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OBJECTIVES: To determine prospectively the sources of risk of non-sterility during aseptic handling and to quantify the risks of each of these sources.METHODS: A risk assessment (RA) of non-sterility according to Failure Mode and Effect Analysis was executed by a multidisciplinary team of (hospital) pharmacists and technicians, a consultant experienced in aseptic processing and an independent facilitator. The team determined the sources of risk of non-sterility, a 5 point scale for severity, occurrence and detection, and risk acceptance levels. Input about general applied risk reduction was collected by audits in 10 hospital pharmacies. The results of these audits were used for determining the remaining risks. The results, as well as scientific information and the experience of the team members, was used to determine scores for severity, occurrence and detection.RESULTS: Multiplying the scores for severity, occurrence and detection results in the risk prioritisation number (RPN) which is a relative value of the remaining risks of non-sterility for each source. Incorrect disinfection techniques of non-sterile materials and the chances of touching critical spots were estimated as the greatest risks. The risk of non-sterility via the airborne route was low. RPN values were helpful in prioritising measures for additional risk reduction (this will be described in an accompanying article).CONCLUSION: The RA, described here, was a systematic survey related to all sources of risk of non-sterility during aseptic handling. The determined RPN values were helpful in prioritising measures for additional risk reduction.

OBJECTIVES: To transfer sterile medical devices (SMD), infusion bags (IB), ampoules (A), injection vials (V) and infusion bottles (B) into a laminar airflow cabinet (LAF) or safety cabinet (SC) with a surface bioburden as low as possible.METHODS: Surface bioburden of the outer layer of SMD, IB, A, V and B was determined by contact plates. Surface bioburden determination of critical spots on A, V and B (ampoule necks and stoppers) was determined by high-recovery swabs and contact plates. Particle emission from white cardboard boxes was determined by a particle counter.RESULTS: The chances of a contaminated outer layer of SMD is negligible as long as they stay in their original boxes. The outer layer of double-packed IB can contain a considerable number of micro-organisms. As found in previous studies, the surface bioburden of A, V and B is low as long as they stay in their original cardboard boxes. Particle emission from white boxes is low. The necessity of a final disinfection step inside LAF/SC of critical sspots of A, V and B cannot be proven. SmallSMD, ampoules and injection vials can be transferred into the background areain their original white boxes. Other materials have to be unpacked in front ofthe lock while the operator wear disposable gloves. Disinfection of the outerlayer of IB, before transfer trough the lock, is advised. Tohave materials with a low chance of contamination in LAF/SC, transfer bypresentation for SMD and IB and using a sterile tray for disinfected materialsis an effective procedure. Wiping of ampoule necks and stoppers inside LAF/SC isadvised based on risk assessment.Small SMD, ampoules and injection vials can be transferred into the background areain their original white boxes. Other materials have to be unpacked in front ofthe lock while the operator wear disposable gloves. Disinfection of the outerlayer of IB, before transfer trough the lock, is advised.CONCLUSION: When SMD, ampoules, injection vials and infusion bottles stay in their original boxes as long as possible, the aseptic transfer and the disinfection procedure can be maintained effectively and efficiently.

OBJECTIVES: To determine prospectively the risk reducing measures of non-sterility during aseptic handling and to develop a method for prioritising these measures.METHODS: In the first part of this series of articles, we identified all sources of risk which could contaminate a product during aseptic handling, and calculated the remaining risks of non-sterility using a risk assessment (RA) model. We concluded that additional research of some risk sources was needed before risk control (RC) could be executed on all risk sources.The chances of technical problems with a laminar airflow cabinet or safety cabinet (LAF/SC) were collected from 10 hospital pharmacies using a questionnaire. The chances of blocking first air were examined by airflow visualisation (smoke studies). For checking the way of working during aseptic handling, a checklist for an audit was developed.Risk control was executed by a multidisciplinary team of (hospital) pharmacists and technicians, a consultant experienced in aseptic processing and an independent facilitator. They determined the risk reducing measures for each source of risk and the influence of these measures on the remaining risk (expressed as risk prioritisation number).RESULTS: The chances of defects of the LAF/SC were low. Airflow visualisation is a sensible method to find the correct location of materials and equipment inside the LAF/SC and to detect a way of working without blocking first air on critical spots. Audits will provide valuable information about the way aseptic handling is executed and the remaining risks as a consequence. The risk of non-sterility caused by needle or spike contact with critical spots of vials and ampoules (stopper or ampoule neck), blocking first air under downflow and touching critical spots cannot be eliminated completely.CONCLUSION: The RA/RC model shows the impact of risk reducing measures on the probability of non-sterility during aseptic handling. The calculated risk prioritisation numbers are helpful in prioritising these measures. Audits result in risk reduction for nearly all sources of risk.

