Holistic Extractables and Leachables Program: Evaluations of Prefilled Syringe Systems for Biotechnology Products.

Prefilled syringes (PFS) are a container and delivery device of choice for storing and administering therapeutic protein products to patients. Addressing concerns and regulatory expectations related to the risk to biologic drug product quality and patient safety from PFS requires implementation of an extractable and leachable program based on understanding of materials, risk assessment, review of existing literature, and testing supported by a sound scientific foundation. Extractables and leachables data generated as part of a thorough and holistic program are presented for five PFS systems, including glass and plastic syringes filled with 12 biologic drug products encompassing the implementation of traditional and single-use biotechnology manufacturing processes. The comprehensive extractables and leachables data presented demonstrate and substantiate a holistic extractable and leachable program designed to ensure product quality and patient safety.

Double-chamber syringe versus classic syringes for peripheral intravenous drug administration and catheter flushing: a study protocol for a randomised controlled trial.

BACKGROUND: The prevention of catheter-related complications is nowadays an important topic of research. Flushing catheters is considered an important clinical procedure in preventing malfunction and several complications such as phlebitis or infection. Considering the latest guidelines of the Infusion Nurses Society, the flushing should be carried out both pre- and post-drug administration, requiring different syringes (with associated overall increased times of preparation/administration of intravenous medication by nurses, and also increasing the need for manipulation of the venous catheter). METHODS/DESIGN: A multi-centre, two-arm randomised controlled trial with partially blinded outcome assessment of 146 adult patients. After eligibility analysis and informed consent, participants will receive usual intravenous administration drugs with flushing procedures, with a double-chamber syringe (arm A) or with classic syringes (arm B). The outcomes assessment will be performed on a daily basis by an unblinded ward team, with the same procedures in both groups. Some main outcomes, such as phlebitis and infiltration, will also be evaluated by nurses from a blinded research team and registered once a day. DISCUSSION: The study outlined in this protocol will provide valuable insight regarding the effectiveness and safety of this new medical device. The development of this medical device (dual-chamber syringe, for drug and flush solution) seems to be an important step to facilitate nurses' adoption of good clinical practices in intravenous procedures, reducing catheter manipulations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04046770. Registered 13 August 2019.

Safety-Engineered Syringes: An Intervention to Decrease Hepatitis C Burden in Developing Countries-A Cost-Effectiveness Analysis From Egypt.

INTRODUCTION: To assess the cost-effectiveness of introducing the safety-engineered syringe (SES) to decrease hepatitis C burden resultant from unsafe injection practices in healthcare settings. METHODS: A Markov process model for a hypothetical study cohort was developed over a 30-year time horizon to compare the adoption of SES use with the current strategy, conventional syringes (CS), in the Egyptian healthcare settings. The national treatment program was applied in both groups. Health benefits and total direct medical costs were estimated in both strategies. RESULTS: The SES use demonstrated a reduction in the burden of injection-associated HCV infection because of unsafe practices in the Egyptian healthcare settings. The probability of HCV infection was 1.4% in the SES group and 40% in the CS group. Adoption of the SES use averted 177 hepatitis C cases and 157 hepatitis C-related deaths per 10 000 individuals. Introducing SES as a preventive strategy resulted in better quality-adjusted life-years (QALYs) (difference; 0.95 QALYs) and lower costs (difference; $-1712). CONCLUSIONS: Adoption of SES in the Egyptian healthcare settings is a more effective and cost-saving strategy. Our results are consistent with the WHO Injection Safety Program and Safe Injection Global Network initiatives, which call for adoption of smart syringes. The introduction of SES as one of the most urgently needed interventions is mostly encouraged to decrease hepatitis C burden in similar resource-limited settings. The use of SES as a prevention strategy may bring substantial population-level health gains and governmental cost savings in developing countries.

Usage of low dead space syringes and association with hepatitis C prevalence amongst people who inject drugs in the UK.

