In-Use Stability of Biological Parenteral Products:

Transcription

1 In-Use Stability of Biological Parenteral Products: Aspects of physicochemical and microbiological stability after container penetration, reconstitution, dilution and hold time University Medical Center, Pharmacy Department Prof. Dr. Irene Krämer

2 Aseptic preparation of parenterals in hospital pharmacy Apotheke, Prof. Dr. I. Krämer

3 Aseptic Preparation of Parenterals in Hospital Pharmacies Preparation (Ph. Eur. 7.7) the manufacture of the unlicensed pharmaceutical preparations by or at the request of pharmacies or other health care establishments Reconstitution (CM ResAP 2011) Manipulation to enable the use or application of a medicinal product with a marketing authorisation in accordance with the instructions given in the SPC or the patient information leaflet Perferably in the pharmacy

4 Specialties in preparation/reconstitution of ready-to-use Parenterals Continuous preparation of single or unit doses (batch?) Medicinal product with a marketing authorisation, sterile containers and sterile devices used (Semi)Manual or robotic preparation Preparation in closed systems Limited shelf life Internal supply

5 In use stability EMEA Note for Guidance CPHP/QW/159/96 on maximum shelf life for sterile products for human use after first opening following reconstitution «Chemical and physical in use stability has been demonstrated for x hours/days at y C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 C, unless reconstitution / dilution (etc) has taken place in controlled and validated aseptic conditions»

6 Shelf life according to SMPC (EMA) Example of a monoclonal antibody product Mab The Mab

7 Important issues of GPP in hospital pharmacies Aseptic preparation in Class A environment Controlled environment Class B or C Clothing Cleaning and desinfection Environmental monitoring in operation Process validation by media fills Daily microbiological quality control tests Expiration dating based on physico-chemical and microbiological stability

8 Physicochemical and microbiological quality of ready-to-use parenteral products

9 Physicochemical stability of Proteins

10 Microbiological Stability of Parenterals Sterility or resistance to microbial growth Microbiological degradation = contamination with microbes, microbial growth Microbiological contamination risk = cumulative function of risk factors Type and complexity of preparation Environmental cleanliness Closed systems Operator s knowledge, skills, reliability, responsibility Higher risk for microbial contamination caused by contact contamination than by airborne contamination

11 Antimicrobial activity of antineoplastic drug solutions Declining of CFU over time caused by exhaustion of nutritive substances Lack of antimicrobial activity of most cytotoxic drug substances and drug products No antineoplastic drug solutions with growth promotion activities (including folinates, MABs) Endproduct sterility testing possible by direct transfer of a sample aliquot into sterile culture media (e.g. Bactec blood culture system, aerobic and anaerobic vials)

12 Viability of microorganisms in diluted Trabectidin (Yondelis ) Solution Apotheke, Prof. Dr. I. Krämer Trabectidin mg/ml and 0.9 % NaCl vehicle solution Sarakbi I, Federici M, Krämer I. Viability of micro-organisms in novel chemical and biopharmaceutical anticancer drug solutions 2014, submitted for publication

13 Viability of microorganisms in nab-paclitaxel (Abraxane ) 5 mg/ml Suspension Sarakbi I, Federici M, Krämer I. Viability of micro-organisms in novel chemical and biopharmaceutical anticancer drug solutions 2014, submitted for publication

14 Viability of microorganisms in Aflibercept (Zaltrap ) 1,2 mg/ml Solution 1.2 mg/ml in 0.9 % NaCl solution Sarakbi I, Federici M, Krämer I. Viability of micro-organisms in novel chemical and biopharmaceutical anticancer drug solutions 2014, submitted for publication

15 Viability of P. aeruginosa in Biological Parenteral Products Drug/ Control Solution P. aeruginosa (CFU log/ml) Apotheke, Prof. Dr. I. Krämer 0 h 1 h 3 h 5 h 24 h 48 h 144 h 0.9% NaCl % Dextrose Aflibercept Brentuximabvedotin Ofatumumab Ipilimumab Panitumumab

