Reference samples and retention samples are stored samples that answer two different questions regarding a batch of investigational medicinal products. A reference sample is used for subsequent analytical testing of starting materials, packaging materials, or the product; a retention sample, as a fully packaged unit, documents how the finished product was presented and labeled. Both types of samples thus ensure the subsequent assessment of quality and identity without serving the same function.
Two Purposes of Sample Retention
The reference sample is stored so that it can be examined if necessary. It may come from a batch of starting material, packaging material, or finished product; if stability is suitable, critical intermediate stages may also be considered, for example, after analytical testing or before transport outside the manufacturer’s control. Its selection must be representative of the batch, as only then can a subsequent analysis support conclusions about its quality.
In contrast, the retention sample is a fully packaged unit of the finished product. It is kept for identification purposes and makes the presentation existing at the time of the batch verifiable: packaging, labeling, package leaflets, batch numbers, and expiration dates can be traced during an investigation. Its informative value lies not primarily in laboratory results, but in the reconstruction of what was actually dispensed.
The storage of both sample types supports investigations into quality defects. In the event of a complaint, suspected mislabeling, or a question regarding compliance with the authorization, it can first be clarified whether an analytical test, an identity check of the packaging, or both are required. The sampling strategy must therefore fit the product, the packaging process, and the expected investigative path.
Scope, Storage, and Accessibility
For investigational medicinal products, a reference sample should be large enough to perform all critical quality attribute tests from the Investigational Medicinal Product Dossier (IMPD) approved by the competent authority at least twice. This is more than a formal proof of quantity: if a sample does not allow for the necessary repeat testing, it cannot fulfill its analytical function in the event of an incident.
The storage location, conditions, and access are defined in the technical agreement between the sponsor and the manufacturer or multiple manufacturers. Authorities must be able to access the samples in a timely manner. For reference samples of the finished product, the Commission guidelines require defined storage conditions and, in principle, storage within the EU, with specific arrangements described for third-country scenarios.
In the case of multiple packaging operations, a single sample cannot fully represent a batch. The regulations therefore require at least one retention sample per packaging operation for different packaging operations. Especially with multilingual labels or country-specific packaging variants, this avoids a situation where only one variant is preserved and the specific packaging status can no longer be proven later.
Differentiation and Special Scenarios
Reference samples and retention samples are not automatically identical. One is kept for analytical testing, the other for the identification of the fully packaged product. However, if both samples are available as identical, fully packaged units, they may be considered interchangeable. This exception is based on the equality of their specific design, not on a general equation of the terms.
For an unblinded comparator in its original packaging from the authorized EU supply chain, no samples are expected for investigational medicinal products. It may be different if a comparator has been repackaged or over-encapsulated for blinding: in that case, a reference sample should be taken and stored from a point in time representative of this additional processing, as stability or identifiability may be affected by the processing.
Relevance for clinical trials
In the event of a complaint from a clinical site, the clear type of sample determines the initial investigative hypothesis. A suspicion of an incorrect label or a damaged package requires access to the retention sample of the relevant packaging operation; a conspicuous test result may require an analysis of the reference sample. Missing or non-attributable samples prolong the root cause analysis and complicate decisions regarding further shipments or a possible recall.
Full-service CROs like Mediconomics support the coordination of sampling plans with packaging and logistics processes, the documentation of country-specific packaging variants, and the tracking of which samples are accessible at the agreed location. This allows inquiries from clinical sites, safety functions, and quality management to be traced back to the correct batch and packaging version.
Sample planning must be made visible even before packaging, because the number of units for quality control and retention should be taken into account in the planned packaging quantity. Subsequent removal can impair the representative character or availability for the study.
Frequently Asked Questions (FAQ)
Which sample is required for a labeling question?
The retention sample is intended for the assessment of presentation, labeling, batch designation, and expiration date. It represents a fully packaged finished product unit.
How large must a reference sample of an investigational medicinal product be?
It should allow for at least two complete tests of all critical quality attributes specified in the approved Investigational Medicinal Product Dossier (IMPD).
Who determines the storage location of the samples?
The storage location is defined between the sponsor and the manufacturer or manufacturers in a technical agreement. Access for competent authorities must be possible in a timely manner.
Regulatory References
- Detailed Commission Guidelines C(2017) 8179 final, Section 7 – contains the IMP-specific requirements for reference and retention samples.
- Delegated Regulation (EU) 2017/1569, Article 10 – requires a quality control system and the retention of sufficient samples.
- EU GMP Guidelines, Annex 19 – explains the purpose, identification, and storage of reference and retention samples.