Questions and Answers on the Use of Advanced Therapy Medicinal Products with Out-of-Specification Release Test Results

State Institute for Drug Control issues Questions and Answers document to clarify possibility of administration of advanced therapy medicinal products (ATMPs) in case some of the release test results have not met acceptance criteria   

Under exceptional circumstances, advanced therapy medicinal products (ATMPs) may be administered to patients also in case some of the release test results have not met acceptance criteria (out-of-specifications; OOS). This possibility and the necessary conditions are described under section 11.5 of guideline Good Manufacturing Practice for Advanced Therapy Medicinal Products (GMP for ATMP)  / Czech translation of this guideline is SÚKL guidance VYR-43.

Centrally authorised ATMPs

The basic questions and answers regarding centrally authorised ATMPs have been published on the website of the European Medicines Agency (EMA) at:

https://www.ema.europa.eu/en/documents/other/questions-answers-use-out-specification-batches-authorised-cell-tissue-based-advanced-therapy_en.pdf


Question 1: Does SÚKL require a report on the administration of an authorised ATMP with the OOS results above the scope of conditions stipulated by the GMP for ATMP guideline and in what manner?

Yes. The GMP for ATMP guideline requires reporting to EMA and the surveillance authority competent for the batch release site. At the same time, SÚKL requires that a report on the use of an authorised ATMP with OOS results to be submitted, if the concerned batch of the medicinal product is to be administered to a patient in the Czech Republic.

The report for SÚKL should be submitted via the zavady@sukl_cz address within the scope of the report form for quality defects: http://www.sukl.cz/hlaseni-podezreni-na-zavadu-v-jakosti-leciv.

SÚKL does not assess/approve such notification, but only take note of the fact.

The report shall be submitted within 48 hours of the delivery of the medicinal product to the site – regardless of the scheduled time of application. If the medicinal product is subsequently not administered, this fact has to be also reported.

Investigational ATMPs and Products Authorised within the Scope of Hospital Exemptions


Question 1: What steps need to be taken when learning about OOS results in the manufacture of an investigational ATMP? Does SÚKL require reporting of the manufacture of the investigational ATMP with an OOS result and in what manner?

The manufacturer of the investigational medicinal product shall investigate the case (shall analyse the causes and the necessity for the implementation of corrective action, if applicable) and shall document it as a deviation from manufacture in line with the relevant Good Manufacturing Practice (GMP) requirements. The need to report the manufacture of an investigational ATMP with an OOS result to SÚKL differs depending on the time when the deviation is detected:

a)       In case the OOS result is established only after the batch has been released by the Qualified Person (applicable to certain tests the final results of which are known only subsequently, such as the sterility test, which is in compliance with the approved documentation), such finding is considered a quality defect. Reporting to SÚKL should be done via the zavady@sukl_cz address within the scope of the report form for quality defects: http://www.sukl.cz/hlaseni-podezreni-na-zavadu-v-jakosti-leciv.

 The quality defect should be reported to SÚKL without any unnecessary delay.

 b)      In case the OOS result is established prior to the batch release by the Qualified Person, the batch in questions shall not be released by the Qualified Person and in this case, it shall not be considered a quality defect and the quality defect report is not relevant.

 If this batch is subsequently administered to the patient upon request of the treating doctor in compliance with section 11.5 of the GMP for ATMP guideline, the manufacturer shall document the product acceptance confirmation by the treating doctor and shall forthwith notify the sponsor of the clinical trial about these facts. Information on the method of reporting this fact to SÚKL is provided under Question 2 below.


Question 2: Does SÚKL require reporting of the use of an investigational ATMP with an OOS result and in what manner?

SÚKL requires that the use of an investigational ATMP with an OOS result be reported in case the OOS result was established prior to the batch release by the Qualified Person (i.e. the product is administered upon the doctor's request) and the medicinal product in question is to be administered to a patient in the Czech Republic. The sponsor of the clinical trial should submit a copy of the Certificate of Analysis for the concerned batch of the product, a rationale, and a risk analysis assessing the potential impact of the deviation upon the quality, safety, and efficacy of the product. The report of use of an investigational ATMP with an OOS result together with the aforementioned background materials and identification of the concerned clinical trial (EudraCT number) should be sent to klinsekret@sukl_cz. In respect of clinical trials on ATMPs, it is appropriate to cater for the possibility of OOS submission already in the protocol of the clinical trial. The doctor shall be always obliged to inform the patient about the benefit and risks of an OOS ATMP administration and to document that the patient has been informed to this effect.

SÚKL does not assess/approve such notification, but only take note of the fact.

Notification of planned use should be done without any unnecessary delay. 


Question 3: Is it possible to keep the patient, to whom a product with an OOS result is to be administered, in the clinical trial?

Yes. Nevertheless, the administration of an OOS product should be provided for in the protocol, which should mention how data from such batches are to be evaluated; the administration of a product with an OOS result must be reflected in the processing of results from the clinical trial. 


Please be notified that it is always necessary to observe the basic condition stipulated by the GMP for ATMP guideline, i.e. that the administration of a medicinal product with an OOS result of batch analysis is possible only in exceptional cases when the administration of the medicinal product is necessary to prevent an immediate significant hazard for the patient, and with a view to other options available to the patient and the consequences of non-administration of the cells/tissues contained in the medicinal product to the patient.

Marketing Authorisation Section and Surveillance Section

17. 7. 2020