Implementation and operational management of marketed chimeric antigen receptor T cell (CAR-T Cell) therapy-a guidance by the GoCART Coalition Pharmacist Working Group.

Chimeric Antigen Receptor T cells (CAR-T cells) are a type of Advanced Therapy Medicinal Product (ATMP) classified as ex-vivo (cell-based) gene therapy. CAR-T cells constitute an immunotherapy that works by enabling T cells to specifically recognise cancer cells and destroy them [1]. CAR-T cells are currently licensed to treat certain blood cancers including relapsed or refractory lymphomas, B-cell acute lymphoblastic leukaemia or multiple myeloma [2]. The indications for their use are expanding and are expected to encompass other therapeutic areas. CAR-T cells are used both in children and adults [2]. CAR-T cells are biologic drugs and are therefore more complex than traditional medicinal products. T cells collected from the patient (or donor) are sent to a Good manufacturing Practice (GMP) manufacturing facility where they are genetically modified to contain a chimeric antigen receptor (CAR). This receptor is designed to recognise and target a specific protein on cancer cells. Once manufactured, they are delivered to the hospital where they are administered to the designated patient. Hospital pharmacies are central in the process of ensuring appropriate organisational governance, operational handling, clinical suitability, and pharmacovigilance [1, 3]. The GoCART Coalition Pharmacist working group's mission was to develop standards of care to advance the field of cellular therapies in Europe. The purpose of this document is to provide practical guidance on the implementation and safe operational use of marketed CAR-T cell products within hospital pharmacies primarily throughout Europe. This document outlines the key areas where pharmaceutical expertise should focus and the key considerations for the hospital pharmacy. Countries may have different requirements and there may be variation in practice between hospitals. This document is intended as a guide and the recommendations should be adapted to meet local requirements. This document does not provide clinical information relating to the use of CAR-T cell products. The Summary of medicinal Product Characteristics (SmPC) [4, 5], and national and international clinical guidelines (where in place) should be followed for the most up-to-date clinical management of CAR-T cell patients. An example is the UK "institutional readiness documents" for pharmacy which includes detailed checklists for each stage of the pathway [6]. Spain developed the Plan of Advanced Therapies in the National Health System: CAR medicines published in November 2018 [7], the CAR-T Medicines Management Procedure of the Spanish Society of Hospital Pharmacy [8] or the Hospital pharmacist's roles and responsibilities with CAR-T medicines article published also by the Spanish Oncology group of the Spanish Society of Pharmacy [9]. This guide has been designed to support the implementation of marketed CAR-T products; however, the principles may also be applicable to clinical trials. For CAR-T cell products being used in clinical trials, additional trial regulation and clinical trial protocols must be followed. This document is divided into two sections. Section 1 outlines considerations for hospital pharmacies during the implementation of a CAR-T cell service. Section 2 outlines the key operational considerations for hospital pharmacies in the patient and product pathway.

In Vitro Release Mechanisms of Doxorubicin From a Clinical Bead Drug-Delivery System.

The release rate of doxorubicin (DOX) from the drug-delivery system (DDS), DC Bead, was studied by 2 miniaturized in vitro methods: free-flowing and sample reservoir. The dependencies of the release mechanisms on in vitro system conditions were investigated experimentally and by theoretical modeling. An inverse relationship was found between release rates and bead size, most likely due to the greater total surface area. The release rates correlated positively with temperature, release medium volume, and buffer strength, although the release medium volume had larger effect than the buffer strength. The sample reservoir method generated slower release rates, which described the in vivo release profile more accurately than the free-flowing method. There was no difference between a pH of 6.3 or 7.4 on the release rate, implying that the slightly acidic tumor microenvironment is less importance for drug release. A positive correlation between stirring rate and release rate for all DDS sizes was observed, which suggests film controlled release. Theoretical modeling highlighted the influence of local equilibrium of protonation, self-aggregation, and bead material interactions of DOX. The theoretical release model might describe the observed larger sensitivity of the release rate to the volume of the release medium compared to buffer strength. A combination of miniaturized in vitro methods and theoretical modeling are useful to identify the important parameters and processes for DOX release from a micro gel-based DDS.

Treatment of intermediate stage hepatocellular carcinoma: a review of intrahepatic doxorubicin drug-delivery systems.

The biopharmaceutical properties of doxorubicin delivered via two drug-delivery systems (DDSs) for the palliative treatment of unresectable hepatocellular carcinoma were reviewed with relation to the associated liver and tumor (patho)physiology. These two DDSs, doxorubicin emulsified with Lipiodol(®) and doxorubicin loaded into DC Bead(®) are different regarding tumor delivery, release rate, local bioavailability, if and how they can be given repeatedly, biodegradability, length of embolization and safety profile. There have been few direct head-to-head comparisons of these DDSs, and in-depth investigations into their in vitro and in vivo performance is warranted.