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Out-of-specification (OOS) results are usually a hard stop in the batch release of a medicinal product, but ATMPs do not always fit neatly into conventional batch release logic. For patient-specific, time-critical cell/tissue-based ATMPs, an OOS outcome can create an urgent dilemma: discard a potentially lifesaving dose or consider exceptional administration with robust safeguards.

In a revised Q&A released by the EMA in February 2026 (Rev.1), the European Medicines Agency (EMA) sets out how exceptional use of OOS batches of authorised cell/tissue-based ATMPs may be handled, anchored in Section 11.5 of the EU GMP for ATMP guideline (EudraLex, Volume 4, GMP for ATMPs), and framed around immediate significant hazard to the patient, strict roles and responsibilities, and clear reporting expectations.

In this FAQ-style article, we summarise the Q&A in practical regulatory terms, including who can request use, what the manufacturer must provide, what the Qualified Person (QP) can/cannot do, and the notifications and reporting that EMA expects. We also discuss how to embed this into a compliant pharmaceutical quality system (PQS) and quality risk management (QRM) approach.

FAQ 1: What does ‘OOS’ mean in the context of authorised ATMPs?

OOS means a that batch has a test result that does not meet the approved specification during testing. For authorised ATMPs, those specifications are part of the approved quality dossier and normally underpin routine batch release decisions.

However, the EMA recognises that for some cell/tissue-based ATMPs, which are often personalised medicines with a short shelf-life, and are often medically urgent, there may be exceptional scenarios where administering an OOS batch is considered to avoid an immediate significant hazard to the patient.

FAQ 2: Under what circumstances can an OOS batch of an authorised cell/tissue-based ATMP be administered in the EU?

Section 11.5 of the EU GMP for ATMPs guideline states that in exceptional cases, an OOS cell/tissue-based ATMP could still be given to a patient only if withholding it would pose an immediate and significant risk, and no suitable alternatives exist. When a treating physician requests such a product, the manufacturer must provide a risk evaluation, clearly inform the physician that the product is OOS, and record the physician’s confirmation to proceed.

Critically, it is not a “routine flexibility” mechanism. The EMA frames this as a risk-based, case-specific exception rather than an alternative release pathway. The Q&A reinforces that the conditions in Section 11.5 must be met, including documented risk evaluation and a physician’s request.

FAQ 3: Who makes the decision to use an OOS batch – manufacturer, MAH, QP, or treating physician?

The Q&A places the treating physician at the point of requesting administration after considering (1) the patient’s specific condition and (2) the risk evaluation provided by the manufacturer.

At the same time, the EMA is clear that the manufacturer must remain central to (a) investigating the OOS/root cause and (b) evaluating risks, so this is not a clinical-only judgement and cannot be pushed onto the hospital.

FAQ 4: What must the manufacturer provide before an OOS batch is supplied?

The manufacturer must provide an evaluation of the risks to the treating physician, and the batch is supplied only when the physician requests it after considering the specific condition of the patient and the evaluation of the risks provided by the manufacturer.

From a compliance perspective, that “risk evaluation” should look and feel like structured QRM: defined hazard(s), severity/likelihood thinking, uncertainty, risk controls, and a clear decision rationale, consistent with internationally harmonised QRM principles (ICH Q9(R1)).

FAQ 5: Who must be notified, and what are the timelines?

In clinical trials, the manufacturer must promptly inform the sponsor, who then notifies the relevant competent authority. For authorised (marketed) products, both the marketing authorisation holder and the supervisory authority responsible for batch release must be informed.

The EMA’s revised Q&A is specific on notification timing:

Immediate priority: inform the treating physician and conduct a risk evaluation.
When a patient in the EU has been administered an OOS batch, the Supervisory Authority should be informed (the authority responsible for the MIA site manufacturing/importing within the EU).
Expected timeline: following supply at the treating physician’s request, EMA expects notification to the Supervisory Authority within 48 hours from the manufacturer/importer/MAH.
The manufacturer/importer/MAH should also contact the National Authority of the treating site(s) to confirm whether they must be informed, and, where required, inform NCAs at the same time as the Supervisory Authority.

Where manufacturer, importer, and MAH are different legal entities, the EMA expects a written agreement defining roles, including communications with physicians and competent authorities.

This sits alongside broader EU expectations that quality issues and defects are handled via defined processes and risk-based escalation, so organisations should map OOS ATMP use into their deviation/quality defect and recall decision trees.

FAQ 6: Does the QP certify an OOS batch?