INTRODUCTION: Syringes with attached needles (low dead space syringes [LDSS]) retain far less blood following injection than syringes with detachable needles (high dead space syringes [HDSS]). People who inject drugs (PWID) who share needles/syringes may be less likely to acquire Hepatitis C virus (HCV) infection using LDSS, compared with HDSS, but data are limited. METHODS: Utilizing drug behavior and HCV antibody testing data from the UK 2014/2015 Unlinked Anonymous Monitoring Survey of PWID, we calculated the percentage of syringes used in the past month that were LDSS. We investigated which injecting characteristics and demographic factors were associated with 100% LDSS (against 0-99%) usage, and whether 100% LDSS use was associated with antibody HCV-status, after adjusting for confounders. RESULT: Of 2174 participants, 55% always used LDSS, 27% always used HDSS, and 17% used both LDSS and HDSS. PWID that had injected into their groin during the past month were unlikely to use LDSS, adjusted odds ratio (aOR) 0.14 (95% confidence interval 0.11-0.17), compared to those not using the groin. Those injecting crack were less likely to use LDSS than those not, aOR 0.79 (0.63-0.98). Polydrug use was negatively associated with LDSS use, aOR 0.88 (0.79-0.98) per additional drug. LDSS use was associated with lower prevalent HCV among all PWID (aOR 0.77, [0.64-0.93]), which was stronger among recent initiates (aOR 0.53 [0.30-0.94]) than among experienced PWID (aOR 0.81 [0.66-0.99]). DISCUSSION: People who inject into their groin were less likely to use LDSS. Exclusive LDSS use was associated with lower prevalence of HCV amongst PWID that started injecting recently, suggesting LDSS use is protective against HCV.

The impact of harm reduction programs and police interventions on the number of syringes collected from public spaces. A time series analysis in Barcelona, 2004-2014.

BACKGROUND: To estimate the effect of opening two services for people who use drugs and three police interventions on the number of discarded syringes collected from public spaces in Barcelona between 2004 and 2014. METHODS: We conducted an interrupted time-series analysis of the monthly number of syringes collected from public spaces during this period. The dependent variable was the number of syringes collected per month. The main independent variables were month and five dummy variables (the opening of two facilities with safe consumption rooms, and three police interventions). To examine which interventions affected the number of syringes collected, we performed an interrupted time-series analysis using a quasi-Poisson regression model, obtaining relative risks (RR) and 95% confidence intervals (CIs). RESULTS: The number of syringes collected per month in Barcelona decreased from 13,800 in 2004 to 1655 in 2014 after several interventions. For example, following the closure of an open drug scene in District A of the city, we observed a decreasing trend in the number of syringes collected [RR=0.88 (95% CI: 0.82-0.95)], but an increasing trend in the remaining districts [RR=1.11 (95% CI: 1.05-1.17) and 1.08 (95% CI: 0.99-1.18) for districts B and C, respectively]. Following the opening of a harm reduction facility in District C, we observed an initial increase in the number collected in this district [RR=2.72 (95% CI: 1.57-4.71)] and stabilization of the trend thereafter [RR=0.97 (95% CI: 0.91-1.03)]. CONCLUSION: The overall number of discarded syringes collected from public spaces has decreased consistently in parallel with a combination of police interventions and the opening of harm reduction facilities.

Trends in use of health care and HIV prevention services for persons who inject drugs in San Francisco: results from National HIV Behavioral Surveillance 2005-2012.

BACKGROUND: Multiple developments addressing health of people who inject drugs (PWIDs) in San Francisco were initiated from 2003 to 2012, including expanded health care coverage, syringe access, HIV testing and universal HIV treatment. METHODS: We evaluated 3 PWID cycles of the National HIV Behavioral Surveillance for several healthcare measures related to the expanded services. Using RDSAT estimators, we applied the Cochran-Armitage test for trend to evaluate signals of improvement during the time in which health system changes were made. RESULTS: Participant demographics were similar (n=565, 535, and 570 in 2005, 2009, and 2012, respectively). There was a substantial increase in healthcare coverage (37.6 to 82.5%, P<0.0001). Obtaining syringes from pharmacies (17.8 to 32.1%, P<0.0001) increased substantially. Past year hepatitis C testing increased (16.5 to 33.1%, P<0.0001) with stable self-reported prevalence (45.7-54.2%, P=0.8). Among those with known HIV, antiretroviral treatment was reported among 46.6% in 2005 and 66.3% in 2012. Past year HIV testing declined from 74.2 to 42.1%, (P<0.0001) and the prevalence of unrecognized HIV among PWIDs was 42.2-42.7% in 2009 and 2012. CONCLUSIONS: There is evidence of improvement in some health measures for PWIDs in San Francisco from 2005 to 2012. However, there are also some concerning findings, such as declining prevalence of HIV testing and high prevalence of undiagnosed HIV. There is a need for renewed attention and innovative ideas to track and address HIV and other medical sequelae among PWIDs.