OBJECTIVES: To improve the disinfection methods for materials with a non-sterile surface to be used in aseptic handling.METHODS: The surface bioburden on ampoules (A) and injection vials (IV) is determined by contact plates and total immersion. The occurrence of spore-forming bacteria is determined by strain colouring and matrix-assisted laser desorption ionisation-time of flight mass spectrometry. The disinfection procedures of non-sterile materials in 10 hospital pharmacies are judged by observing.RESULTS: After wiping according to local disinfection methods, the mean surface bioburden determined by contact plates in 10 hospital pharmacies is 0.36 (plastic A), 0.50 (glass A) and 0.29 colony-forming unit (cfu) (IV). The observers found great differences in accuracy of wiping and degree of wetting the sterile gauzes.After improved wiping with commercially available alcohol impregnated sterile wipes and a two-towel technique (one-step TT disinfection), the mean surface bioburden determined by contact plates is 0.03 (plastic A), 0.2 (glass A) and 0.13 cfu (IV). Further improvement can be reached by submerging A and IV in ethanol 70% followed by improved wiping (two-step TT disinfection), but still micro-organisms will remain (mean surface bioburden determined by total immersion is 0 (plastic A) and 0.3 cfu (IV); glass A not determined). Two-step TT disinfection is more labour intensive. Spilling of alcohol is another disadvantage. However, we presume one-step TT disinfection is effective enough in daily practice. Routine surface bioburden determinations have to prove this.The effectiveness of the combination of spray and wipe is not examined because we observed a quick disappearance of alcohols from vertical as well as horizontal surfaces, which shortens the contact time to far below the advised 2 min.Spore-forming bacteria disappear as quickly as other micro-organisms during disinfection by alcohols.CONCLUSION: Local disinfection procedures can be improved. Complete removal of micro-organisms from materials with a non-sterile surface, even after two-step TT disinfection, is impossible. Routine surface bioburden determinations have to prove if one-step TT disinfection is effective enough.

OBJECTIVES: To describe the application of the model described in part A and part B of this series of articles for risk assessment (RA) and risk control (RC) of non-sterility during aseptic handling. The model was applied in nine hospital pharmacies.METHODS: The starting point was an audit of each hospital pharmacy. The determined risk reduction and remaining risks were entered into a risk assessment model. The corresponding risk prioritisation numbers (RPNs) for each source of risk were calculated and these values were summed up to a cumulative RPN. Subsequently, all hospital pharmacies started an improvement programme, using the risk assessment as input. Results of aseptic process simulation (APS) and microbiological monitoring (MM) were also collected. The participants were informed about their progress of risk reduction and results of APS and MM during the study period. At the end of the study (about 4 years after the start), a final assessment was executed by using a checklist with risk reducing measures for each source of risk. Additional risk reduction and remaining risks were put in an RA and RC template and corresponding RPN values and a new cumulative RPN were determined.RESULTS: At the start of the study differences in cumulative RPN values were relatively small (from 630 to 825). At the end they were relatively great (from 230 to 725), which illustrates a different sense of urgency for reducing the risk of non-sterility. Of all the risk reducing measures, a yearly audit of all operators had the greatest impact on reducing the risk of non-sterility. Except for glove prints, there was no correlation between process improvement (lower cumulative RPN) and results of microbiological controls.CONCLUSION: A systematic and science-based reduction of the risks of non-sterility can be done by using a checklist with risk reducing measures and an RA & RC template. Prospectively, the relevance of each risk reducing measure can be demonstrated by RPN calculations. Microbiological controls are an important part of the overall assurance of product quality. However, the results are less useful for assessing the risk of non-sterility.

