Container Closure Integrity (CCI) for single-use systems (SUS): Regulatory trends, challenges and technology transfer of test methods

Single-use fluid management solutions are being applied in critical downstream and final filling applications including applications requiring container closure integrity testing. Single-use bags are increasingly used for the storage, mixing, shipping, freezing of drug substances and drug products. Since single use bags are migrating towards more critical process steps and applications, there is a growing regulatory scrutiny and industry requirement for testing the containers in order to guarantee their integrity and their sterility before their use in commercial production processes. This presentation will consider the regulatory trends for Container Closure Integrity of single-use systems with a focus on the proposed revision to USP\u3c1207\u3e Sterile Product Packaging – Integrity Evaluation and the challenges for vendors and users in the implementation of single-use systems in critical applications subject to container closure integrity testing. The presentation will show a case study of the development of two different non-destructive test methods, one being a Helium test method at supplier, the second one being a point-of-use pressure decay leak test method. The sensitivity, reproducibility and accuracy of each method are explored as well as the relevance to the required level of closure integrity. All through the presentation, the emphasis will be given on container closure integrity as a concern throughout the product life cycle from its development, validation and manufacturing phase at supplier to its intended final use. An analysis of the defect type expected at each step of the life cycle of a flexible bulk container is presented as well as a proposed implementation strategy for these test methods to manage the risks of defects

Understanding the science behind the liquid leak and microbial ingress mechanisms as the foundation for single-use container closure integrity (SU-CCI)

This presentation describes a scientific approach to establishing a relation between liquid leakage and microbial ingress mechanisms in single use plastic containers and developing the appropriate physical integrity testing methods and specifications. With the expansion of Single Use Systems (SUS) in all process steps of commercial manufacturing, integrity failure can significantly impact drug safety, availability and costs. The use of closed systems in cell & gene therapy can support the reduction of production costs when moving the manufacturing process from class B to class C or even D environment. More significantly, in very critical autologous applications, like e.g. CAR–T cell therapy on terminally ill patients, a single bag integrity failure can result in the loss of the only possible batch, followed by the death of the patient. As current approved sterility test methods take longer than the shelf-life of the cell preparation, additional integrity testing for risk mitigation can help to support the final cell product release before injection to the recipient. A combination of an integrity test of the bioprocess containers with a quantitative, real-time PCR of a product sample (e.g. on mycoplasma) can provide a strong indication that the cell preparation has not been contaminated. During lentivirus production, operator safety is of great concern as the components are derived from viruses that target human cells, and feature an inherent risk for insertional oncogenesis. Assuring that the virus is contained by technical means is favorable to relying on organizational or personal means, such as use of safety equipment and personal hygiene, as it should present lower risk. Consequently, there is an increasing industry scrutiny on SU CCI, raising the need to develop good science behind liquid leakage and microbial ingress and appropriate physical integrity testing technologies. The authors will first review the emerging industry association initiatives and introduce an integrated quality by design (QbD), material science and process control approach as the prerequisite to SU-CCI. The presentation will then describe how applying good science can help determine the maximum allowable leakage limit (MALL) under which no product leakage and no bacteria ingress occur with SUS under various fluids and process conditions. The understanding of liquid leakage and bacteria ingress mechanisms also enables the validation of robust liquid leak tests and microbial aerosol challenge which are both correlated to the detection limits of physical integrity testing methods. The authors will conclude with the development of highly sensitive deterministic integrity testing technologies, such as gas tracer detection and pressure decay, which are able to detect the MALL determined during the scientific study. The Helium based Supplier Integrity Test (SIT) for instance is able to control the finished products with a detection limit of 2µm and is correlated to both, liquid leakage and microbial ingress, under all tested process conditions. Audience take home messages: • QbD, QRM, Process Control and Quality Control ensure CCI along the entire production cycle • Understand the science behind SUS films’ behavior and the determination of the Maximum Allowable Leakage Limit (MALL) • Integrity testing technologies can detect the MALL in all parts of complete SUS assemblies at both the supplier and point of use and can be correlated to a bacterial challenge • Use of closed systems in combination with an appropriate integrity assurance strategy can support cost reduction and risk mitigation for product release in cell & gene therapy applications

Intraband and intersubband many-body effects in the nonlinear optical response of single-wall carbon nanotubes