16 Viability of S. aureus in Biological Parenteral Products Drug/ Control Solution S.aureus (CFU log/ml) Apotheke, Prof. Dr. I. Krämer 0 h 1 h 3 h 5 h 24 h 48 h 144 h 0.9% NaCl n.a. 5% Dextrose Aflibercept Brentuximabvedotin Ofatumumab Ipilimumab Panitumumab

17 Specialties in preparation of extemporaneous ready-to-administer parenterals Statistics adopted to batch production not applicable Destructive quality controls of finished products not applicable Content, purity testing of finished products mostly not applicable before use Sterility testing and endotoxin testing not applicable before use Aliquots withdrawn from dummy solutions transferred to blood culture bottles for sterility testing in parallel to use High relevance of process validation Quality is to be ensured by the process

18 Media-fill simulation tests - manual preparation Day of preparation LAF 1 LAF 2 n of preparations [n] Turbidity (after 14 days) Turbidity (after 4 weeks) 1 24 (1-24) 24 (1-24) 48 None None 2 24 (25-48) 24 (25-48) 48 None None 3 24 (49-72) 24 (49-72) 48 None None 4 24 (73-96) 24 (73-96) 48 None None 5 36 (97-132) 48 (97-144) 84 None None 6 36 ( ) 24 ( ) 60 None None 7 24 ( ) 24 ( ) 48 None None 8 24 ( ) 24 ( ) 48 None None 9 24 ( ) 24 ( ) 48 None None ( ) 10 ( ) 20 None None Krämer I, Federici M, Kaiser V, Thiesen J. Media-fill simulation tests in manual and robotic aseptic preparation of ready-to-use cytotoxic injection solutions 2013 submitted for publication

19 Media-fill simulation tests during robotic preparation in APOTECAchemo n of Day of preparation Batch n n of preparations [n] Turbidity (after 14 days) Turbidity (after 4 weeks) preparations inoculated with S. epidermidis Turbidity (after 14 days) [n] 1 1 (1-63) 63 None None 3 All 2 2 (64-125) 62 None None 3 All 3 3 ( ) 63 None None 3 All 4 4 ( ) 63 None None 3 All 5 5 ( ) 62 None None 3 All 6 6 ( ) 62 None None 3 All 7 7 ( ) 63 None None 3 All 8 8 ( ) 62 None None 3 All Krämer I, Federici M, Kaiser V, Thiesen J. Media-fill simulation tests in manual and robotic aseptic preparation of ready-to-use cytotoxic injection solutions 2013 submitted for publication

20 Environmental monitoring during manual media-fill simulation tests Settle plates Contact plates Fingerprints [CFU/24 cm²] [CFU/24 cm²] [CFU/5 fingers] Position WB 1 WB 2 WB 1 WB 2 T1R T1L T2R T2L Day Day Day Day Day 5 n.a. n.a. n.a. n.a. n.a. n.a. 2 2 Day n.a. n.a. 4 0 n.a. n.a. Day n.a. 0 n.a. n.a. 0 6 Day Day Day 10 n.a. 0 n.a. n.a. n.a. n.a. 1 3 Mean

21 Fig. 3

22 Environmental monitoring in ApotecaChemo during media fills Apotheke, Prof. Dr. I. Krämer Syringe holder Suction device Robotic arm balance Carousel Loading area Monitor Krämer I, Federici M, Kaiser V, Thiesen J. Media-fill simulation tests in manual and robotic aseptic preparation of ready-to-use cytotoxic injection solutions 2013 submitted for publication

