The use of investigational medicinal products (IMPs) in clinical trials and expanded access programs (EAPs) requires standard operational procedures (SOPs) outside investigational protocols, to assure traceability of the product from patient’s enrollment to follow-up. This requirement is established by the European Regulation No. 536/2014 (Clinical Trials Regulation), the Good Clinical Practice ICH E6(R2), the Good Manufacturing Practice (EudraLex Volume 4, Annex 13), the Italian National Ministerial Decrees (30 November 2021, and 7 September 2017 for compassionate use), and by the most recent Italian Pharmacy Agency AIFA determinations (No. 425/2024). IMPs are patient-specific drugs and they play a critical role in ensuring the correct allocation of treatment. In randomized studies, IMPs must be correctly assigned, as subjects can either receive IMP or placebo/standard of care, in single- or double-blinding. Incorrect patient-IMP matching would result in study deviations and misleading results, as well as suspected unexpected serious adverse reactions (SUSARs).
IMP management involves multiple professional figures and coordinated activities across different hospital units: (i) the Medical Doctor is responsible for patient’s evaluation, eligibility assessment and IMP administration; (ii) the doctor also requests access to the IMP and prepare the appropriate documents for approval by the Ethics Committee; (iii) the Study Coordinator or Data Manager verifies the completeness of the documents; (iv) the Ethics Committee authorizes the use within a clinical trial or an EAP; (v) the Investigator has to communicate to the Pharmacy Unit this authorization and, eventually, the beginning of the study; (vi) the Doctor has to request the drug to the Pharmacy and the Pharmacist has to formally request it to the Pharmaceutical Company; and (vii) the Pharmacist has the responsibilities of IMP management, procurement, verification, storage, and dispensing. Once received, the Pharmacist verifies that the product corresponds to the approved protocol or EAP, checks the integrity of the packaging, and confirms compliance with shipping conditions. The Pharmacist is also responsible for ensuring that the IMP is handled and stored according to sponsor’ or manufacturer’s specifications. A fundamental component of IMP management is drug accountability, defined as the systematic and real-time documentation of all operations involving the IMP. Dedicated logs must record quantities received, dispensed, returned, and destroyed. These records must be continuously updated and readily available for audits and inspections by regulatory authorities, ensuring full traceability throughout the product lifecycle.
IMPs must be maintained under controlled temperature conditions throughout transport and storage, with continuous monitoring (e.g., data loggers). Procedures must be in place to manage temperature excursions, including product quarantine and sponsor assessment of usability. Upon receipt, the Pharmacy Unit must verify: the consistency between shipment and transport documentation; correct study and product identification; integrity of packaging and absence of physical damage; and compliance with shipping conditions, including temperature. Following verification, the Pharmacist has to fill out the receipt, which includes the date, time, quantity, and transport details, and has to ensure drug storage in accordance with according to the sponsor's or manufacturer's specifications. IMPs must be stored in designated areas, separated by protocol and from other medicinal products, with continuous temperature monitoring (e.g., controlled room temperature or refrigerated conditions <8°C, where applicable). Upon Investigator’s request, the Pharmacist produces the documentation, delivers the IMP, and ensures appropriate recording of the transaction. The investigational products are delivered directly to the Principal Investigator or his/her delegate, only prior to administration to the volunteer or patient, in an organized manner with sufficient advance notice. The Investigator (or delegate) confirms receipt by signing the relevant documentation, which is archived in the study file. Upon delivery, the Principal Investigator, or his/her delegate, signs the declaration of receipt of clinical trial products, which is retained in the study file. The investigator must receive a copy of the declaration of receipt and a copy of the DDT. Temperature-controlled drugs are transported from the pharmacy to the clinical unit in special thermal bags.
Transport from the pharmacy to the clinical unit must ensure maintenance of required conditions (e.g., thermal containers for temperature-sensitive products), and IMPs should be delivered immediately prior to administration to minimize risks. If unused drugs are to be returned, after determining the reason and in agreement with the Investigator and the supplier, the Pharmacist has to prepare a return form. All returned products must be handled according to sponsor’s instructions, with appropriate documentation of quantities, dates, and conditions. The sponsor is responsible for drug collection. Risks associated with IMP shipping include incorrect package labeling or unsuitable hygiene and environmental conditions. The package must be labeled with the following information: Pharmacy’s contacts and address, trial protocol and investigator identification, and storage temperatures. All packages must travel at controlled temperatures with a temperature recording device to verify proper storage during transport. Furthermore, experimental products with a storage temperature <8°C must be stored in appropriate thermal containers equipped with a temperature monitoring system, and in a dedicated space.
Risks associated with the receipt of IMP include mismatch between transport documents (DDT) and delivered packages, labeling that does not comply with regulatory requirements (Annex 13 of the GMP guidelines), or unsuitable hygiene and environmental conditions. Risks associated with IMP storage at the Pharmacy include damage of the packaging or unsuitable hygiene and environmental conditions. Furthermore, products requiring storage below 25°C must be kept in an area equipped with an air conditioning system capable of maintaining this temperature threshold, which must be continuously monitored. Risks associated with the delivery to the Principal Investigator include substitution with an IMP of a different protocol, unsuitable hygienic and environmental conditions, inaccurate documentation, or damage.
During storage, associated risks include damage of the packaging or wrapping, or unsuitable hygienic and environmental conditions. Any non-conformities found must be managed according to the Institution’s SOPs for risk and non-conformities, near misses, adverse events, and sentinel events management.
In conclusion, the IMP journey must follow strict controls, from the verification of patient’s eligibility to drug release to the clinical unit, as different professional figures are involved, and patient-IMP matching must be assured throughout the process. For these reasons, SOPs for the management of IMPs, clinical trials, records, non-conformities and adverse events must be present in all clinical units, outside the enrollment in clinical trials. Indeed, EAPs can be activated in all Centers, as they are programs to release drugs not yet available on the market for a certain indication to a specific patient. Therefore, also in EAPs, it is essential to maintain high quality standards and traceability, to minimize the risks related to inaccurate request, storage, and release of the drug.
References
[1] https://eur-lex.europa.eu/eli/reg/2014/536/oj/eng
[2] https://www.ema.europa.eu/en/ich-e6-good-clinical-practice-scientific-guideline
[3] https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en
[4] https://www.gazzettaufficiale.it/eli/id/2022/02/19/22A01189/SG
[5] https://www.gazzettaufficiale.it/eli/id/2017/11/02/17A07305/sg
[6] https://www.aifa.gov.it/documents/20142/1654269/Det-Pres-425-2024-Linea_Guida_osservazionali.pdf