International audienceWe report on the nonlinear optical response of a mono-chiral sample of (6,5) single-wall carbon nanotubes by means of broad-band two-color pump-probe spectroscopy with selective excitation of the S11 excitons. By using a moment analysis of the transient spectra, we show that all the nonlinear features can be accurately accounted for by elementary deformations of the linear absorption spectrum. The photo-generation of S11 excitons induces a broadening and a blue shift of both the S11 and S22 excitonic transitions. In contrast, only the S11 transition shows a reduction of oscillator strength, ruling out population up-conversion. These nonlinear signatures result from many-body effects, including phase-space filling, wave-function renormalization and exciton collisions. This framework is sufficient to interpret the magnitude of the observed nonlinearities and stress the importance of intersubband exciton interactions. Remarkably, we show that these intersubband interactions have the same magnitude as the intraband ones and bring the major contribution to the photo-bleaching of the S22 excitonic transition upon S11 excitation through energy shift and broadening

Measuring the effectiveness of integrated vector management with targeted outdoor residual spraying and autodissemination devices on the incidence of dengue in urban Malaysia in the iDEM trial (intervention for Dengue Epidemiology in Malaysia): study protocol for a cluster randomized controlled trial

In common with many South East Asian countries, Malaysia is endemic for dengue. Dengue control in Malaysia is currently based on reactive vector management within 24 h of a dengue case being reported. Preventive rather than reactive vector control approaches, with combined interventions, are expected to improve the cost-effectiveness of dengue control programs. The principal objective of this cluster randomized controlled trial is to quantify the effectiveness of a preventive integrated vector management (IVM) strategy on the incidence of dengue as compared to routine vector control efforts

Targeted outdoor residual spraying, autodissemination devices and their combination against Aedes mosquitoes: field implementation in a Malaysian urban setting

Currently, dengue control relies largely on reactive vector control programmes. Proactive vector-control using a rational, well-balanced integrated vector management approach may prove more successful for dengue control. As part of the development of a cluster randomized controlled epidemiological trial, a study was conducted in Johor Bahru, Malaysia. The study included one control site (three buildings) and three intervention sites which were treated as follows: targeted outdoor residual spraying only (TORS site, two buildings); deployment of autodissemination devices only (ADD site, four buildings); and the previous two treatments combined (TORS + ADD site, three buildings). The primary entomological measurement was per cent of positive ovitraps—ovitrap index (OI). The effect of each intervention on OI was analyzed by a modified ordinary least squares regression model. Relative to the control site, the TORS and ADD sites showed a reduction in the Aedes OI (−6.5%, P = 0.04 and −8.3%, P = 0.10, respectively). Analysis by species showed that, relative to control, the Ae. aegypti OI was lower in ADD (−8.9%, P = 0.03) and in TORS (−10.4%, P = 0.02). No such effect was evident in the TORS + ADD site. The present study provides insights into the methods to be used for the main trial. The combination of multiple insecticides with different modes of action in one package is innovative, although we could not demonstrate the additive effect of TORS + ADD. Further work is required to strengthen our understanding of how these interventions impact dengue vector populations and dengue transmission

Non-Standard Errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: Non-standard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for better reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants

Renal involvement in children with HNF1β mutation: Early sonographic appearances and long-term follow-up

Objectives: The aim was to report ultrasound (US) patterns of hepatocyte nuclear factor (HNF1β) mutation throughout childhood and determine whether ultrasound could be predictive of renal failure. Methods: The sonographic examinations in 34 children with HNF1β mutation were reviewed. Their sonographic characteristics were compared with renal function. Results: At first postnatal examination renal length was normal in 44 % of the patients, decreased in 24 %, increased in 12 % and asymmetrical in 20 %. Renal cortex was hyperechoic in 97 %. Corticomedullary differentiation was abnormal in 59 %. Cysts were present in 77 % of patients. Cysts were mostly subcapsular (64 %). Twenty-eight patients had follow-up examinations. A modification of the sonographic appearance was observed in 91 % of patients. Eight patients (23 %) had renal failure; no specific US pattern could be demonstrated. Conclusions: At birth, HNF1β mutation was typically associated on US with the combination of hyperechoic, normal-sized kidneys with abnormal corticomedullary differentiation (CMD) and multiple cortical cysts. In older children, the appearances can be variable: kidneys may have decreased (32 %) or normal size (33 %); they are usually hyperechoic (50 %) with abnormal CMD (78 %) and (sub)cortical cysts (71 %). No pattern appears to be associated with renal failure. Key Points: • HNF1β mutations determine significant anomalies of sonographic appearances of kidneys in children. • Kidneys appear mainly hyperechoic, with or without CMD and with subcapsular cysts. • The US pattern may evolve throughout childhood in the same patient. • No correlation was found between any sonographic pattern and renal failure.SCOPUS: ar.jinfo:eu-repo/semantics/publishe