Quality Control of 3D Printed Pharmaceuticals using Process Analytical Technologies

Three-dimensional (3D) printing is forecast to cause a paradigm shift in pharmaceuticals, transitioning away from a ‘one-size-fits-all’ treatment approach towards personalised medicine. However, a major barrier to clinical integration lies in the inability to ensure the quality of the 3D printed tablets. Current quality control (QC) methods are inherently destructive, which would be unsuitable for the real-time release of printed medicines at the point-of-care. As such, this PhD thesis aims to evaluate the ability of process analytical technologies (PAT), including near infrared (NIR), Raman and terahertz spectroscopy, to act as alternative non-destructive QC methods for 3D printed medicines produced using selective laser sintering (SLS). The major findings were as follows: 1) NIR spectroscopy enabled the dose quantification of a single drug (paracetamol) and two distinct drugs (amlodipine and lisinopril) in a rapid, point-and-shoot process. Raman microscopy was found suitable to evaluate the drug distribution and solid-state characteristics across the dosage form surface and cross-section; 2) Amorphous solid dispersions of a BCS II drug (itraconazole) were produced using SLS 3D printing. Amorphous quantification was successful using NIR spectroscopy and Raman spectroscopy, which were comparable to reference x-ray powder diffraction (XRPD) analysis; 3) Laser scanning speed has a significant impact of 3D printed drug product density and drug release. Due to the different surface presentations of the dosage forms, preliminary data showed that FT-NIR spectroscopy may be a promising tool for the prediction of density and drug release. Overall, for the first time, this research demonstrates the potential for PAT technologies to undertake QC of 3D printed pharmaceuticals, overcoming a major barrier and hence supporting the integration of this technology into the clinic

3D Printed Tablets (Printlets) with Braille and Moon Patterns for Visually Impaired Patients

Visual impairment and blindness affects 285 million people worldwide, resulting in a high public health burden. This study reports, for the first time, the use of three-dimensional (3D) printing to create orally disintegrating printlets (ODPs) suited for patients with visual impairment. Printlets were designed with Braille and Moon patterns on their surface, enabling patients to identify medications when taken out of their original packaging. Printlets with different shapes were fabricated to offer additional information, such as the medication indication or its dosing regimen. Despite the presence of the patterns, the printlets retained their original mechanical properties and dissolution characteristics, wherein all the printlets disintegrated within ~5 s, avoiding the need for water and facilitating self-administration of medications. Moreover, the readability of the printlets was verified by a blind person. Overall, this novel and practical approach should reduce medication errors and improve medication adherence in patients with visual impairmentThe authors thank the Engineering and Physical Sciences Research Council (EPSRC), UK, for their financial support (EP/L01646X)S

Prediction of Solid-State Form of SLS 3D Printed Medicines Using NIR and Raman Spectroscopy

Selective laser sintering (SLS) 3D printing is capable of revolutionising pharmaceutical manufacturing, by producing amorphous solid dispersions in a one-step manufacturing process. Here, 3D-printed formulations loaded with a model BCS class II drug (20% w/w itraconazole) and three grades of hydroxypropyl cellulose (HPC) polymer (-SSL, -SL and -L) were produced using SLS 3D printing. Interestingly, the polymers with higher molecular weights (HPC-L and -SL) were found to undergo a uniform sintering process, attributed to the better powder flow characteristics, compared with the lower molecular weight grade (HPC-SSL). XRPD analyses found that the SLS 3D printing process resulted in amorphous conversion of itraconazole for all three polymers, with HPC-SSL retaining a small amount of crystallinity on the drug product surface. The use of process analytical technologies (PAT), including near infrared (NIR) and Raman spectroscopy, was evaluated, to predict the amorphous content, qualitatively and quantitatively, within itraconazole-loaded formulations. Calibration models were developed using partial least squares (PLS) regression, which successfully predicted amorphous content across the range of 0–20% w/w. The models demonstrated excellent linearity (R^{2} = 0.998 and 0.998) and accuracy (RMSEP = 1.04% and 0.63%) for NIR and Raman spectroscopy models, respectively. Overall, this article demonstrates the feasibility of SLS 3D printing to produce solid dispersions containing a BCS II drug, and the potential for NIR and Raman spectroscopy to quantify amorphous content as a non-destructive quality control measure at the point-of-care

3D printed pellets (miniprintlets): A novel, multi-drug, controlled release platform technology

[ENG]Selective laser sintering (SLS) is a single-step three-dimensional printing (3DP) process that can be leveraged to engineer a wide array of drug delivery systems. The aim of this work was to utilise SLS 3DP, for the first time, to produce small oral dosage forms with modified release properties. As such, paracetamol-loaded 3D printed multiparticulates, termed miniprintlets, were fabricated in 1 mm and 2 mm diameters. Despite their large surface area compared with a conventional monolithic tablet, the ethyl cellulose-based miniprintlets exhibited prolonged drug release patterns. The possibility of producing miniprintlets combining two drugs, namely paracetamol and ibuprofen, was also investigated. By varying the polymer, the dual miniprintlets were programmed to achieve customised drug release patterns, whereby one drug was released immediately from a Kollicoat Instant Release matrix, whilst the effect of the second drug was sustained over an extended time span using ethyl cellulose. Herein, this work has highlighted the versatility of SLS 3DP to fabricate small and intricate formulations containing multiple active pharmaceutical ingredients with distinct release propertiesS

