Background: In non-small cell lung cancer (NSCLC), chemoradiotherapy (CRT) yields pathological complete response (pCR) rates of approximately 30%. We investigated using ipilimumab plus nivolumab (IPI-NIVO) with neoadjuvant CRT in resectable, and borderline resectable NSCLC. Methods: This single-arm, phase-II trial enrolled operable T3-4N0–2 patients with NSCLC without oncogenic drivers. Primary study endpoints were safety, major pathological response (MPR) and pCR. Treatment encompassed platinum-doublet concurrent CRT, IPI 1 mg/kg intravenous and NIVO 360 mg intravenous on day-1, followed by chemotherapy plus NIVO 360 mg 3 weeks later. Thoracic radiotherapy was 50 or 60 Gy, in once-daily doses of 2 Gy. Resections were 6 weeks post-radiotherapy. Results: In a total of 30 patients in the intention-to-treat (ITT) population, grades 3–4 treatment-related adverse events (TRAEs) occurred in 70%, one TRAE grade 5 late-onset pneumonitis on day 96 post-surgery (1/30, 3.3%) occurred, and one non-TRAE COVID-19 death (1/30, 3.3%). pCR and MPR were achieved in 50% (15/30) and 63% (19/30) of the ITT; and in 58% (15/26) and 73% (19/26) of the 26 patients who underwent surgery, respectively. Postoperative melanoma was seen in one non-pCR patient. The R0 rate was 100% (26/26), and no patient failed surgery due to TRAEs. In peripheral blood, proliferative CD8⁺ T cells were increased, while proliferative regulatory T cells (Tregs) were not. On-treatment, pCR-positives had higher CD8⁺CD39⁺ T cells and lower HLA-DR⁺ Tregs. Conclusions: Neoadjuvant IPI-NIVO-CRT in T3-4N0–2 NSCLC showed acceptable safety with pCR and MPR in 58% and 73% of operated patients, respectively. No patient failed surgery due to TRAEs. Trial registration number: NCT04245514.

Introduction: In 2017 the drug chenodeoxycholic acid (CDCA) became unavailable to Dutch patients with the rare inborn error of metabolism cerebrotendinous xanthomatosis (CTX). This was a direct result of a steep price increase after CDCA was authorized in the EU as an orphan drug. As a result, Dutch health insurance companies were unable to reimburse this drug and the availability of CDCA to patients with CTX was directly at risk creating an unmet medical need. CTX is characterized by juvenile cataract, tendon xanthomas, infantile-onset diarrhea, psychomotor retardation and progressive cerebellar ataxia. Treatment with CDCA, when initiated before neurological symptoms are present, can prevent the onset of neurological complications.Methods: To assure continuation of patient treatment with a high quality product, the hospital pharmacy of the Amsterdam UMC developed CDCA capsules as a pharmacy preparation. A simple and robust formulation was developed for capsules in a broad dose range of 35–250 mg, ensuring that both pediatric and adult patients can receive an exact dose tailored to their specific needs. Capsules are prepared manually on a small scale for the individual patient. To assure the quality of the product, product validation and stability studies were performed.Results: The results show that the product complies with all specifications based on the requirements of the European Pharmacopoeia. The capsules contain the declared amount of CDCA, no degradation product or other (microbiological) impurities are formed during the production process and the capsules show a quick dissolution profile. Stability studies indicate that it is a stable product and no impurities increase or arise over time. These results show that these pharmacy preparations are of high quality and comply to Good Manufacturing Practice (GMP) requirements.Discussion: Through our research, we have demonstrated that pharmacy compounding can be a viable alternative in situations where immediate access to essential medication is crucial or when certain drugs are temporarily inaccessible. The purpose of this paper is to offer comprehensive guidance to other pharmacies to improve the availability of currently inaccessible drugs through the practice of pharmacy compounding, thereby facilitating improved patient care.

In 2018 the Amsterdam University Medical Centre decided to prepare chenodeoxycholic acid (CDCA) capsules (also known as pharmacy compounding) for patients with the genetic metabolic disease cerebrotendinous xanthomatosis (CTX) when the product with a marketing authorization was commercially unavailable for patients. However, after reanalysis, unknown impurities were identified in the CDCA active pharmaceutical ingredient (API) using thin-layer chromatography from the European Pharmacopoeia (Ph.Eur.) monograph. Therefore, the API did not comply with the Ph.Eur. specifications for related substances and as a result, pharmacy compounding was halted and an investigation was initiated to identify and quantify the unknown impurities. Meanwhile, a second CDCA API was sourced from another manufacturer. However, this API also appeared to contain an unknown impurity. This impurity could be identified as a dimer of CDCA using reversed phase liquid chromatography mass spectrometry. Since the Ph.Eur. at the time did not describe a suitable analytical method for the quantification of this new impurity, a high pressure liquid chromatography with differential refractometer (HPLC-RI) method was developed to quantify the dimer. Subsequently, in 2019, a new draft version of the CDCA Ph.Eur. monograph was published, including the dimer as a new impurity together with a HPLC-RI method for its identification and quantification. The CDCA-dimer is classified as non-toxic and permitted in the CDCA API up to a maximum of 0.5 %. Because the API complied with the updated Ph.Eur. specifications, pharmacy compounding of CDCA capsules could be resumed.

