Pr Pascal BONNABRY Head of pharmacy

Transcription

1 Hôpitaux Universitaires de Genève Evaluating the risk of aseptic preparations Pr Pascal BONNABRY Head of pharmacy Etre les premiers pour HPE Live, Birmingham vous September 9, 2014 Facts Medication errors kill persons each year in the USA To err is human, 1999 Parenteral medication errors are nearly 3 times as likely to cause harm or death compared with other drugs (3% vs 1.2%) Am J Health-Syst Pharm 2008;65: The high-risk is related to the complexity of the process and the major clinical impact for the patient Risk = probability x consequences 2 1

2 Quizz Frequency of errors during the preparation of injectables in wards? A. 0.5% B. 1% C. 5% D. 10% 4 Preparation errors Simulation study Mean error rate: 6.5% (n=28) 20% 28% 52% Selection errors Dilution errors Quantity errors 5 Garnerin Ph, Eur J Clin Pharmacol 2007;63:769 2

3 Preparation errors Real-life study Unused syringes in anaesthesiology >± 10%: 29% >± 50%: 8% >± 100%: 4% n=500 mean= 114% Atracurium Fentanyl Lidocaine Thiopental 6 Stucki C, Am J Health-Syst Pharm 2013;70:137 Quizz Frequency of microbial contamination of injectables in wards? A. 0.01% B. 0.1% C. 05% 0.5% D. 5% 8 3

4 Microbial contamination Review of published studies Clinical environment 5.0% for individual doses 2.0% for batches Real life 0.5% 2 syringes/day Stucki C, HUG, Austin P, J Pharm Pharmaceut Sci 2009;12:233 How to progress? Implement strategies to Improve the reliability of controls Reduce the frequency of errors 13 4

5 How to progress? Industrializing the preparation of high-alert injectables Standardisation of dilutions and labelling Production under GMP conditions Preparation by batches when possible Quality control even for individualized preparations IT and automation 14 Standardisation of dilutions and labelling Intra-institution (emergency, intensive care, anaesthesiology, acute care) Inter-institution 15 5

6 Production under GMP conditions Risk management Aviation Production Structure Aircraft Cleanrooms, isolator Training Flying licence Production licence Organisation Flight procedures SOP s, protocols,... Documentation Check-list Production files Traceability Black box IT management 17 GMP: improved safety? Suppress opportunities for errors Production protocols and procedures (chemical) Clean environment (microbiological) Specifically trained operators (chemical, microbiological) Intercept errors before they reach patients Quality control (chemical, microbiological) 18 6

7 Chemical risk Deviation >10%: 22% of the ICU manually prepared samples 5% of samples from pharmacy machine-made solutions Mean concentrations: ICU: 97.2% (45 129%) Pharmacy: 101.1% (90 114%) 19 Dehmel C, Intensive Care Med 2011;37: Microbial contamination Review of published studies Clinical environment 5.0% for individual doses 2.0% for batches 20 Pharmacy environment 1.9% for individual doses 0.0% for batches Austin P, J Pharm Pharmaceut Sci 2009;12:233 7

8 Microbial contamination Results of media-fill testing Annual qualification of operators Protocol with 4 production contexts Horizontal laminar airflow hood Vertical laminar airflow hood Cytotoxic BSC III Horizontal laminar airflow hood with BAXA for TPN Qualification of operators From 2004 to sterile samples (0 positive) Risk of contamination < 0.02% Qualification of process 21 Preparation by batches when possible Parenteral nutrition Cytostatics Others, CIVAS Standard formulation (first days of life) 22 Dose-banding Standardized dilutions 8

9 24 CIVAS: developed syringes Stability Qty/yr Phenylephrine 1mg=10mL 1 year (room T ) Suxamethonium 100mg = 10mL 6 months (room T ) Insuline 50UI=50mL 6 months (4 C) Atropine 1mg=10mL 1 year (room T ) Ketamine 10mg=10mL 7 months (room T ) Cefuroxime 5mg=0.5 ml 4 months (-18 C) Vancomycine neonat 50mg=10ml 6 months(4 C) 1000 Caffeine citrate 10mg = 1mL 1 year (room T ) 500 Isoprenaline 5mg=50mL 6 months(4 C) ophtalmic injectables 6 months (-18 C) 100 Ceftazidine 22.5mg=1mL Dexamethasone 4mg=1mL Vancomycine 10mg=1mL Total Quality control even for individualized preparations Quality control mandatory for batches Can also be developed to improve the safety of individual preparations Cytostatics Post-process (at the QC lab) In-process in the future (Raman)? Parenteral nutrition 26 9

10 Analysis of parenteral nutrition Rapid analysis methods are necessary Prescription Analysis Production Patient 27 Parameters analysed Glucose Cations Na K Ca Mg sodium potassium calcium magnesium Endotoxins Sterility (for quality assurance) Cations (K +, Na +, Mg ++, Ca ++ ) Analysis by capillary electrophoresis (CE) mv 60 K + Ca 2+ Na + Mg 2+ Li + signal min time Electropherogram obtained for the CE-C4D analysis of a sample containing sodium, potassium (1 mm), calcium, magnesium (0.5 mm) and lithium (1.25 mm) in an aqueous solution. BGE: 100 mm Tris-acetate at ph 4.5 : acetonitrile (80:20, v/v) 28 Nussbaumer S, J Pharm Biomed Anal 2010;53:130 10

11 Usefulness of parenteral nutrition analysis January 2009 June bags analyzed 63 non-conformity detected ( 1%) Content from 19 to 150% Examples of correctives measures: Re-mix (especially manual additions) Re-production of the bag Reset of the full system 29 IT and automation Documentation and traceability Computer-assisted production management Detecting the occurrence of error Gravimetric in-process control Avoiding the occurrence of errors Automated systems Intel,

12 Gravimetric in-process control Cytostatics (Cato) Batch production 31 Automation Parenteral nutrition (Baxa) Cytostatics (PharmaHelp) CIVAS syringes (Smartfiller) (Kiro, Apoteca, Cytocare, ) 32 12

13 Automation Main objectives Avoid errors (i.e. wrong drug) Increase the accuracy Reduce the inter-operator variability Increase the efficiency, the productivity Improve the traceability 33 Accuracy of a robot for cytostatics 120% 115% 110% Accuracy 105% 100% 95% 90% 85% 80% Volume (ml) Mean ± CI95%, n=54/volume 37 Verrey AS, Carrez L, HUG,

14 Quizz In your context, what is the more difficult objective to reach? A. Standardisation of dilutions and labelling B. Production under GMP conditions C. Preparation by batches when possible D. Quality control even for individualized preparation E. IT and automation 38 Conclusion 39 The preparation of injectables in wards is not reliable (human factors) Producing aseptic injectables at the pharmacy improves the chemical and the microbiological safety, by changing the paradigm (industrialization) A high quality assurance system (GMP) and automation are key factors to optimize the safety 14

15 Thank you for your attention + Info The presentation can be downloaded: 40 Pascal.Bonnabry@hcuge.ch 15