Imported Injectable: Temperature Excursion and an Unfiled Primary Packaging Change
You are the QP responsible for certification of imported finished product at an EU site. A shipment of 5,000 packs of a 2-8 °C injectable arrives from a third-country manufacturer. The data logger shows 14.8 °C for 5 h 40 min during tarmac handling at the EU airport; the product was in its secondary carton. The marketing authorisation dossier contains a supported excursion claim of up to 25 °C for 7 days for the unopened vial. Separately, the manufacturer emailed four days after shipment to say it had changed the supplier of the vial stopper four months earlier. No variation has been filed; the site says the new stopper is 'technically equivalent' and that container closure integrity and leachables studies are complete. The batch is needed to cover a market shortage and the commercial team wants certification this week. Your importer's contract with the manufacturer makes the manufacturer responsible for regulatory filings.
1. How would you evaluate the temperature excursion, and what documentation would you require before accepting it?
Read the worked answer
The excursion is potentially acceptable because 14.8 °C for 5 h 40 min falls within the supported 25 °C/7-day claim, and the product was in its secondary carton. But I would not accept it on the logger printout alone. I would require:
- The complete logger file, including start and end times, sampling interval, placement in the load, and the calibration certificate covering the period.
- Confirmation that the excursion claim in the dossier applies to this presentation, strength and container, not just to bulk drug or a different pack size.
- The manufacturer's formal excursion assessment tying the measured data to the approved stability package, signed by a responsible person.
- A check for freezing or other excursion events elsewhere in the route, not only the airport window.
If those documents are satisfactory, the excursion can be closed as acceptable and the batch remains eligible for certification on that point. If the claim is narrower than I am being told, or the logger was uncalibrated or badly placed, the batch must be held pending a proper stability assessment. The QP should not sign off a deviation of this kind on the basis of a commercial shortage.
2. What is the significance of the stopper change, and can you certify the batch while it remains unfiled?
Read the worked answer
A change of supplier for a vial stopper is a change to a primary packaging component, and it is not something a manufacturer can declare 'technically equivalent' and implement at will. It affects container closure integrity, extractables and leachables, and possibly the stability profile, and it must be managed through the marketing authorisation variation process.
QP certification is an attestation that the batch was manufactured in accordance with its marketing authorisation and with GMP. If the batch contains a stopper that is not the approved component, I cannot honestly give that attestation, however good the technical data are. The container closure integrity and leachables studies are necessary GMP evidence, but they do not substitute for regulatory approval. I would also want to see the manufacturer's change control record, validation of the new stopper on the filling line, and stability data covering the change.
The contractual clause making the manufacturer responsible for filings does not transfer the QP's personal legal duty. I would seek written confirmation from the marketing authorisation holder of the filing status and, if necessary, advice from the competent authority. Until the position is clear, certification should be refused.
3. If you refuse certification, what actions and communications would you take?
Read the worked answer
Refusal is a decision that must be documented and acted on, not simply a withheld signature:
- Quarantine the batch physically and in the quality system, with a clear hold status and no possibility of release by another route.
- Record the decision with the specific grounds: unapproved primary packaging change, and the evidence still required.
- Notify the marketing authorisation holder and the manufacturer in writing, asking for the variation status and a commitment to file if needed, and setting out the data required for reassessment.
- Inform the competent authority where the situation warrants it, for example if the change has already affected distributed batches.
- Escalate internally so that the shortage is managed by supply, not by pressure on the QP. Alternative stock, including an unaffected batch, should be sourced if possible.
- Assess previous batches. If the new stopper has been used for four months, earlier imported batches may also contain it; the QP should establish whether any have been certified and whether a field action is needed.
The communication should be factual and non-blaming, but it must not soften the refusal or imply that certification will follow automatically once the shortage becomes acute.