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Revised EU GMP Annex 19 (2026): What the New Requirements Mean for Reference and Retention Samples

Understanding the Difference: Reference Samples vs Retention Samples

Although the terms are often used interchangeably, Annex 19 clearly distinguishes between reference samples and retention samples.

Reference Samples

A reference sample is a sample of a batch of starting material, packaging material or finished product that is retained for analytical purposes. It allows future investigations and testing if quality concerns arise during the product’s lifecycle.

Reference samples should contain sufficient material to perform two complete analytical examinations whenever necessary.

Retention Samples

A retention sample is a fully packaged finished medicinal product retained for identification purposes. It represents exactly what was released to the market and includes:

• Primary packaging
• Secondary packaging
• Patient insert Leaflet
• Labelling
• Batch number
• Expiry date
• Safety features, where applicable

Retention samples enable manufacturers and regulatory authorities to verify the presentation of the product supplied to patients or healthcare professionals.

In simple terms:

• Reference samples support laboratory testing.
• Retention samples support product identification and packaging verification.

What Has Really Changed?

While Annex 19 has been rewritten, the majority of the requirements remain unchanged.

Sections 1 to 8 and Section 10 largely preserve the existing expectations regarding:

• Sample quantities
• Retention periods
• Storage conditions
• Technical agreements
• Responsibilities between contract partners
• Obligations following site closure

For most pharmaceutical manufacturers, existing Annex 19 procedures will therefore remain largely compliant.

The most significant changes are concentrated in Section 9, which addresses parallel imported, distributed and traded medicinal products.

Key Changes in Section 9

1. A More Prescriptive Approach

The previous version of Annex 19 relied largely on a risk-based interpretation for parallel-traded products. The revised Annex introduces clear and specific requirements.

Rather than asking companies to determine the appropriate approach based on perceived risk, the updated text now explicitly defines what must be retained and under which circumstances.

This reduces ambiguity and promotes greater consistency across the industry.

2. Packaging Material Retention Is Now Explicit

The revised Annex now clearly requires physical samples of packaging materials used during repackaging activities to be retained for the entire shelf life of the repackaged medicinal product.

Examples include: Labels, cartons, Patient Information Leaflets (PILs), Package inserts.

While many companies already followed this practice, it is now explicitly stated within Section 9.

3. Reference Samples of Repackaged Products Are Not Required

One of the most welcome clarifications is the explicit statement that reference samples of repackaged products are not required.

Since the medicinal product itself has already been manufactured and released under GMP, the regulatory focus during repackaging is on verifying the final market presentation rather than repeating analytical testing.

This clarification may allow some organisations to simplify existing sampling procedures.

4. Retention Samples Are Required for Each Repackaging Operation

The revised Annex introduces a more structured requirement for retention samples.

A retention sample of the repackaged finished product should now be retained for each repackaging operation and stored for at least one year after the expiry date.

Importantly, the wording refers to the repackaging operation itself rather than simply the product batch.

This means that:

• Different language versions
• Different market-specific presentations
• Separate repackaging runs

may require separate retention samples, even when the same original product batch is involved.

Where the secondary packaging remains unopened and unchanged during the repackaging operation, retaining a sample of the secondary packaging material used may be considered sufficient instead of retaining a sample of the finished repackaged product.

5. Digital Retention Samples Become Possible

Perhaps the most innovative aspect of the revision is the introduction of a pathway for photographic or digital retention samples.

Under specific circumstances, a physical retention sample may be replaced by a digital alternative when:

• Retention of a physical sample cannot reasonably be justified;
• The approach is agreed in advance with the competent authority;
• The digital record allows a full visual examination equivalent to a physical sample;
• All packaging details are visible, including batch number and expiry date;
• Safety features and Braille information can be verified;

Electronic records comply with the requirements of Annex 11 for computerised systems and data integrity.

It is important to note that this is not intended as a routine cost-saving measure. The digital approach remains an exception and requires robust justification and regulatory acceptance.

Why Was Annex 19 Revised?

The revision was partly driven by the separation of human and veterinary GMP requirements (EU) 2025/2091) following the adoption of new veterinary GMP regulations in 2025.

At the same time, the European Commission used the opportunity to modernise a section of Annex 19 that had remained largely unchanged for almost twenty years.

The updated Section 9 reflects the realities of today’s pharmaceutical supply chains, including:

• Multiple language versions
• Parallel trade activities
• Repackaging operations
• Falsified Medicines Directive requirements
• Increased reliance on digital quality systems

The introduction of digital retention samples also aligns with the broader regulatory trend towards digitalisation and enhanced data integrity expectations.

Clarification: This article focuses on the application of Section 9 of the revised Annex 19 in the context of parallel trade, parallel import and parallel distribution. Other relabeling activities (e.g. manufacturer-authorized rework or shortage-related relabeling) may be subject to different regulatory requirements.