23 Environmental monitoring during automated (APOTECAchemo ) media-fill simulation tests Settle plates Contact plates Fingerprints [CFU/24cm²] [CFU/24cm²] [CFU/5 fingers] Position L1 C2 W3 L1 W2 W3 W4 W5 T1R T1L T2R T2L Day Day Day Day Day Day Day Day Mean CFU=colony forming units, L=loading area, C=carousel, W=working area, T1R/T2R= technician 1 or 2, right hand, T1L/T2L= technician 1 or 2, left hand

24 Balanced Risk Assessment Apotheke, Prof. Dr. I. Krämer

25 Proposals for shelf lives of ready-to-use parenteral preparations If physicochemical stability is proven and Sterility testing not feasible before use USP <797> : Low risk level Compounded Sterile Product RT: max. 48 h, 2-8 C max. 14 d, -20 C max. 45 d USP <797>: Medium risk level Compounded Sterile Product RT: max. 30 h, 2-8 C max. 7 (9) d, -20 C max. 45 d If preparations passed sterility tests according to physico-chemical stability under defined storage conditions

26 Time for Questions and Discussion

27 I.V. Admixture Contamination Rates Thomas et al. Am J Health-Syst Pharm 2005: Contamination rates reported under different conditions 0% to 14.5% Test setting: Medium-risk compounding of simulated product media fills in a LAF in non-classified room versus a LAF in class 1000 = ISO Class 6 cleanroom Samples tested: 2000 per site and person (100 per run) No significant difference in the contamination rates of products prepared in different sites (p=1.0) Significant difference in the contamination rates of products prepared by different operators (p=0.012) Operator most important variable affecting microbial contamination

28 I.V. Admixture Contamination Rates Stucki et al. Am J Health-Syst Pharm 2009: Microbial Contamination of syringes during preparation Test setting: Simulated media fills of syringes in 3 different environments (LAF in Class 6 cleanroom, operating room, ward) and 5 manipulations (simple filling, air introduced into syringe, syringe without cap, syringe tip in contact with fingers, syringe tip in contact with object) Samples tested:100 per site and manipulation (total 1500) Microbial contamination correlates with the rate of environmental contamination and the occurance of high risk manipulations Airborn contamination is rare, high contamination rates (11%, 23%) after touch contact with non-sterile surfaces

29 CM/ResAP(2011) Ph. Eur. 7.0 Preparation and Reconstitution Preparationes Pharmaceuticae Draft monograph High risk preparations EU GMP Guide Low risk preparations PIC/S PE GPP Stock preparations approved/not approved Extemporaneous preparations

30 Microbiological Contamination of 10% Amino acid solution Specific strains of Enterobacter cloacae and E. hermanni were not identified in the cleanroom area or pharmacy staff Up to 10 7 bacteria/ml no turbidity Simulation tests in 10% amino acid solution with Enterobacter cloacae High concentrations of bacteria and endotoxins not measured only after 24 hours Low level contamination = long lag time High concentrations of bacteria remain over months

31 Bhakdi, Krämer et al. Med Microbiol Immunol 2012; 201:231-7

32 Microbial contamination risk Cumulative function of risk factors Type and complexity of preparation Environmental cleanliness Hygiene Closed systems Operator s knowledge, skills, reliability, responsibility Higher risk for microbial contamination caused by contact contamination than by airborne contamination

33 CM/ResAP (2011)1: Closed system Closed-system procedure for sterile medicinal products: a procedure whereby a sterile medicinal product is prepared by transferring sterile starting materials or solutions to a presterilised sealed container, either directly or by using a sterile transfer device, and without exposing the solution to the external environment (such as intravenous infusion services: services for cytotoxic medical products or total parenteral nutrition (TPN)).

34 Good Stability Testing A. Bardin et al Guidelines for the practical stability studies of anticancer drugs: A European consensus conference Annales Pharmaceutiques Françaises 2011; 69: Williams LA, Hastings MB Identifying the criteria of a valid stability study. Int J Pharm Compound 2009;13:32-6. Vigneron J Stability studies: ten pieces of advice EJHP Sci 2008;14:2