Vial coring and fragmentation incidence after angled penetration of rubber stoppers with single-use hypodermic needles

Objectives Particles due to fragmentation present a clear risk to the patient. Reported fragmentation rates vary, and an insertion angle at 45°, as opposed to 90°, has been proposed as a mitigation strategy. So, this study evaluated the fragmentation rates induced by single-use hypodermic needles using different angled penetration techniques. Methods Needles underwent fragmentation testing using two penetration techniques. In method 1, the needle was inserted through the stopper at 45° and rotated to 90° upon exiting the stopper underside, and in method 2 the needle was rotated only after the bevel was fully enveloped by the stopper. Methods were tested with 18, 20, and 22-gauge needles with bevel faced up, down, and sideways. Fragmentation data sets were subjected to ANOVA and a fit to a General Linear Model was attempted to ascertain the significance of needle size, bevel position, and penetration method; p-values less than 0.05 indicated statistical significance. Results Incidence varied from 0 to 49% and depended on the test method. Needles larger than 22-gauge induced fragmentation the most when the bevel was down. The bevel up position induced fragmentation the least. Generation of large fragments designated “cores” depended on all factors examined, and generation of small fragments designated “fragments” depended on all factors except for the penetration method. Conclusions Clinical context and intended application need to be communicated to manufacturers and considered for functional testing when devising end-user recommendations which must reflect a combination of factors.

Risks associated with the evolution in the compounding process of parenteral nutrition solutions: use of the “FMECA” method

Objectives An audit of the practices of our compounding unit was performed in 2016: areas of improvement were proposed, such as the automatization of our process. An automated compounder was acquired (MediMixmulti® MF4120R). The aim of the study was to anticipate the risks of the new process, in order to improve its security and to support the professionals during this evolution of our compounding process. Methods The Failure Modes, Effects and Criticality Analysis (FMECA) method was carried out in order to detect potential failures brought by the automatization of parenteral nutrition (PN) manufacturing in the new process. The FMECA method included four steps that were divided into five work sessions of one and a half hour each over a period of two months. A working group made up of professionals involved in the PN production process was set up (pharmacists, pharmacy resident, manager and pharmaceutical technician). Results Fifty failure modes were determined by this analysis, of which 96% could have an impact on the patient, 90% on the health staff and 74% on the product. The FMECA shows that 18 failure modes have a tolerable or unacceptable CI (CI≥100) for which it is necessary to implement preventive measures as a priority. This work also made it possible to review the barrier measures already in place for the current process. Conclusions The risk analysis allowed us to analyze the failures of both the actual and the future manufacturing processes. Once the most critical failure modes were identified, specific recommendations were proposed and an improvement plan was established. First, the compounder needs to be fully qualified. Then, the quality manual of the PN process will be reviewed and updated. Once these steps are completed, the pharmacy professionals (pharmacists, pharmacy technicians) will be trained and the PN production will be performed using the automated compounder on a daily basis.

Antimicrobial preservation efficacy of liquid glucose and liquid maltitol syrups with and without 0.1% sorbic acid

Objectives Amongst paediatric pharmaceutical forms, syrups offer advantages such as ease of administration and good palatability. They also exhibited microbial self-preservation properties that may be useful to enhance shelf life of liquid formulation. The objective of our works is to test the self-preservation efficacy of maltitol and glucose syrup without or with sorbic acid as described in the European pharmacopoeia. Methods The European Pharmacopoeia test of antimicrobial preservation efficacy was performed on liquid glucose syrup and liquid maltitol syrup with and without 0.1% sorbic acid. Results Unpreserved glucose and maltitol syrups did not meet the European Pharmacopoeia acceptance criteria for antimicrobial preservative efficacy due to the regrowth of Aspergillus brasiliensis on day 28 whereas glucose and maltitol syrups with 0.1% sorbic acid pass the test. Conclusions The addition of a preservative (sorbic acid) in glucose and maltitol syrups allows the validation of the antimicrobial preservative efficacy test of the European Pharmacopoeia. Further tests are needed to see if preservative efficacy is maintained despite dilutions or in the presence of active pharmaceutical ingredients.

Risk management in an anticancer drug preparation unit: use of Preliminary Risk Analysis method and application to the preparation process