Drug analysis of residual content of used syringes: a new approach for improving knowledge of injected drugs and drug user practices.

BACKGROUND: Since their inception, harm reduction services, including needle exchange programs, have aimed to improve and update knowledge about illicit drug consumption and injection practices in order to assess and regularly revise the effectiveness of preventive strategies. METHODS: In this paper we describe the development of a scientific approach to obtaining this type of information through analysis of the residual content of used syringes. This was done using a validated liquid chromatography method with mass spectrometry detection to identify different molecules. Used syringes were collected from automatic injection kit dispensers at 17 sites in Paris and the surrounding suburbs each month for one year. RESULTS: In total, 3489 syringes were collected. No compounds were detected in 245 syringes. Heroin was the most commonly observed compound (42%), followed by cocaine (41%), buprenorphine (29%) and 4-methylethylcathinone (23%). These analyses also showed the increased appearance of 4-methylethylcathinone between the summer and winter of 2012. CONCLUSIONS: Despite the bias involved in this approach, the method can provide rapid data on patterns of drug consumption for specific time periods and for well-defined locations. This kind of analysis enables the detection of new substances being injected and thus enables harm reduction services to revise and adapt prevention strategies.

Design, evaluation, and dissemination of a plastic syringe clip to improve dosing accuracy of liquid medications.

Pediatricians in Africa requested a tool to improve caregiver dosing of liquid antiretroviral medication. We developed, evaluated and disseminated a clip to control the amount of medication drawn into an oral syringe. In a laboratory, a user tested clips of different lengths, corresponding to different volumes, by drawing water into a syringe with a clip. In Texas and Malawi, 149 adults attempted to measure Pepto-Bismol™ using a syringe with a clip, a syringe without a clip, and a dosing cup, in a randomly assigned order. In the laboratory, the volume of liquid, ranging from 1 to 4.5 mL, drawn into the syringe was always within at least 5 µL of the intended dose. In Texas, 84% of doses were accurate within ±10%, vs. 63% using the syringe alone, and 21% with the dosing cup. In Malawi, 98% of doses were accurate to within ±10%, vs. 90% using the syringe alone, and 27% with the dosing cup. For target accuracy values within ±45% (±21%), a significantly higher fraction of Houston (Kamangira) participants delivered an accurate dose using the syringe with the clip than with the syringe alone (p < 0.05). The clip enables a greater proportion of users to accurately measure liquid medication.

The cost of providing primary health-care services from a needle and syringe program: a case study.

INTRODUCTION AND AIMS: Targeted primary health-care services for injecting drug users have been established in several countries to reduce barriers to health care, subsequent poor health outcomes and the considerable costs of emergency treatment. The long-term sustainability of such services depends on the resources required and the coverage provided. This study assesses the additional cost required to operate a nurse-led primary health care in an existing needle syringe program setting, estimates the costs per occasion of service and identifies key factors influencing improved service utilisation. DESIGN AND METHODS: Using standard costing methods and the funder perspective, this study estimates costs using the 'ingredients' approach where the costs of inputs are based on quantities and unit prices (the ingredients). RESULTS: During the 2009-2010 fiscal year, the primary health-care clinic provided 1252 occasions of service to 220 individuals, who each made an average of 3.9 presentations. A total cost of AU$250,626 was incurred, 69% of which was for personnel and 22% for pathology. During the study period the average cost per occasion of service was AU$199.96, which could be as low as AU$93.32 if the clinic reached its full utilisation level. DISCUSSION AND CONCLUSIONS: Although the average number of presentations per client was satisfactory, the clinic was underutilised during the study period. Proactive engagement of clients at the needle syringe program shopfront and an increased range of services offered by the clinic may help to attract more clients.

Needle and syringe distribution trends in Western Australia, 1990 to 2009.

