How Tight is a Syringe? PDA: A Global. CCI Case Studies From. Association. Development and Manufacturing. Dr. Derek Duncan Director Product Line

Transcription

1 How Tight is a Syringe? PDA: A Global CCI Case Studies From Association Development and Manufacturing Dr. Derek Duncan Director Product Line

2 Presentation Outline Setting up syringe CCI studies using laser-based headspace as the analytical tool Use of positive controls with known critical defects Monitoring the tightness of a syringe over shelf life Industry case study: 100% inspection of syringe batches 2

3 Presentation objective From the Conference Agenda: These data should stimulate ideas for designing CCI tests for syringes/cartridges and other small volume containers from research through manufacturing. 3

4 Previous syringe CCI work H. Wolf, D. Guazzo, et al, PDA J PharmSci& Technol., 63, 2009, p Three methods compared for detecting critical leaks in syringes: 1) blue dye, 2) HVLD, 3) pressure decay Blue dye did NOT reliably detect leaks down to 5, 10 microns only good for gross leak detection HVLD and Vacuum decay are effective leak detection methods HVLD detected a larger % of potential leaking packages 4

5 Laser-based Headspace for CCI determination RESULT : Increase O 2 levels Increase H 2 O levels Decreased vacuum levels AIR defect

6 Physical closure integrity test Blue dye test Ingress of methylene blue Qualitative visual inspection Destructive method Permanent leaks Useful for gross leak detection Laser-based headspace Ingress of O 2 and/or N 2 Analytical measurement Non-destructive method Permanent and temporary leaks Sensitive to all leak sizes Described by gas flow physics Methylene blue: C 16 H 18 N 3 SCl Diatomic gas molecule: O 2 and/or N 2

7 Headspace oxygen (% atm) O 2 ingress by diffusion through laser drilled holes 1ml Ampoule Oxygen Ingress Defect sizes (microns) time (min)

8 Laser-drilled holes as positive controls Source: Dana Guazzo, presentation Sterile Product Integrity Testing, May 17,

9 Laser-drilled hole study Laser-drilled holes in 1ml glass syringes control 2 µm Syringes purged with nitrogen Oxygen ingress monitored over time (diffusion) 5 µm 10 µm 9

10 Laser-drilled hole study: Determining diffusion rates Find function fit to the diffusion curve O(t) Obtain the function derivative do/dt Enables calculation of the instantaneous oxygen diffusion rate at any point Alternaltively, approximate the initial diffusion with a straight line fit. Initial diffusion rate is the slope. 10

11 Oxygen diffusion rates 2 µm 5 µm 10 µm Avg rates: (mbar L/sec) 2.65 E E E-3 11

12 Oxygen level (% atm) