A Rapid Qualitative Screening Method for Isoniazid Tablets Using Handheld NIR Spectrometers in Two Countries.

BACKGROUND: Isoniazid is a leading tuberculosis treating medication. Global supply chains provide essential medicines such as isoniazid to resource-limited areas. Ensuring the safety and efficaciousness of these medicines is essential to public health programs. Handheld spectrometers are becoming increasingly approachable in cost and usability. As supply chains expand, quality compliance screening of essential medications is necessary in site-specific locations. Here, a brand-specific qualitative discrimination analysis of isoniazid is approached by collecting data from two handheld spectrometers in two countries with the intent to build a multi-location quality compliance screening method for a brand of isoniazid. METHODS: Two handheld spectrometers (900-1700 nm) were used to collect spectra from five manufacturing sources (N = 482) in Durham, North Carolina, USA, and Centurion, South Africa. A qualitative brand differentiation method was established from both locations by applying a Mahalanobis distance thresholding method as a measure of assessing similarity. RESULTS: Combining data from both locations resulted in a 100% classification accuracy, at both locations, for brand 'A' and resulted in the four other brands classifying as dissimilar. Bias was found between sensors in terms of resulting Mahalanobis distances, but the classification method proved to be robust enough to accommodate. Several spectral peaks found in isoniazid references appear within the 900-1700 nm range, as well as variation in the excipients per manufacturer. CONCLUSIONS: Results show promise for compliance screening isoniazid as well as other tablets in multiple geographic locations using handheld spectrometers.

Stability enhancement of clinical grade multipotent mesenchymal stromal cell-based products.

BACKGROUND: Successful delivery of cell-based therapeutics into patients is compromised by their short shelf-life upon release from production facilities due to the living nature of the active component that rapidly loses viability, and therefore its properties. In this context, the use of appropriate additives may contribute to the stabilisation of the cellular component within specifications for a longer time until administration. RESULTS: In the present study, we evaluated the effect of different formulations on the stability of viability, identity, and potency of clinical grade multipotent mesenchymal stromal cells in suspension, both electrolyte solution and protein content were found to impact on their shelf-life. Particularly cryopreservation of cells in a Plasmalyte 148 supplemented with 2% (w/v) AlbIX (a yeast-derived recombinant albumin) and 10% (v/v) dimethyl sulfoxide, and final formulation post-thawing in Plasmalyte 148 supplemented with 2% (w/v) AlbIX enabling prolonged stability from 24 h up to 72 h in optimal conditions. Further investigation on the mechanisms of action involved revealed a delay of apoptosis progression into late stage when AlbIX was present. CONCLUSIONS: The use of optimal formulations for each cell type of interest is crucial to extend the shelf life of cell-based pharmaceuticals and contribute to solve logistical challenges. We demonstrated that the use of Plasmalyte 148 supplemented with 2% (w/v) AlbIX resulted in superior stability of multipotent mesenchymal stromal cells without affecting their identity and multipotency.

Quality compliance in the shift from cell transplantation to cell therapy in non-pharma environments.

Along with academic and charitable organizations, transfusion centers have ventured into the stem cell field, with the aim of testing of novel cell-based therapeutics in a clinical setting for future marketing approval. The fact that quality management structures, which are required for compliance with good scientific practice regulations, were originally designed for product development in corporate environments represents a major challenge for many developers. In this Commentary, challenges that non-pharmaceutical institutions must overcome to translate cell-based products into clinical therapies will be discussed from a quality standpoint. Furthermore, our development experience for a mesenchymal stromal cell-based therapy will be shared as a case study.

A tool for a comprehensive assessment of treated wastewater quality.

