Development and Bioequivalence of 3D-Printed Medication at the Point-of-Care: Bridging the Gap Toward Personalized Medicine.

Personalized medicine is currently hampered by the lack of flexible drug formulations. Especially for pediatric patients, manual compounding of personalized drug formulations by pharmacists is required. Three-Dimensional (3D) printing of medicines, which enables small-scale manufacturing at the point-of-care, can fulfill this unmet clinical need. This study investigates the feasibility of developing a 3D-printed tablet formulation at the point-of-care which complies to quality requirements for clinical practice, including bioequivalence. Development, manufacturing, and quality control of the 3D-printed tablets was performed at the manufacturing facility and laboratory of the department of Clinical Pharmacy and Toxicology at Leiden University Medical Center. Sildenafil was used as a model drug for the tablet formulation. Along with the 3D-printed tablets a randomized, an open-label, 2-period, crossover, single-dose clinical trial to assess bioequivalence was performed in healthy adults. Bioequivalence was established if areas under the plasma concentration curve from administration to the time of the last quantifiable concentration (AUC0-t ) and maximum plasma concentration (Cmax ) ratios were within the limits of 80.00-125.00%. The manufacturing process provided reproducible 3D-printed tablets that adhered to quality control requirements and were consequently used in the clinical trial. The clinical trial was conducted in 12 healthy volunteers. The 90% confidence intervals (CIs) of both AUC0-t and Cmax ratios were within bioequivalence limits (AUC0-t 90% CI: 87.28-104.14; Cmax 90% CI: 80.23-109.58). For the first time, we demonstrate the development of a 3D-printed tablet formulation at the point-of-care that is bioequivalent to its marketed originator. The 3D printing of personalized formulations is a disruptive technology for compounding, bridging the gap toward personalized medicine.

Reducing the risk of non-sterility of aseptic handling in hospital pharmacies, part C: applying risk assessment and risk control in practice.

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.

Microbiological controls of aseptic handling in Dutch hospital pharmacies: Results, limits, and methods for assessing.

INTRODUCTION: '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 controls are an important part of the overall assurance of process and product quality of aseptic handling. They consist of the End-of-Session Broth Test (ESBT) using Tryptone Soya Broth, Microbiological Monitoring (MM) using Ø 55- and 90-mm agar plates and a periodical Operator Broth Transfer Validation Test (OBTVT) using Tryptone Soya Broth. This study describes the results of these controls over a 7-year period, involving between 44 and 49 pharmacies (mostly hospital pharmacies). All pharmacies use a web-based programme for processing, evaluation and assessing microbiological controls ('Microbio'). Aggregated results in Microbio are used for benchmarking and feedback information. OBJECTIVE: The objective of this study is to analyse the results of the 7-year period and to develop methods for assessing of, and determining realistic limits for, microbiological controls during aseptic handling. As secondary objective the role of Microbio is highlighted. RESULTS AND DISCUSSION: Results of ESBT are expressed as Contamination Rate (CR), which is the percentage of units filled in a process simulation that are positive for microbial growth after incubation. Compared with the first 3 years of the study, the results in the last 4 years were significantly better: mean CRs are 0.20 and 0.11, respectively (p-value <0.01). For assessing CRs of ESBT, the approach 'the more frequent samples with growth, the stronger the corrective actions' was adopted. Levels of investigative and corrective actions, based on the 95% Upper Confidence Limit, are suggested. Microbiological Monitoring (MM) during aseptic handling into a laminar airflow cabinet or safety cabinet consists of settle plates, glove prints, contact plates of the worktop and surface bioburden determination of disinfected ampoules and vials. The results are expressed as the Contamination Recovery Rate (CRR), which is the rate at which MM samples contain any level of contamination. During the study period, the results of glove prints and contact plates improved substantially. The most probable explanation of this finding is improved disinfection procedures of the gloved hands, the worktop inside LAF/SC and the ampoules and vials. Results of settle plates did not change. There were too few results available to evaluate the surface bioburden of disinfected ampoules and vials. Benchmarking and feedback information from Microbio may have contributed to the improved ESBT and MM results. Results of the Operator Broth Transfer Validation Test (OBTVT) are expressed as Contamination Rate (CR). The target is zero samples with growth (CR = 0). The overall CR result over the study period is 0.50%. This is worse than ESBT (overall CR is 0.14%). This is probably due to the high number of critical steps in OBTVT compared to ESBT. CONCLUSION: Results of microbiological controls improved during the study period. Realistic limits as well as methods for assessing ESBT and MM results are given and discussed.