INTRODUCTION AND AIMS: To describe needle and syringe distribution trends of needle and syringe programs (NSP) between 1990 and 2009 in Western Australia, and explore contributing factors within the national and state strategic and legislative environment. DESIGN AND METHODS: The number of needles and syringes distributed by each of the four NSP types [needle and syringe exchange program (NSEP); health service; pharmacy; vending machine] between 1990 and 2009 were stratified by time period and geographic location using Microsoft Excel. RESULTS: Total needle and syringe distribution over the 20-year period increased by eight-fold. Regional areas experienced the highest growth: 20-fold increase compared with seven-fold increase in metropolitan areas. The proportion of needles and syringes distributed through NSEPs increased from 33% to 62% between 1990 and 2009, and through health services increased from 3% to 8% between 1994 and 2009. The proportion distributed through pharmacies decreased from 67% to 28% between 1990 and 2009, and through vending machines from 7% to 1.3% between 1992 and 2009. National and state HIV and hepatitis C strategies guided NSP provision at an early stage, and expedited legislative amendments to allow for the operation of approved NSPs. DISCUSSION AND CONCLUSIONS: The majority of growth occurred through the NSEPs and health service NSPs, which are publicly funded NSPs and provide injecting equipment either on 'exchange' or free-of-charge respectively. The Health Department of Western Australia recognises the increasing reliance on publicly funded NSPs and the need to continue this cost-effective public health program.

Development of biotechnology products in pre-filled syringes: technical considerations and approaches.

A monoclonal antibody (mAb) product development case study is presented to address some of the issues faced during developing a pre-filled syringe (PFS) product for a biotherapeutic. In particular, issues involving incompatibility with silicone oil and a stability-based approach for selection of PFS barrel and tip cap components have been discussed. Silicone spiking studies followed by exposure to agitation stress or accelerated temperature conditions were used to check for incompatibilities of the mAb with silicone oil, a necessary product contact material in PFS. In addition, screening studies to compare various closure materials as well as syringe barrel processing methods were used to select the optimum closure materials as well as the correct syringe processing method. Results indicate that the model mAb formulation used was sensitive to high levels of silicone oil especially under accelerated temperature conditions resulting in formation of protein-silicone particles in the solution for samples that were spiked with the silicone oil. Agitation stress did not have any significant impact on the quality attributes tested. Samples stored in syringe barrels that were processed with sprayed-on silicone had higher levels of subvisible particles as compared to those that were processed with the baked-on process. The tip cap comparability study resulted in one tip cap material having superior compatibility among the three that were tested. The quality attribute that was most impacted by the tip cap materials was mAb oxidation. An approach for evaluation of primary packaging components during the development of pre-filled syringe presentations for biotechnology-based compounds has been highlighted.

A first semimanual device for clinical intramuscular repetitive cell injections.

Intramuscular cell transplantation in humans requires so far meticulous repetitive cell injections. Performed percutaneously with syringes operated manually, the procedure is very time consuming and requires a lot of concentration to deliver the cells exactly in the required region. This becomes impractical and inaccurate for large volumes of muscle. In order to accelerate this task, to render it more precise, and to perform injections more reproducible in large volumes of muscle, we developed a specific semimanual device for intramuscular repetitive cell injections. Our prototype delivers very small quantities of cell suspension, homogeneously throughout several needles, from a container in the device. It was designed in order to deliver the cells as best as possible only in a given subcutaneous region (in our case, skeletal muscles accessible from the surface), avoiding wasting in skin and hypodermis. The device was tested in monkeys by performing intramuscular allotransplantations of beta-galactosidase-labeled myoblasts. During transplantations, it was more ergonomic and considerably faster than manually operated syringes, facilitating the cell graft in whole limb muscles. Biopsies of the myoblast-injected muscles 1 month later showed abundant beta-galactosidase-positive myofibers with homogeneous distribution through the biopsy sections. This is the first device specifically designed for the needs of intramuscular cell transplantation in a clinical context.

[The development tendencies of infusion pumps/syringe pumps].

Through the investigation about the current infusion pumps, the development tendencies of the next generation infusion pumps/Syringe Pumps with regarding to human-factors, practicality and application under MRI (Magnetic resonance imaging) were put forward.

A flexible system for hands-free intracranial microinjection.