Prediction of Solid-State Form of SLS 3D Printed Medicines Using NIR and Raman Spectroscopy

Selective laser sintering (SLS) 3D printing is capable of revolutionising pharmaceutical manufacturing, by producing amorphous solid dispersions in a one-step manufacturing process. Here, 3D-printed formulations loaded with a model BCS class II drug (20% w/w itraconazole) and three grades of hydroxypropyl cellulose (HPC) polymer (-SSL, -SL and -L) were produced using SLS 3D printing. Interestingly, the polymers with higher molecular weights (HPC-L and -SL) were found to undergo a uniform sintering process, attributed to the better powder flow characteristics, compared with the lower molecular weight grade (HPC-SSL). XRPD analyses found that the SLS 3D printing process resulted in amorphous conversion of itraconazole for all three polymers, with HPC-SSL retaining a small amount of crystallinity on the drug product surface. The use of process analytical technologies (PAT), including near infrared (NIR) and Raman spectroscopy, was evaluated, to predict the amorphous content, qualitatively and quantitatively, within itraconazole-loaded formulations. Calibration models were developed using partial least squares (PLS) regression, which successfully predicted amorphous content across the range of 0–20% w/w. The models demonstrated excellent linearity (R2 = 0.998 and 0.998) and accuracy (RMSEP = 1.04% and 0.63%) for NIR and Raman spectroscopy models, respectively. Overall, this article demonstrates the feasibility of SLS 3D printing to produce solid dispersions containing a BCS II drug, and the potential for NIR and Raman spectroscopy to quantify amorphous content as a non-destructive quality control measure at the point-of-care

Track-and-trace: novel anti-counterfeit measures for 3D printed personalized drug products using smart material inks

Printing technologies have been forecast to initiate a new era of personalised medicine in pharmaceuticals. To facilitate integration, a non-destructive and robust method of product authenticity is required. This study reports, for the first time, the interface between 3D printing and 2D inkjet printing technologies in order to fabricate a drug-loaded 3D printed tablet (printlet) with a unique track-and-trace measure in a single step process. In particular, quick response (QR) codes and data matrices were printed onto the surface of polymeric-based printlets for scanning using a smartphone device, and were designed to encode tailored information pertaining to the drug product, patient and prescriber. Moreover, a novel anti-counterfeit strategy was designed, which involved the deposition of a unique combination of material inks for detection using Raman spectroscopy. The inks were characterised for printability by measuring surface tension, viscosity and density, and each was successfully detected on the 3D printed tablet post-printing. Overall, this novel approach will enable an enhanced transparency and tracking of 3D printed medicines across the supply chain, leading to a safer treatment pathway for patients

COVID-19 and pneumothorax: a multicentre retrospective case series.

INTRODUCTION: Pneumothorax and pneumomediastinum have both been noted to complicate cases of coronavirus disease 2019 (COVID-19) requiring hospital admission. We report the largest case series yet described of patients with both these pathologies (including nonventilated patients). METHODS: Cases were collected retrospectively from UK hospitals with inclusion criteria limited to a diagnosis of COVID-19 and the presence of either pneumothorax or pneumomediastinum. Patients included in the study presented between March and June 2020. Details obtained from the medical record included demographics, radiology, laboratory investigations, clinical management and survival. RESULTS: 71 patients from 16 centres were included in the study, of whom 60 had pneumothoraces (six with pneumomediastinum in addition) and 11 had pneumomediastinum alone. Two of these patients had two distinct episodes of pneumothorax, occurring bilaterally in sequential fashion, bringing the total number of pneumothoraces included to 62. Clinical scenarios included patients who had presented to hospital with pneumothorax, patients who had developed pneumothorax or pneumomediastinum during their inpatient admission with COVID-19 and patients who developed their complication while intubated and ventilated, either with or without concurrent extracorporeal membrane oxygenation. Survival at 28 days was not significantly different following pneumothorax (63.1±6.5%) or isolated pneumomediastinum (53.0±18.7%; p=0.854). The incidence of pneumothorax was higher in males. 28-day survival was not different between the sexes (males 62.5±7.7% versus females 68.4±10.7%; p=0.619). Patients aged ≥70 years had a significantly lower 28-day survival than younger individuals (≥70 years 41.7±13.5% survival versus <70 years 70.9±6.8% survival; p=0.018 log-rank). CONCLUSION: These cases suggest that pneumothorax is a complication of COVID-19. Pneumothorax does not seem to be an independent marker of poor prognosis and we encourage continuation of active treatment where clinically possible