The QP cannot certify the OOS batch.

However, the Q&A also emphasises that responsibilities are not waived; the QP must still ensure that batch verifications are performed, and that the importation of OOS batches follows standard import procedures.

In practice, this is where many quality systems need careful wording – the batch is not “released” in the usual sense, however robust oversight, documentation integrity, and appropriate controls consistent with EU GMP expectations for a functioning PQS must still be demonstrated.

FAQ 7: What records must be retained for an OOS ATMP batch that is supplied?

The manufacturing/importing site should, as a minimum, keep records of details on:

Batch manufacture records
All testing
Transport and storage of the product
The treating physician’s request
The risk analysis provided by MAH/manufacturer
The OOS investigation and associated risk assessment (impact on product quality)

This aligns with the wider GMP principle that investigations must be thorough, scientifically justified, and traceable, particularly where decisions deviate from approved specifications. A strong QRM approach (ICH Q9(R1)) can help ensure documentation is structured and defensible under inspection.

FAQ 8: How does the MAH report OOS ATMP use to the EMA?

In addition to notifying the Supervisory Authority when an OOS batch has been administered, the EMA expects the MAH to submit a periodic review to the EMA which should:

Be submitted as a Quality Defect Report every 6 months.
Include an overview comparing OOS batches administered vs batches released-to-spec in the same period.
Aim to verify process consistency, appropriateness of specs, highlight trends, and identify improvements.

The EMA then provides the review to the CAT rapporteur; trends may trigger additional questions and/or regulatory action. This is important – the EMA is not only permitting an exception, but it is also actively requiring trend evaluation and lifecycle learning, echoing modern expectations that knowledge management and QRM are core PQS enablers.

FAQ 9: What does ‘trend evaluation’ mean here, and why does it matter?

The EMA’s Q&A makes “periodic review” and “trend detection” central. That means organisations should be prepared to demonstrate:

How OOS cases are categorised (type, attribute, severity)
How comparators are selected (released-to-spec batches)
Whether drift or repeatability issues exist
Whether specifications remain clinically and scientifically appropriate
How CAPA or post-approval changes are triggered when trends emerge

This is consistent with broader GMP/QRM thinking: risk reviews should not be static; they should be refreshed based on manufacturing performance and quality feedback, especially when patient risk trade-offs are being made.

FAQ 10: Are pharmacovigilance and follow-up obligations different when an OOS batch is used?

No, the MAH’s obligations are not waived.

Pharmacovigilance reporting and any specific follow-up obligations (e.g., registry requirements) continue to apply for OOS batches. Organisations should ensure traceability between the OOS decision record, the administered dose, and downstream PV systems, so any safety signals can be assessed in the context of the specific OOS attribute(s).

FAQ 11: What information must be provided to the patient?

The patient should be informed that they will receive an OOS ATMP and that the content and format are governed by national legislation at the treating site. Information provided to the patient should be in lay language.

Crucially, the EMA stresses that patient information documents cannot transfer responsibility to the patient or discharge the MAH/manufacturer’s responsibilities.

FAQ 12: What should companies do if they see recurring OOS outcomes? Could this trigger regulatory change?

The EMA’s periodic review is explicitly intended to assess process consistency and specification appropriateness, and to identify product/process improvements. If trends are detected, the EMA notes that additional information may be requested and regulatory actions considered.

In practical terms, recurring OOS signals may point toward a need for CAPA, comparability/validation updates, or post-approval changes, especially if the “exceptional” pathway becomes frequent. A mature QRM system should drive timely escalation and management review.

Conclusion

The EMA’s 26 February 2026 Q&A revision provides a clearer regulatory blueprint for one of the toughest edge cases in ATMP manufacturing – exceptional administration of an authorised cell/tissue-based ATMP batch that fails specification. The key message that underpins this strategy is balancing patient protection and urgency on one side, and non-negotiable GMP discipline on the other.

For organisations, compliance comes down to building a strong risk-based approach – manufacturer-led investigation and risk evaluation, physician request based on patient need, timely notification (including the 48-hour expectation), meticulous documentation, and 6-monthly EMA trending through Quality Defect reporting.

DLRC can support ATMP developers and MAHs by helping design and stress-test these workflows, spanning quality agreements, QRM frameworks aligned to ICH Q9(R1), inspection-ready documentation packs, and authority communication strategies, so that if an OOS scenario arises, teams can act quickly without compromising compliance. Contact us by emailing our experts at hello@dlrcgroup.com.