The main goal of a wastewater treatment plant (WWTP) is to comply with the treated wastewater (TWW) quality requirements. However, the assessment of this compliance is a rather complex process for WWTPs in the EU Member States, since it requires the integration of a large volume of data and several criteria according to EU Directives 91/271/EEC and 2000/60/EC. A tool for a comprehensive assessment of TWW quality in this context is herein presented. The tool's novelty relies on an integrated analysis of performance indicators (PIs) and new performance indices (PXs). PIs integrate the several compliance criteria into a single framework, supported by flowcharts for a straightforward assessment of TWW compliance by practitioners. PXs are obtained by applying a performance function to the concentration values analysed in the TWW for discharge or reuse. PXs are dimensionless and the scale adopted (0-300) defines three performance levels: unsatisfactory, acceptable and good performance. The reference values proposed for these levels and for the PIs were based on the EU legislation. The PXs complement the information provided by the PIs. While the latter assess the plant effectiveness in a given year (i.e. the TWW compliance with the requirements), PXs tackle the plant reliability, i.e. they allow to easily compare the performance of different parameters over the time and to identify when the performance did satisfy or fail the pre-established objectives and the distance that remains to achieve these targets. The tool was tested in 17 WWTPs and the most representative results are herein illustrated.

Establishment of instrument operation qualification and routine performance qualification procedures for handheld near-infrared spectrometers used at different locations within a laboratory network.

Quality assurance of finished pharmaceuticals is a necessity in ensuring the safety of consumers. There is a need for low-cost and portable rapid screening methods of pharmaceuticals in resource limited areas. Recent advances in technology have made handheld and low-cost diffuse reflectance spectrometers available to the public. While these handheld spectrometers offer advantages over benchtop spectrometers, the accuracy and repeatability must be assessed before these instruments can be used for quality assurance screening. Here, five handheld spectrometers of the same model were purchased, where an in-house installation qualification and operational qualification (IQOQ) was subsequently established for the instruments. Wavelength and photometric accuracy (and repeatability), spectroscopic noise, stray light, and bandpass were assessed between instruments. Results were found to be consistent between the spectrometers, passing IQOQ procedures, and were determined to be ready for field use. Once the handheld spectrometer's performance was verified, a practical and low-cost daily performance verification was established using common high density polyethylene vial caps on location in South Africa, Thailand, and the United States. A Mahalanobis distance-based classifier found the five spectrometers to be in agreement.

The Quality Management Ecosystem in Cell Therapy in Catalonia (Spain): An Opportunity for Integrating Standards and Streamlining Quality Compliance.

Cell therapies are required to meet with compulsory regulations that co-exist with other optional standards and guidelines that together compose a complex quality management system. Indeed, reliable insights on the mechanisms of action and safety of novel cell-based therapies require adherence to solid quality management structures in all steps of the value chain, from early research and tissue procurement to clinical trials and biovigilance, thus guaranteeing reproducibility and solid foundations for better science and improved clinical practice. Herein we present the concept of the quality ecosystem as a tool to understand and assist all stakeholders involved in developing and structuring the integration of standards as novel developments are taking place. We conclude that the various quality management initiatives can all be thought about under the umbrella of an ecosystem.

Compliance in Non-Clinical Development of Cell-, Gene-, and Tissue-Based Medicines: Good Practice for Better Therapies.

The development of cell-, gene- and tissue engineering (CGT)-based therapies must adhere to strict pharmaceutical quality management standards, as for any other biological or small-molecule drug. However, early developments often failed to fully comply with good laboratory practices (GLP) in non-clinical safety studies. Despite an upward trend of positive opinions in marketing authorization applications, evidence of adherence to the principles of GLP is not openly reported; therefore, their relative impact on the overall quality of the product development program is unknown. Herein we investigated the actual degree of GLP implementation and the underlying factors impeding full compliance in non-clinical developments of CGT-based marketed medicines in the EU and USA, including (i) the co-existence of diverse quality management systems of more strategic value for small organizations, particularly current Good Manufacturing Practices n(GMP); (ii) lack of regulatory pressure to pursue GLP certification; and (iii) the involvement of public institutions lacking a pharmaceutical mindset and resources. As a final reflection, we propose conformity to good research practice criteria not as a doctrinaire impediment to scientific work, but as a facilitator of efficient clinical translation of more effective and safer innovative therapies.

The challenge of developing human 3D organoids into medicines.