Bile acid synthesis defects (BASDs) comprise a group of rare diseases that can be severely disabling. Bile acid supplementation with 5 to 15 mg/kg cholic acid (CA) has been hypothesized to decrease endogenous bile acid production, stimulate bile secretion, and improve bile flow and micellar solubilization, thereby improving the biochemical profile and potentially slowing down disease progression. Currently, CA treatment is unavailable in the Netherlands, and CA capsules were compounded by the Amsterdam UMC Pharmacy from CA raw material. This study aims to determine the pharmaceutical quality and stability of the pharmacy compounded CA capsules. Pharmaceutical quality tests were performed on 25 mg and 250 mg CA capsules according to general monographs of the European Pharmacopoeia 10th ed. For the stability study, the capsules were stored under long-term conditions (25 °C ± 2 °C/60% ± 5% RH) and accelerated conditions (40 °C ± 2 °C/75% ± 5% RH). Samples were analyzed at 0, 3, 6, 9 and 12 months. The findings demonstrate that the pharmacy compounded CA capsules within a range of 25–250 mg that complied with the European regulations in regard to product quality and safety. The pharmacy compounded CA capsules are suitable for use in patients with BASD, as clinically indicated. With its simple formulation, pharmacies are provided a guidance on product validation and stability testing when commercial CA capsules are unavailable.

Objectives Several studies have investigated the effectiveness of high-dose ambroxol in treating patients with Gaucher disease type 3. Since there are no registered high-dose ambroxol preparations available, information on the development of this preparation can be important to improve access. The pharmacy and clinical pharmacology department of Amsterdam University Medical Center has developed a simple 75 mg ambroxol hydrochloride (HCl) capsule formulation for this purpose. The aim of this study was to investigate the stability of 75 mg ambroxol capsules. Methods Three batches (n=1000) of 75 mg ambroxol HCl capsules were produced and stored in climate chambers for 6 months under accelerated (40±2°C and 75% relative humidity (RH)±5% RH) and long-term (25±2°C and 60% RH±5% RH) conditions. At 0, 3 and 6 months, appearance, identity, related substances, assay, uniformity of dosage units (content uniformity (CU)), dissolution and microbiology were evaluated. The specifications and acceptance criteria were derived from the European Pharmacopoeia and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. Results All parameters met the predefined specifications from t=0 to t=6 months for both the accelerated and long-term stability studies. There were no visible changes in appearance of the capsule content, no degradation products above 0.05%, and no decrease in ambroxol content. Furthermore, the capsules met the criteria for CU with an acceptance value ≤15.0. The dissolution was rapid, with ≥80% of ambroxol released from the capsules within 30 min, and no microbiological growth was observed. Conclusions The 75 mg ambroxol HCl capsules are stable for at least 6 months at room temperature. This paper provides guidance to pharmacies for compounding of high-dose ambroxol HCl capsules to ensure the availability of ambroxol for patients in need.

Background/Objectives: Ambroxol hydrochloride (AMB) is a promising chaperone for treating neurological manifestations in Gaucher disease type 3 (GD3). The Amsterdam University Medical Center planned to conduct an n-of-1 clinical trial using high-dose AMB (25 mg/kg/day). As an adequate commercial AMB formulation is unavailable for this high target dosage, we aimed to develop high-dose AMB capsules and assess the formulated capsule’s quality. Methods: AMB API was sourced and tested according to the requirements of the European Pharmacopoeia. Capsule formulations of 75 mg and 200 mg AMB were developed. Drug product specifications were set following international guidelines (ICH Q6A) and the European Pharmacopoeia. Analytical methods were developed and validated, and three validation batches of each capsule strength were produced and analyzed. Results: The contents and the Acceptance Values (AVs) of the initial AMB batches (both strengths) varied between 89.1% to 92.7% (specification: 90% to 110%) and 12.4 to 17.6 (specification ≤ 15.0), respectively, indicating non-uniform AMB distribution. Consequently, the production of 200 mg capsules was discontinued, and modifications were made to the 75 mg capsule formulation, followed by the production of three optimized 75 mg validation batches. These batches met the specified criteria, with an AMB content and AV values ranging from 93.9% to 96.5% and 12.4 to 14.9, respectively. Furthermore, rapid dissolution profiles were observed (>80% dissolution within 15 min). No degradation products or microbiological impurities were detected after production. Conclusions: The optimized formulation of 75 mg AMB capsules formulated within the hospital pharmacy setting resulted in qualitative and uniform capsules which can be used in clinical trials.