Reducing the risk of non-sterility of aseptic handling in hospital pharmacies, part A: risk assessment.

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.

Improving the aseptic transfer procedures in hospital pharmacies part C: evaluation and redesign of the transfer process.

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.

Improving the aseptic transfer procedures in hospital pharmacies. Part B: evaluation of disinfection methods for materials with a non-sterile surface.

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.

Reducing the risk of non-sterility of aseptic handling in hospital pharmacies, part B: risk control.

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.

Improving the aseptic transfer procedures in hospital pharmacies part A: methods for the determination of the surface bioburden on ampoules and vials.

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.

Unlicensed pharmaceutical preparations for clinical patient care: Ensuring safety.

Most medicinal products dispensed to patients have marketing authorization (MA) to ensure high quality of the product, safety, and efficacy. However, in daily practice, to treat patients adequately, there is a medical need for drugs that do not hold MA. To meet this medical need, medicinal products are used in clinical care without MA (unlicensed), such as products prepared by (local) pharmacies: the pharmaceutical preparations. Three types of pharmaceutical preparations are distinguished: (i) reconstitution in excess of summary of product characteristics; (ii) adaptation of a licensed medicinal product (outside its official labeling); (iii) medicinal products from an active pharmaceutical ingredient. Although unlicensed, patients may expect the same quality for these unlicensed pharmaceutical preparations as for the licensed medicinal products. To assure this quality, a proper risk-benefit assessment and proper documentation in (centralized) patient registries and linking to a national pharmacovigilance database should be in place. Based on a risk assessment matrix, requirements for quality assurance can be determined, which has impact on the level of documentation of a pharmaceutical preparation. In this paper, the approach for good documentation including quality assurance and benefit-risk assessment will be discussed and possibilities for patient registries are described to make these crucial preparations available for regular patient care. KEY POINTS Ensuring pharmaceutical quality and performing a proper benefit-risk assessment will guarantee safe use of pharmaceutical preparations. Good documentation of (ultra-)orphan treatments can be collected in centralized patient registries and should be combined with existing information in (inter)national databases and self-reflection of patients. Linking patient registries to a centralized database for adverse drug events is highly recommended as it increases safety control of the (ultra) orphan pharmaceutical preparations.

Design and in vitro performance testing of multiple air classifier technology in a new disposable inhaler concept (Twincer) for high powder doses.

Dry powder inhalation of antibiotics in cystic fibrosis (CF) therapy may be a valuable alternative for wet nebulisation, because it saves time and it improves lung deposition. In this study, it is shown that the use of multiple air classifier technology enables effective dispersion of large amounts of micronised powder (up to 25mg). X(50)-values of the aerosol from laser diffraction analysis obtained with the Twincer disposable inhaler concept (containing multiple air classifier technology) are practically the same as that for the pure drug in the range of dose weights between 0 and 25mg. Only for the highest dose weights, a minor fraction (5-7.5%) of small agglomerates (5-15microm) is released from the inhaler. Moreover, the size distribution of the aerosol is practically the same at 1 and 4kPa. Cascade impactor results confirm the good performance of the multiple classifier concept. Unprocessed micronised particles or soft spherical agglomerates can be used, and special particle engineering processes are not necessary. Only a minor fraction of coarse sweeper crystals in the formulation is desired to reduce the total inhaler losses for colistin sulfomethate to less than 5-6% at 4kPa. The classifiers can be designed to retain these crystals with more than 95% efficiency.