The capacity of organoids to generate complex 3D structures resembling organs is revolutionizing the fields of developmental and stem cell biology. We are currently establishing the foundations for translational applications of organoids such as drug screening, personalized medicine and launching the future of cell therapy using organoids. However, clinical translation of organoids into cell replacement therapies is halted due to (A) a few preclinical studies demonstrating their efficacy and (B) the lack of robust, reproducible, and scalable methods of production in compliance with current pharmaceutical standards. In this issue of Stem Cell Research & Therapy [ref], Dossena and collaborators present a validated bioprocess design for large-scale production of human pancreatic organoids from cadaveric tissue in accordance with current good manufacturing practice. The authors also propose a set of specifications of starting materials and critical quality attributes of final products that are of interest to other developments provided that this type of medicines are different than any other medicinal product due to their complex composition and living nature of the active ingredient. Although large-scale production of functional cells secreting insulin is still a challenge, the development of methods such as the one presented by Dossena and collaborators contributes to move toward clinical use of organoids in the treatment of type 1 diabetes and opens avenues for future clinical use of organoids in degenerative pathologies.

HLA-DR expression in clinical-grade bone marrow-derived multipotent mesenchymal stromal cells: a two-site study.

BACKGROUND: Contrary to the minimal criteria proposed by the International Society for Cell and Gene Therapy for defining multipotent mesenchymal stromal cells (MSC), human leukocyte antigen (HLA)-DR expression is largely unpredictable in ex vivo-expanded clinical-grade cultures. Although activation of MSC in culture does not appear to affect their functionality, a large study investigating the impact of HLA-DR expression on cell identity and potency is still missing in the literature. METHODS: A retrospective analysis of HLA-DR expression in 130 clinical batches of bone marrow (BM)-MSC from two independent Good Manufacturing Practice-compliant production facilities was performed in order to identify the consequences on critical quality attributes as well as potential activation cues and dynamics of MSC activation in culture. RESULTS: HLA-DR+ cells in culture were confirmed to maintain fibroblastic morphology, mesenchymal phenotype identity, multipotency in vitro, and immunomodulatory capacity. Interestingly, the use of either human sera or platelet lysate supplements resulted in similar results. CONCLUSIONS: HLA-DR expression should be considered informative rather than as a criterion to define MSC. Further work is still required to understand the impact of HLA-DR expression in the context of product specifications on BM-MSC qualities for clinical use in specific indications.

Conformity evaluation of afinion 2 analyzer maintainability: Compliance practicality for Philippine National Standard PNS ISO 15189:2013 Accreditation

Objectives@#The implementation of Philippine National Standard PNS ISO 15189:2013 to support the medical laboratory to produce competent results is a recognised challenge. It is apparent that the approach of ensuring the equipment availability can be specifically optimised. No known research has focused on exploring on the conduct of conformity evaluation of Afinion 2 Analyzer maintainability for the PNS ISO 15189:2013 accredited medical laboratory. The aim of the current study was to develop a practical tool for the medical laboratory to support the internal audit process by determining the compliance status of Afinion 2 Analyzer maintainability. @*Methods@#The relevant conformance requirements in Clauses 4 (Management requirements) and 5 (Technical requirements) of PNS ISO 15189:2013, manufacturer requirements and specific requirements for accreditation from 70/101 (69%) accreditation bodies in 80/249 (32%) countries were identified as specific audit criteria for Afinion 2 Analyzer conformity evaluation checklists for the maintenance and reference equipment.

Conformity evaluation of afinion 2 analyzer maintainability: Compliance practicality for Philippine National Standard PNS ISO 15189:2013 accreditation

Objectives@#The implementation of Philippine National Standard PNS ISO 15189:2013 to support the medical laboratory to produce competent results is a recognised challenge. It is apparent that the approach of ensuring the equipment availability can be specifically optimised. No known research has focused on exploring on the conduct of conformity evaluation of Afinion 2 Analyzer maintainability for the PNS ISO 15189:2013 accredited medical laboratory. The aim of the current study was to develop a practical tool for the medical laboratory to support the internal audit process by determining the compliance status of Afinion 2 Analyzer maintainability.