Infusion Kit compatibility James Baker - CHAOTIC 2 nd November

What do we do Kit compatibility is performed to check that the formulation does not adsorb to the infusion apparatus. For AZ and contracted out AZ studies we use the lowest flow rate, for the duration of the infusion on the study, using the lowest concentration in the formulation method. This is used for all dog, monkey and rat infusion systems studies. (Worst case scenario) Study conducted using the same infusion kit as on the study. If a maintenance flush is used this is performed first, prior to the infusion starting. Samples are collected at appropriate intervals and analysed for loss of concentration. Compatibility confirmed if the initial formulation is ±10% of theoretical and the % difference after infusion is ≤5%. 2

Infusion Kits |3

Example infusion problem We had a new formulation ( 10% Kleptose ®, 4.5% w/v sodium chloride in WFI) and AZDXXXX. We performed a 2 hour infusion, 2mL/kg on a 0.05mg/mL formulation for use on a MTD dog study Hour 0-165% initial Hour 1-257% initial The infusion system consisted of a PEGA bag, PEGA tube, interlink and catheter. Infusion bag contents was then analysed and found to be 39% of initial. This was after about an hour left in the lab at room temperature after the 2 hour infusion. Investigated, and was not an analytical dilution problem or recovery during analysis. 4

Interim conclusion Formulation was adhering to the infusion system. Assumed to be the bag, could it be the material? Change the bag (not PVC)? The bags for our infusion systems are not available in different materials (e.g. polyurethane). Does this happen for a 0.5mg/mL concentration (the top concentration for the method)? Repeat the compatibility in duplicate and also singularly on the infusion line using a syringe to investigate if the formulation adheres to the infusion line. 5

Compatibility with 100mL bags Result for syringe line at 120mins was a sample taken from the remainder in the line 6

Results from infusion Appears that sticking is occurring in the infusion line and the 100mL bag. Study director contacted. Results low but after delivering 7mLs the results became stable. Dose to be altered by flow rate, 20 min flush to waste in the lines prior to dosing starting. Experiment to be re-run at 2 flow rates (2mL/kg/hr & 10mL/kg/hr). 7

Flow rates 8

Results from flow rates Results were satisfactory, doses were low but consistent at the 2mL flow rate. Noted that at the higher flow rate less compound was being adsorbed. Suggestion to use a larger bag volume to reduce the surface area/mL ratio. 9

Compatibility performed on 300ml bag 10

Results from 300mL bag 300mL bag gave better results. Stability in the bag to be evaluated for 100mL and 300mL bags. 11

Stability in 100 and 300mL bags 12

Conclusion on analytical investigation Changing to a 300mL bag has improved the compatibility result by approximately 2%. Stability also improved by 1 day for RT. Stability improved by using large bags - 3% loss for 2-8°C compared to 5% loss at 2-8°C for 100mL bags. For the study samples to be taken after the flush and again after the 2 hour infusion for analysis and TK’s corrected for actual concentration delivered. (no significant change was noted). 13

Pre and post analysis samples (% of initial) 300mL bag Animal pre to post (max 3% change) Animal pre to post (max 3% change) Animal pre to post (max 2% change) Animal pre to post (max 2% change) 14

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Can of worms? Do we need extra room temperature stability. Stability required in bags/syringes at 2-8C as a real time stability e.g. cycle from RT (formulation) to 2-8C (storage) to RT(Acclimatising before dosing) to 37C (in jacket)? Stability at body temperature if an extended study e.g. 4 hrs? How long to leave a formulation in a dosing line before dosing? Saline precipitation / precipitation with flush vehicles? Use of Heparin. Are inline filters are present in the infusion system? 16