell out period after regulatory procedure approval and grace period. Grace period has different regulations across EU. In this article we will give an overview of these requirements in EU countries.

Grace period regulation at EU level

Even though grace period may have several definitions, in the context of this article, when we mention the “grace period,” we are specifically referring to the time available before a batch must be released with a newly implemented change, such as update of product packaging or updating the manufacturing process, etc. So, the grace period essentially represents the timeframe within which the shift from “old product” and “new product” should happen and after which “old product” can no longer be released. Let’s start by examining how the grace period is regulated at the European level.

Commission Regulation (EC) No 1234/2008 and Guidelines on the details of the various categories of variations lay down the rules of implementation of variations. These guidelines aim to streamline the variation implementation process while ensuring compliance with safety standards and regulatory requirements.

Minor variation(s) of Type IB approved via a worksharing procedure, may be implemented upon receipt of the favourable opinion of the reference authority.

• In general, grace period is not applicable for type IA variations (do and tell), since it should be implemented up to 12 months before variation submission. Also, type IA_IN since it should be implemented up 14 days before variation submission.
• Major variation(s) of Type II (including those which contain grouped minor variation(s) of Type IB) approved via a worksharing procedure may be implemented 30 days after receipt of the favourable opinion from the reference authority provided that the necessary documentation to amend the marketing authorisation has been submitted to the Member States concerned.
• Variations related to safety issues must be implemented within a timeframe agreed between the reference Member State and the Marketing Authorisation holder.
• In those cases where the application has been the object of a referral, the variation(s) must not be implemented until the referral procedure has concluded that the variation(s) is accepted. Variations related to safety issues must be implemented within a time-frame agreed between the marketing authorisation holder and the reference authority.

Table 1 Summary of variation implementation guidelines

As seen from the summary above, the earliest implementation date is well defined in the guidelines. However, the changes, especially ones which affect the printed components, cannot be implemented into production immediately and require careful planning, thus it becomes very important to understand what is “deadline” to implement the changes, i.e., what is the grace period? Unfortunately, this aspect is not clearly regulated at European level and different national interpretations come into play.

Grace period regulation at National level

It is expected that when a variation involves changes to the product information, the Marketing Authorization Holder (MAH) should wait for the NCA to complete the linguistic review process before implementing the variation. This is because accurately checked translations are crucial for the correct implementation of the variation. Therefore, for commercially significant variations, MAHs may engage in internal preparatory work, such as preparing artworks at risk and organising all necessary personnel internally to ensure a smooth implementation and avoid delays caused by internal processes. However, MAHs should still wait for the final decision from the competent authority before printing these artworks and releasing batches. This is because product information and labeling are subject to change during regulatory assessment by NCA. In the case of European procedures (DCP/MRP), following approval from the Reference Member State (RMS), MAH could wait for approval from each concerned member state before proceeding with implementation.

For CMC changes or other changes that do not effect product information MAHs usually follow “silent approval” strategy and start implementing changes after RMS approval.

Grace period regulation at national level

As those rules set in previous chapter seem obvious, MAHs still have troubles to adapt production plans to meet required implementation since it is not always easy to predict the duration of the procedure, especially if there is significant variation in national approval timelines for shared packs. In addition, each member state has guideline or legislation on local level for the grace period. Unfortunately, these are most often available only in national languages and hidden somewhere in the NCAs website or its legislation archives.

At the national level, grace period rules typically fall into four main categories:

• Regulated based on the data applicant provided in Application Form
• Regulated based on national legislation or NCA guidelines
• No grace period is allowed based on EU or national legislation or guidelines
• Exceptional cases

The most common expectation from local Health Authorities regarding the implementation date is compliance with the proposed date provided during the submission of the variation in the Application Form. MAH should be precise specifying exact date or “next batch/next production” and is obliged to commit to statement in eAF. Countries which follow this approach are for eg. Austria, Germany, Hungary, Iceland, Romania etc.

Some countries regulate grace period at national level and have indicated exact period. For example, United Kingdom, Norway, Italy, Lithuania and Malta have a standard grace period which is 6 months.

No grace period is allowed for some variations related to safety and legal status changes. For those variations some countries even do not allow to sell out stocks. In addition, Slovakia and Czechia outstand in EU and those are the only countries that follow under “no grace period” category. After variation approval changes should be implemented for the production immediately. It is not allowed to release new batch after variation approval. In those countries, the grace period serves as a beneficial allowance for goods that were dispatched from the manufacturing site before the change implementation date specified in the electronic Application Form (eAF) but had not yet been delivered to local warehouses in Czechia and Slovakia.

In exceptional cases eg. Variations related to safety issues, including urgent safety restrictions, must be implemented within a timeframe agreed by the MAH and the National Competent Authority. Also, MAH transfers follows under exceptional cases. After MAH transfer approval, only new MAH could release new produced batches, therefore submission strategy should be carefully planed in order avoid out of stock and non-compliance situations. More information about MAH transfer and tips for submission strategy is available in our previous blog Marketing Authorization Transfer Considerations.

Detail overview of each EU/EEA member state national level requirements is available after filling out the contact form at the bottom of this page.

Typically, Marketing Authorization Holders (MAHs) must consider implementation dates across multiple countries due to European procedures involving several countries, shared packs, and production planning, among other factors. Considering all mentioned factors, MAH develops a strategy for batch releases and QP is responsible to oversee this compliance.

In case MAH fails to implement variation in line with terms laid down in Guidelines on the details of the various categories of variations and national legislation or guidelines, MAH needs to contact local authorities and inform about delay including when variation could be implemented. The approach of National Competent Authorities varies from country to country. Some member states have a more rigorous approach than others. As a result, each NCA assesses cases individually. Marketing Authorization Holders can use this agreement with the NCA as a basis to release a batch and place the product on the market.

Conclusion

Minimal implementation rules outlined in a Variation guideline serve as a basis for Marketing authorisation holders to plan batch release and variations implementations. However, while these guidelines may seem straightforward, actual production planning and alignment within a pharmaceutical company can be quite challenging. This challenge is further compounded by national specificities and varying rules at the national level, adding complexity to the situation. Following four basic principles discussed in this article could be helpful to navigate in EU environment.

And to make it even more easy, Insuvia experts prepared an overview which we are please to share with you. In this overview you will find summary of EU level requirements as well each EU/EEA country national requirements.