Objectives To develop methods for surface bioburden determination of ampoules and vials to be used in the validation of the disinfection procedures and in routine monitoring of ampoules and vials. Methods The surface bioburdens of ampoules and vials are determined before and after disinfection by contact plates and total immersion. Results The mean surface bioburdens of non-disinfected ampoules and vials taken straight from the original boxes are 2.4 and 5.01 cfu (total immersion; n = 20), and 0.97 and 0.94 cfu (contact plates; n = 60). The mean surface bioburdens of ampules and vials after disinfection by wiping are 1.15 and 7.50 cfu (total immersion; n = 20), and 0.12 and 0.10 cfu (contact plates; n = 60). The high number of cfu on vials (total immersion) indicate hidden cfu around the neck not removable by wiping and not detected by contact plates. Total immersion needs special laboratory facilities and is expensive (about €50 a sample). Therefore, it is less appropriate for use in routine monitoring. However, because of the high recovery, it is the method of choice for the validation of the disinfection procedure. Surface bioburden determination by contact plates is relatively simple. Non-flat surfaces cannot be reached, but the recovery from the touched flat part of the surface is high (around 50%). The recovery from swabs is low (around 10%). Another disadvantage of swabs is the laboratory work after sampling. We therefore advise contact plates for routine monitoring. To get a reliable value of the mean surface bioburden at least 30 samples need to be examined. Conclusion Total immersion is the method of choice for the determination of the effectiveness of a disinfection procedure for ampoules and vials. Contact plate is the method of choice for routine monitoring of the surfaces of ampoules and vials.

Aseptic handling is the procedure to enable sterile products to be made ready to administer using closed systems (EU Resolution CM/Res(2016)2). Microbiological monitoring (MM) and media fills are used for environmental and process control. In this study, the application of MM methods during aseptic handling inside, or related to working in, a laminar airflow cabinet or safety cabinet in hospital pharmacies is described and evaluated. Results are expressed as colony forming units (cfu) and Contamination Recovery Rate (CRR; the rate at which MM samples contain any level of contamination -USP-). For trend analysis, a rolling CRR is developed (a rolling CRR calculates a CRR using a predetermined number of most recent samples). Of all MM methods, glove print is the most informative. The added value of air sampling is doubtful. Because of microbiological as well as statistical considerations, the use of CRR for assessing MM results is advised. Glove prints, in general, give the highest CRR. A CRR < 10% is a realistic limit for MM during aseptic handling in hospital pharmacies. A rolling CRR, calculated using the last 100 samples, is a good compromise between reliability of the CRR value and timely prediction of process changes.

The solute concentration in the subsoil beneath the root zone is an important parameter for leaching assessment. Drainage centrifugation is considered a simple and straightforward method of determining soil solution chemistry. Although several studies have been carried out to determine whether this method is robust, hardly any results are available for loess subsoils. To study the effect of centrifugation conditions on soil moisture recovery and solute concentration, we sampled the subsoil (1.5–3.0 m depth) at commercial farms in the loess region of the Netherlands. The effect of time (20, 35, 60, 120 and 240 min) on recovery was studied at two levels of the relative centrifugal force (733 and 6597g). The effect of force on recovery was studied by centrifugation for 35 min at 117, 264, 733, 2932, 6597 and 14,191g. All soil moisture samples were chemically analysed. This study shows that drainage centrifugation offers a robust, reproducible and standardised way for determining solute concentrations in mobile soil moisture in silt loam subsoils. The centrifugal force, rather than centrifugation time, has a major effect on recovery. The maximum recovery for silt loams at field capacity is about 40%. Concentrations of most solutes are fairly constant with an increasing recovery, as most solutes, including nitrate, did not show a change in concentration with an increasing recovery. © 2017, The Author(s).

In western countries, laparoscopic gastric banding is increasingly used in the surgical treatment of morbid obesity. This study aimed to investigate the feasibility, safety, morbidity, and costs of an outpatient procedure (OP) compared with an overnight stay (OS).In a 2-year period, 50 consecutive patients were randomized to an OP group or an OS group.In the OP group, 76% of the patients were successfully discharged the same day, without readmissions. Four procedures were converted, and one complication occurred. The patients in the OP group seemed to experience more pain (p = 0.009). Satisfaction scores were 8.1 (OP) and 8.8 (OS) (p = 0.06). Half of the OP patients and most of the OS patients preferred a clinical admission. The OP treatment cost 600 euros less than OS.With proper patient selection, laparoscopic gastric banding can be performed safely and at lower cost as an outpatient procedure.