Neuroscience research projects often use intracranial (IC) microinfusions to target drug delivery to specific brain areas during behavioral testing. These experiments require accurate and precisely-timed delivery of small volumes. We present here a stepper motor-powered micropump assembly for such delivery. This system is hands-free, does not use a potentially leaky fluid swivel or use long delivery tubes that are subject to peristaltic forces during animal movements, and has been applied in combination with other paradigms. This micropump system reliably delivers a wide range of fluid volumes (e.g. 50 nL to 1 microL in tissue or greater for intraventricular injections) bilaterally from two independent, commercially available microsyringes through standard surgically implanted guide cannulae. It is easy to build and disassemble for cleaning or changing microsyringes. This system can also be used for a variety of purposes, e.g. intracranial self-administration, place conditioning, and many more, with the advantage that it provides a way to gather important data in the seconds and minutes following IC microinfusion without disruption of the animal's behavior by handling.

Cylindrical channel retractor for intraventricular tumour surgery--a simple and inexpensive device.

Ventricular tumors are excised using both microscope and endoscope as the viewing device. Excision of these tumors requires corticectomy. After these corticectomies, brain has tendency to fall because of CSF drainage. Currently available retractor systems are fixed and thus can be traumatic. On the other hand few systems that require small corticectomy need stereotactic or navigation system aid. These all methods and equipment are costly. Our simple method of using a cylindrical channel retractor custom made out of 20 cc plastic syringe in OT helps in making minimum possible corticectomy. It gives surgeon minimally traumatic, inexpensive, hands free retractor.

Efficient measurement of endogenous neurotransmitters in small localized regions of central nervous systems in vitro with HPLC.

High performance liquid chromatography (HPLC) is widely used to determine neurotransmitter concentrations in the central nervous system (CNS). Finding the optimal methods to sample from CNS tissue poses a challenge for neuroscientists. Here, we describe a method that allows assay of neurotransmitters (or other chemicals) in small regions (down to 180mum in diameter) in in vitro preparations concurrently with electrophysiological recordings. The efficiency for measuring small amounts of chemicals is enhanced by a sample collecting pipette with filter paper at the tip that makes close contact with the target region in CNS tissue. With a wire plunger in the calibrated pipette controlled by a microsyringe pump, there is virtually no dead volume. Samples in a volume of 10muL (taken, e.g., at 2muL/min over 5min) can be injected into a HPLC machine with microbore columns. We demonstrate the effectiveness of this method by measuring acetylcholine (ACh) in the ventral horn and its surrounding areas of the spinal cord in en bloc brainstem-spinal cord preparations. In control conditions, endogenous ACh levels in these regions were detectable. Application of neostigmine (an inhibitor of acetylcholinesterases (AChEs)) increased ACh concentrations, and at the same time, induced tonic/seizure-like activity in efferent motor output recorded from cervical ventral nerve roots. Higher ACh concentrations in the ventral horn were differentiated from nearby regions: the lateral and midline aspects of the ventral spinal cord. In addition, ACh in the preBötzinger Complex (preBötC) and the hypoglossal nucleus in medullary slice preparations can also be measured. Our results indicate that the method proposed in this study can be used to measure neurotransmitters in small and localized CNS regions. Correlation between changes in neurotransmitters in target regions and the neuronal activities can be revealed in vitro. Our data also suggest that there is endogenous ACh release in spinal ventral motor columns at fourth cervical (C4) level that regulates the respiratory-related motor activity.

[New generation of disposable syringes].

The goal of this work was to consider the problem of disposable syringe supply to treatment-and-prophylaxis institutions (first of all, primary medical care institutions). It is emphasized that the construction of disposable syringes should make it impossible to use them a second time. The historical background of the problem is considered. Construction of disposable syringes of new generation is described, and the problems of their manufacture are discussed.

Safe and newer injection technologies.

The different technologies available in safe injection practices can be categorised as: (1) Auto disable syringes for immunisation. (2) Prefilled devices. (3) Reuse prevention syringes for curative injections. (4) New safety devices which include safe blood draw and NSI prevention devices. Auto disable syringes are preferred over normal disposable syringes because of its safety and can be used with minimal amount of training. These syringes improved vaccination coverage rates and are being currently introduced in country EPI. Uniject prefill injection device ensures safety by various ways. There are also reuse prevention syringes for curative injections. The new safety devices have also been discussed in a nutshell.