EMA Q&A Guidance: Updated Classification of (Post-Authorisation) Changes

Regulatory teams responsible for lifecycle management know that post-authorisation changes can quickly become complex, especially as products mature, manufacturing processes evolve, and emerging scientific data require frequent updates to quality and clinical documentation.

To support consistent interpretation of EU Variation Regulation (EC) No 1234/2008, the European Medicines Agency (EMA) maintains an extensive Q&A document titled "Classification of Changes"—a practical guide that explains how marketing authorisation holders (MAHs) should classify, justify and submit changes to their dossiers.

The latest revision (Nov 2025) introduces new clarifications and updates across administrative, quality, non-clinical and clinical change categories.

Administrative Changes: Clarity on Address Updates and Site Deletions

The Q&A confirms that changes to the name or address of a marketing authorisation holder or manufacturing site remain administrative only when the physical location and operations do not change. These updates fall under E.4, provided they are limited to administrative corrections such as street renaming or postal code changes. However, if a facility relocates, the appropriate quality variation category must be applied. The EMA reiterates that only official documents from competent authorities are acceptable, and self-declarations cannot support such updates.

When MAHs need to delete several manufacturing sites, the guidance allows a single Type IA variation (E.5) provided at least one authorised site remains capable of completing the same manufacturing function.

Quality Changes: New Clarifications for Site Additions, Module 3 Updates and CEP Revisions

The 2025 update devotes significant attention to quality variations, reflecting the increasing complexity of global manufacturing networks.

EMA reiterates that MAHs may use a single Type II variation under Q.II.b.1 when introducing a new finished product manufacturing site, as long as all related changes are clearly described. Any unrelated change—such as modifications to excipients or container closure systems—must be submitted separately but may be grouped into the same application. For active substances, the Q&A distinguishes between changes supported by an ASMF, which fall under Q.I.a.1.f, and more extensive changes requiring updates to Module 3, which fall under Q.I.a.1.b.

When extensive updates are made to Module 3.2.S or the ASMF, EMA recommends grouping them into a single Type II variation under Q.I.z, supported by a complete and clearly structured “present/proposed” comparison. Coordination between MAHs and ASMF holders is essential to avoid validation issues.

The guidance also clarifies the handling of revised CEPs. Only versions actually used in manufacturing must be submitted unless the revision concerns safety or quality. MAHs must list all changes introduced in the CEP and confirm whether omitted versions were used; failure to do so may result in a negative Type IA outcome.

EMA further defines how to classify new pack sizes. When a pack size falls within the existing approved range, MAHs should apply IAIN (Q.II.e.6.a.1). Pack sizes outside that range require a Type IB (Q.II.e.6.a.2), and the guidance provides detailed examples illustrating how to combine IB and IAIN scopes in grouped submissions.

Changes Covered by the Quality Management System

The Q&A describes several situations where variations are not required because the changes are managed within the company’s existing quality assurance system. These include moving manufacturing or control activities within the same authorised site, installing new isolators, updating room layouts, or adding equipment that operates within the approved parameter ranges. If any such changes require adjustments to Module 3, the appropriate variation must be filed.

Clinical and Non-Clinical Updates: Managing Study Data, PI Changes and Indication Modifications

EMA’s 2025 revision also addresses how MAHs should manage non-clinical and clinical documentation. Whenever clinical use changes—through altered posology, expanded target populations, or increased maximum daily doses—MAHs must conduct a quality impact assessment. These modifications can influence impurity limits, excipient safety, device compatibility for drug–device combinations, and other quality-critical parameters. The Q&A provides multiple examples illustrating how such changes may require grouped quality and clinical variations.

Final clinical and non-clinical study reports generally require submission via Type II variation under C.12, unless the data directly support specific SmPC or RMP updates, in which case the corresponding C-category variation applies. The guidance provides clear decision-making principles for determining when data sets must be submitted as separate variations and when grouping is justified.

For Study Protocol submissions, the Q&A distinguishes between imposed non-interventional studies under Article 107n/107o and other studies that may be handled via post-authorisation measures unless the protocol affects Annex II or the RMP. Updates to the Summary of the Pharmacovigilance System—such as changes in QPPV or PSMF location—must be reported exclusively via the Article 57 database, eliminating the need for a variation.

Editorial Changes: The Boundaries of What Is Allowed

The EMA stresses that editorial changes are permitted only when they do not alter scientific meaning. Formatting adjustments, alignment of internal terminology, punctuation corrections, and reordering of previously approved content may be included within an upcoming variation, provided MAHs clearly identify and justify them. However, changes that update scientific content, modify specifications, correct calculations, or adjust Module 4 or 5 reports fall outside editorial scope and require formal assessment.

Understanding these clarifications enables more efficient planning of regulatory strategies, especially for complex products with evolving manufacturing and clinical evidence.

This summary is based entirely on the EMA’s Q&A document and For full details, see the official guidance: "Classification of Changes"