Background According to the Dutch GMP-hospital pharmacy directive (1) three types of microbiological controls are required when aseptic dispensing is performed: 1. microbiological monitoring of the air in the working area, the gloved hands of the operator and the work surface at the critical place in the laminar airflow cabinet; 2. microbiological validation of the operators through media fill runs; 3. validation of the aseptic process by repeating the procedures with an appropriate broth. Purpose To develop a web-based program for data of microbiological controls on aseptic dispensing for Dutch hospital pharmacies for: simple processing of environmental monitoring data; trending of environmental monitoring data; comparing individual data with other hospital pharmacies nationwide. Materials and methods The web-based program MICROBIO was designed in collaboration with an expert group of hospital pharmacists. Participating hospital pharmacies collected microbiological control data and entered them into the program. Limits for microbiological contamination are based on EU-GMP recommendations (2). Results Currently 49 of 80 Dutch hospital pharmacies use MICROBIO. More than 85% of the microbiological controls on monitoring comply with the results (air 87%, gloved hands 90%, work surface 86%). Conclusions MICROBIO is a standardised tool which fully supports processing data and evaluation for all three types of microbiological controls and presents them in diagrams and histograms. The results show that the directive on aseptic dispensing in GMP-hospital pharmacy is met. Literature 1. Aseptic dispensing. In GMP-hospital pharmacy. The Hague: Dutch Association of Hospital Pharmacists; 2005; www.nvza.nl. 2. The rules governing medicinal products in European Union. Volume 4. Good manufacturing practices. Medicinal products for human and veterinary use. Annex I. Manufacture of sterile medicinal products. European Commission, revision May 2003.

In order to calculate the minimum sterilization process conditions to obtain the generally accepted sterility level (less than 1.10(-6) probability of microbial survival), we determined the bioburden and its heat resistance of 500 ml large-volume parenteral bottles over a period of 5 years. For the bioburden determination 1,832 bottles were examined by the membrane filtration method. Mean bioburden was 9.36 colony-forming units/bottle. Of the colony-forming units isolated 118 were heat resistant (0.69%). These were spore-forming Bacillus species. Of the isolated Bacillus species heat resistance was determined in 5% glucose, 0.9% sodium chloride and 8% amino acids solution. D values greater than 1 min at 105 degrees C were found for 2, 5 and 4 different Bacillus species in glucose 5%, sodium chloride 0.9% and amino acids 8%, respectively. 2 Bacillus species showed a D value over 2 min at 105 degrees C in all three media. D values at 110 degrees C in sodium chloride 0.9% for these 2 Bacillus species were 1.8 and 2.6 min and in amino acids 8% 0.9 and 1.7 min, respectively. The minimum sterilization process time at 110 degrees C, calculated with the experimentally determined bioburden and D values is less than 25 min. When introducing reduced exposure times/temperatures, each individual manufacturer should assess the bioburden. The time-consuming determination of the heat resistance of bioburden isolates is not always necessary. By dividing the isolated colony-forming units in a 'heat-resistant' group and a 'not-heat-resistant' group, changing from standard overkill sterilization procedures to processes with lower F0 values is possible.

The Laboratory of Dutch Pharmacists determines LVP particulate matter contamination of LVPs produced in Dutch hospital pharmacies. The investigated LVPs must conform to the NVZA/LNA criteria, which prescribes eight samples and sets limits for particlesor = 2 microns,or = 5 microns,or = 10 microns, andor = 25 microns for both mean and mean + 2x standard deviation. LVPs produced in 500 mL glass containers or plastic containers mostly met the NVZA/LNA criteria, but LVPs produced in 100 mL glass containers showed higher levels of particulate matter contamination. The composition of the LVP significantly affected the extent of particulate matter contamination, but the effect was relatively small when compared to the influence of the type of container. LVPs produced in Dutch hospital pharmacies and LVPs obtained from pharmaceutical industries showed comparable amounts of particulate matter contamination.

Reproducible particle counting using the light-obscuration technique is often troublesome because no absolute standard is available. Therefore, at the Laboratory of Dutch Pharmacists the "calibration-in-time" method was developed. This method enables checking of the amount of particles counted from a diluted latex suspension as a function of time. A particularity of the method is the one-step dilution procedure. The calibration-in-time method is compared with the particle-counting accuracy test according to the USP788. Advantages and disadvantages of both methods are discussed.

In dit artikel worden enkele meetmethoden beschreven om bacterie- en deeltjestellingen uit te voeren bij de mens, de apparatuur en in de bereidingsruimten. Vervolgens worden de resultaten van deze tellingen, die zijn uitgevoerd in zeven Nederlandse ziekenhuisapotheken, besproken. Gezien het vrijwel ontbreken van een correlatie tussen de resultaten van de tellingen en de verschillen in werkomstandigheden, is het ons inziens noodzakelijk dat volgens standaardmethoden aanvullend onderzoek wordt verricht. Om een optimale persoonlijke en bedrijfshygiene te handhaven, is het van groot belang dat de medewerkers in voldoende mate microbiologisch worden geschoold.

