For the storage of investigational medicinal products, a documented temperature control is expected. This serves as evidence for the regular checking of the compliance of the temperature conditions for the investigational products with the specifications. Storage temperature requirements must be specified by the sponsor in accordance with ICH GCP Art. 5.13.2 or, if authorised medicinal products are used as investigational medicinal products, taken from the labelling of the medicinal product or the technical information.

Possibilities of temperature monitoring: A documented temperature monitoring can mean the keeping of a temperature protocol (entry of the read min/max temperature values in a document) but also the regular and documented monitoring of a central temperature monitoring system (continuous temperature recorder, centrally controlled temperature records, etc.).

• Min/Max thermometer (liquid or electronic, regularly calibrated)
• Temperature room monitoring by means of temperature sensors (central temperature monitoring etc.)

The choice of thermometer depends on the storage temperature requirements and the sensitivity (stability data) of the investigational product (risk analysis!).

Reading frequency/recordings:

The reading frequency of the thermometer and the recording of the temperature values read (min/max, time period) should depend on the storage conditions at the storage location (temperature fluctuations, air conditioning, etc.) and the storage temperature requirements and the sensitivity (stability data) of the test preparation (risk analysis!). The reading frequency should be defined in such a way that, in the event of a deviation, appropriate measures can be taken in good time (blocking of the goods, re-analysis, etc.). Requirements for temperature recording protocols: Temperature recording protocols must contain a reference to the measuring location and the temperature measuring instrument used. Considerations when storing particularly temperature-sensitive test preparations: The storage temperatures in refrigeration appliances can be subject to fluctuations depending on the storage location in the refrigeration appliance and the filling level of the appliance. A qualification of the device is to be carried out. For particularly temperature-sensitive investigational products, a temperature history check (min/max reading) may be useful prior to each delivery of investigational products to patients.

References:

§ Section 36 para. 7 AMG ICH GCP, Art. 2.12

The sponsor shall, in accordance with ICH GCP Art. 5.14.5a, take measures to ensure the stability of the investigational product(s) during the period of use. This includes the transport of investigational medicinal products. In principle, investigational medicinal products must be transported according to the storage temperature specified in the Investigational Medicinal Product Dossier (IMPD) and indicated on the label. In order to ensure compliance with the storage temperature during transport, temperature-controlled or validated transport (using qualified means of transport, transport packaging) must be risk-based on the basis of quality risk management. Here, existing stability data, among other things, must be taken into account individually with regard to the sensitivity of the active substance/test preparation. A blanket reference to stability data is not a substitute for temperature-controlled or validated transport. Possibilities for temperature monitoring are described in FAQ 1 "What requirements are placed on temperature monitoring for the storage of investigational medicinal products at the trial centre?

References:

• § 30 AMBO 2009
• Questions and Answers from the EMA GDP/GMP IWG - EU GMP guide annexes: Supplementary requirements: Annex 13, Question No. 6 What measures should be taken to ensure that the IMPs are kept under suitable conditions during transportation between the manufacturer or distributor and the investigator sites?

The purpose of drug accountability is the continuous overview/balancing of the trial medication.

According to ICH GCP Art. 4.6.3. an inventory record is required in addition to the delivery documentation, proband-specific accountability logs and return documentation. GCP explicitly lists these required documents. Inventory is an accurate and detailed inventory that provides an overview of test medication received and used at any time during the course of the study and shows what and how much medication is available at the centre at any given time. The existence of only the expenditure per patient (per patient accountability) is not sufficient. Accountability at the trial site is the responsibility of the investigator (ICH GCP Art. 4.6.1.) and must be verified by the monitor (ICH GCP Art. 5.18.4).

In general, the destruction of study medication at the trial site should be limited to exceptional cases (disposal under special precautions to avoid risks to the health of non-affected persons and the environment) for the following reasons:

AMG § 36 (7) indicates: The investigator shall return [...] unused investigational medicinal products to the sponsor.

However, GCP Art. 2.12 and AMBO 2009 § 1(4) and § 2(8) require that the GMP principles and guidelines including annexes (including Annex 13) of the European Commission be used for interpretation:

Annex 13 Art. Destruction 53-55: According to GMP Annex 13, the destruction of the trial medication is the responsibility of the sponsor. Accordingly, the destruction of trial medication at the trial site can only take place after authorization by the sponsor, after verification of all relevant requirements (e.g. drug accountability...). The destruction itself must be documented in detail and this information must be made available to the sponsor".

Derived from the sponsor's responsibility, the provisions for quality control and quality assurance AMG § 47 and ICH GCP Art. 2.13 are also applied during implementation. This includes, among other things, that the sponsor obtains detailed written destruction procedure descriptions from the Centre BEFORE approving destruction at the Centre and authorises destruction at the Centre on the basis of these descriptions.

Temperature data loggers must be able to read out the temperature data without there being any traceable possibility of manipulating the following data:

• Model and number of the temperature data logger (unambiguous and unchangeable traceability of the measurement data to the measuring instrument)
• Measurement times (date, time)
• measured temperature curve

In addition, the permanent traceability of the correctness of the measurements (via calibration certificates) must be ensured. It should be irrelevant with regard to data quality whether the temperature data logger physically (still) exists. If this is not the case, its storage is irrelevant.

Therefore, the following basic principle applies: The process of reading the data must be validated. The corresponding technical documentation of the manufacturer must cover all GCP requirements. If data can be changed from the outset due to the file format, this aspect must be taken into account during process validation.

No, this is not permitted. Test medication may not be sent directly to study participants by the manufacturer/depositor/pharmaceutical wholesaler or by the investigator/test centre. The dispatch of medicinal products to consumers is distance selling reserved for public pharmacies in Austria and authorised pharmacies in the EEA pursuant to § 59 AMG.

However, it is permissible for the manufacturer/deposit taker/wholesaler to send the investigational medicinal products for a particular trial participant to a pharmacy accessible to that patient at the request of an investigator. The pharmacy then hands over the investigational products to the study participant on site.

Investigational medicinal products which are authorised or registered non-prescription human medicinal specialities in Austria (e.g. for Phase IV clinical trials) may be sent directly to study participants by public pharmacies in Austria or by pharmacies in other EEA member states authorised to sell at a distance by order of the investigator.

The GMDP and GCP requirements for the shipping and storage of investigational medicinal products shall in any case be taken into account.

The sponsor pursuant to § 32 (3) AMG as amended shall ensure that neither the trial subjects nor the Austrian social insurance institutions incur any costs in connection with the provision of the investigational product.

The definition of the investigational product pursuant to § 2a (14) AMG as amended includes investigational products in Phase IV (i.e. approved and used in the context of approval) and reference products (i.e. drugs in comparison arms).

The examiner may, however, request the paying entity to assume the costs in accordance with the provisions of Section 32 (3) of the German Medicines Act (AMG) as amended (Z 1-4). From a documentation/GCP perspective, the sponsor must in this case demonstrate that the payer has agreed to pay the costs (individually or collectively) after having been informed in advance.