Objectives Preparation of injectable anticancer drugs in hospital pharmacies, in particular of cytotoxics, is a high-risk activity. We used Preliminary Risk Analysis (PRA) to analyse the risks in the different steps of our anticancer drug circuit, including the preparation step (PRA1). Then, to prepare an important change in management of the circuit with the software Chimio® (pooling of three databases for subcontracting), we repeated the analysis of preparation step (PRA2). PRA is known to be time and resource consuming. To overcome this, we developed a strict organisational framework to perform the analysis within a reasonable amount of time. We present the PRA method including its practical implementation, and its application to the anticancer drug preparation process, before and after pooling of Chimio® databases. Methods PRA has two main stages, PRA “system” and PRA “scenario”. A multidisciplinary working group is created for the entire PRA process. PRA “system” is an exploratory and qualitative stage. PRA “scenario” requires the creation of risk assessment tools and decision tools before actually developing, analysing and treating scenarios, with risk reduction actions structured in an action plan. For PRA2 we used the same working group, assessment and decision tools as for PRA1 and we only analysed dangerous situations (DS) that appeared or changed towards more risk, requiring a new action plan. The different PRA only required four 2 h meetings thanks to the investment of a coordinator who is expert in the method. Results In PRA1, the riskiest phase was production while it was the verification and delivery of the finished product in PRA2. The risks were mainly related to management, human and technical dangers in PRA1. Human danger was found to be the main danger in PRA2, followed by organisational danger. Among the 264 scenarios described in PRA1, six of criticality 3 and 69 of criticality 2 have been associated with risk reduction actions. These actions mainly involved managing the risk of human error, with the control system Drugcam® and the standardisation of the pharmaceutical assistants’ training program. In PRA2, 11 scenarios were analysed, including three of criticality 3 and 4 of criticality 2 for which risk reduction measures were taken. Conclusions PRA allowed us to perform an in depth analysis of the highly specific and technical process of anticancer drug preparation. Human danger was one of the most important dangers identified, and it should always be taken into consideration, whatever the measures taken to prevent it. PRA2 was extremely useful to plan the organisation that would result from the new Chimio® database, while involving the team and winning its commitment. It allowed an exhaustive and structured anticipation of this major change. Practical aspects of PRA method implementation we have adopted facilitate its application and can help to deploy it on many areas in our hospitals. Indeed, besides an exhaustive analysis of the risks, this approach promotes collaboration, develops a quality culture and is an excellent tool for team and project management, as well as communication.

New liquid oral formulations of hydroxychloroquine: a physicochemical stability study

Objectives Hydroxychloroquine (HCQ) presents many drug properties that increase its therapeutic use. There are, indeed, different research pathways in numerous autoimmune, inflammatory, and infectious diseases, as well as in cancerology. HCQ is only marketed as HCQ sulfate in film-coated or coated tablets for oral use. No pediatric liquid form is currently available on the market. The purpose of the present study is to develop oral liquid formulations for HCQ at 50 mg/mL with two different oral vehicle suspensions, namely ORA-Plus®/ORA-Sweet® (ORA) and Syrspend® SF PH 4 (SYR). Methods The suspension stability was assessed in different storage conditions (4 and 25 °C). A high-pressure liquid chromatography (HPLC) stability-indicating method with UV detection was developed to determine HCQ concentrations in the different formulations, and detect potential degradation products. Physical parameters, e.g. pH and osmolality were also monitored during the period of the stability study. Results HCQ concentration, osmolality, and pH remained stable for 90 days at 4 and 30 °C for HCQ in 50% ORA-Plus®/50% ORA-Sweet®. For HCQ suspension in SYR, the suspension remained stable 90 days at 4 °C and 60 days at 30 °C. Conclusions For all preparations, no significant physical or chemical modification was noticed during the period of the study.

Physicochemical stability of human insulin 1 I.U./mL infusion solution in 50 mL polypropylene syringes

Objectives The objective of this study was to investigate the physicochemical stability of human insulin 1 I.U./mL injection solutions (Insuman® Rapid) diluted with 0.9% NaCl solution in 50 mL disposable three-piece polypropylene syringes and stored refrigerated or at room temperature. Methods 1 I.U./mL test solutions were prepared with Insuman® Rapid and 0.9% sodium chloride infusion solution in 50 mL Original-Perfusor® syringes and BD® Perfusion syringes. Test solutions were stored for 90 days at 2–8 °C/dark or 48 h at 20–25 °C/diffuse room light in order to determine chemical stability. Additional test solutions were stored 28 days at 2–8 °C/dark followed by 24 h at 20–25 °C/diffuse room light to measure pH and particle counts. Human insulin concentrations were analysed by reversed-phase high-performance liquid chromatography at predefined time points. Test solutions were regularly inspected; subvisible particles and pH values were measured. Results Insuman® Rapid 1 I.U./mL injection solutions, stored at 2–8 °C/dark for 90 days showed a decrease of insulin content over time, regardless of the syringe type used. When kept at 20–25 °C/diffuse room light for 48 h, a slight decrease of the HI concentration was observed in both syringe types. No evidence of colour change, relevant particle formation or major pH-change was observed throughout the observation period in any test solution. Conclusions Insuman® Rapid 1 I.U./mL injection solutions can be prepared by dilution with 0.9% NaCl infusion solution in disposable 50 mL three-piece polypropylene syringes as suitable primary containers. Physicochemical stability has been demonstrated for at least 21 days stored at 2–8 °C/dark followed by 48 h at 20–25 °C/diffuse room light.