Reticulo-endothelial function was assessed in 20 patients with active rheumatoid arthritis and 11 patients with systemic lupus erythematosus with regard to the clearance of heat-damaged erythrocytes (HDE). In contrast to previous reports, no correlations were found between disease activity, levels of circulating immune complexes and splenic function. There was no evidence of an obvious hypofunction in the reticulo-endothelial system of the spleen in patients with rheumatoid arthritis or systemic lupus erythematosus. Moreover, a splenic hyperfunction is suggested to be present in some patients. A method for measuring the specific uptake by the liver, spleen and the clearance rate (T 1/2) of the HDE is also described.

Measurement of complement components in serum may not accurately assess the degree of activation of the complement system. An alternative approach is the measurement of conversion products of the complement components. The relation between the presence of an increased concentration of C3-conversion products and the metabolism of C3 was investigated. In a group of patients, circulating immune complexes were also measured (Clq-binding test) to see whether the combination of those markers yielded information on the C3 metabolism. In this study it is shown that static measurements of serum C3 levels is of no value for the degree of complement activation. Measurement of C3-conversion products may indicate C3 hypercatabolism (in 8 of the 11 patients with C3-conversion products), but it does not imply depressed C3 synthesis. Detection of circulating immune complexes by the C1q-binding assay did not always indicate a C3 hypercatabolism. Of 12 SLE patients studied, in 9 of them, a C3 hypercatabolism was detected, and 5 of these patients were clinically characterized by the presence of minor disease symptoms. Overall, the results indicated that detection of circulating immune complexes and/or C3-conversion products could not be used as an absolute measure for insight into the C3 metabolism.

In dit artikel worden achtereenvolgens de begrippen besproken die van belang zijn bij het afsterven van microorganismen onder invloed van vochtige hitte

Aan de hand van de produktie van infusievloeistoffen in onze ziekenhuisapotheek zullen de microbiologische contaminatiebronnen worden besproken, die tijdens de bereiding het produkt kunnen besmetten. Tevens zullen enkele onderzoekmethoden worden besproken, waarmee contaminatiebronnen opgespoord en gekwantificeerd kunnen worden. Uit onze waarnemingen blijkt dat het, bij gebruik van micro-organismen-arm water, een microorganismen-arm leidingensysteem, een bubblepoint getest membraanfilter van 0,45 of 0,2μm, micro-organismen-arme verpakkingsmaterialen en een werkwijze van het personeel waarbij direct contact met de oplossing en de verpakkingsmaterialen wordt vermeden, goed mogelijk is infusievloeistof met maximaal 10 micro-organismen per ml te bereiden.

In order to verify whether the sterilization process of 60 min at 100°C for invert sugar 20% is sufficiently effective to attain the generally accepted probability of survival of maximum 1×10−6, we determined the bioburden and the bioburdens heat resistance for this product. We examined 98 bottles by the membrane filtration method and found 84 bottles with o colony forming units (CFU's) and 14 bottles with 1–9 CPU's. Because none of the isolated CPU's was heat resistant (Bacillus species), we isolated heat resistant CPU's from the environment and determined the heat resistance in invert sugar, water and NaCl solution 0.9% of four differentBacillus species. The results in invert sugar for the most heat resistantBacillus species were a D-value of 0.92 min at 100°C. For the determination of the D-value the end-point method is the most practical one, and the D-value calculation with the most probable number method is sufficiently accurate. Because of unavoidable inaccuracies in the experimentally determined D-value, safety margins of 100% have to be taken into account in the sterilization process calculations in which these D-values are used. Hence, in our case, we have to use a D-value of 2×0.92 min in the sterilization process calculation for invert sugar 20%. The maximum bioburden in the examined 98 test bottles was 9 CFU's. The maximum heat resistant bioburden which must be used in sterilization process calculations may be safely fixed at 10% of the total bioburden, therefore we have to use 0.9 micro-organisms in our calculation. Hence using these values of 0.9 microorganisms and the maximum bioburden heat resistance (D-value=2×0.92 min at 100°C), the minimum sterilization process time for invert sugar 20% in our hospital pharmacy is calculated to be 10.96 min at 100°C.