Efficacy of two intensive decontamination protocols and their effects after 30 days on environmental contamination by cyclophosphamide

Objectives To evaluate the efficacy of two decontamination protocols on cyclophosphamide surface contamination and to explore its lasting effect 30 days later. Methods All sampling sites that were systematically contaminated with cyclophosphamide in 2017–2020 were included, from a convenience sample of centers. The first decontamination protocol consisted of four steps, each with 20 mL and a Wypall® wipe: detergent, sodium hypochlorite 2%, isopropyl alcohol 70% and water. The second decontamination protocol consisted of eight steps, each with 15 mL and a Micronsolo® microfibre wipe: detergent, sodium hypochlorite 2%, isopropyl alcohol 70%, water and then a second round with each of the four products. A first sampling was done at the end of a regular working day (T0), a second immediately following decontamination (T1) and a third 30 days later (T2) after regular operations. Cyclophosphamide was quantified by ultra-performance liquid chromatography – tandem mass spectrometry (limit of detection 0.001 ng/cm2). Results Seventeen sampling sites were included: six biological safety cabinet (BSC) front grilles, eight floors in front of BSCs and three cyclophosphamide storage shelves. The second protocol was more effective; however they both failed to completely remove all cyclophosphamide traces. BSCs and floors were found to be contaminated again 30 days later, at similar concentrations than at T0. A lasting effect was observed on the cyclophosphamide storage shelves that were less prone to be contaminated again. Conclusions Periodic decontamination with many cleaning steps is necessary on all surfaces, including those less frequently contaminated. Regular surface monitoring identifies systematically contaminated areas.

Fifth DSRG symposium at CHU UCL Namur, 18/10/2019. “Centralization of injectables and robotization”

The physico-chemical stability of an injectable preparation (IV) is conditioned by different parameters. A collaboration between the pharmacy, the chemistry laboratory and the statisticians of the scientific support unit was established in 1996, in order to carry out long-term chemical stability studies of commonly used IVs and to be able to take charge of their preparation in pharmacy. In 24 years of activity, the Drug Stability Research Group (DSRG) tested 39 IV at different concentration and temperature of storage. The DSRG has organized an annual symposium since 2015. The theme of the 2019 edition was devoted to the robotization of injectable reconstitution operations, focused on their impact on the workplace and the existing equipment.

Lyophilization-free proliposomes for sustained release oral delivery of hydrophobic drug (cinnarazine): a comparative study

Objectives Cinnarizine is used for the treatment of vestibular disorders. However, its poor solubility limits its clinical uses due to many challenges. Liposomes were utilised to improve the release profile of many poorly soluble drugs. However, liposomes face many stability challenges during the storage period. This study aims to develop proliposomes designed for the oral delivery of cinnarizine with enhanced stability characteristics. Methods Three cinnarizine entrapping Proliposomal formulations were prepared with different ingredients and compared with their liposomal counterparts. Both vesicular approaches were characterised for their particle size, encapsulation efficiency, drug release and stability. Results The proliposomes were superior to liposomes in their stability and release profiles. Although no significant changes were noticed between the encapsulation efficiency percentage of the liposomal and proliposomal formulations on the day of preparation, storing the formulations for two weeks ended up with significant leakage of the drug from liposomes (p < 0.05) due to stability issues, but not in proliposomes. Moreover, the proliposomes released 100% of cinnarizine throughout the dissolution experiment in gastric fluid in comparison with the total released drug of 70% from the liposomes. Conclusions Proliposomes provided a successful approach to deliver lipophilic drugs orally to improve their pharmacokinetic properties by converting their crystalline nature into more amorphous agents.

Use and impact of technology-assisted workflow (TAWF) systems for drug compounding in pharmacy practice: a scoping literature review

Objectives The aim of this study was to review studies describing the use and the impact of technology-assisted workflow (TAWF) systems for drug compounding in hospital pharmacy. Content This is a scoping literature review. A search was conducted on studies describing or evaluating the use of TAWF published from January 1st, 2015 to July 31st, 2021. Two databases were searched (PubMed and Embase), followed by a search on Google Scholar. Summary 218 articles were screened and 17 were identified as meeting the inclusion criteria. TAWFs all included preparation assistance software (17/17), barcode reader (17/17), photo or video taking (17/17), and some included gravimetric systems (8/17), and the use of robots (2/17). A majority of the studies included used technology for parenteral preparations (15/17, one for oral preparations only (1/17), and one used technology for both types of preparations (1/17). Most of the articles selected presented drugs prepared for adults (10/17), the others presented drugs intended for children (4/17) or for a mix of adults and children (3/17). Four parameters were evaluated: error detection rate (n=15), preparation and validation time (n=7), and costs generated or saved (n=7). Ten studies evaluated the pre-post impact of implantation of a TAWF (10/17). Outlook Given the heterogeneity of the data available, the use of TAWF was associated with an increased ability to detect preparation errors, a reduction in preparation time and costs, and increased satisfaction of pharmacy technicians and pharmacists. However, better quality studies are needed to confirm the positive impacts studied.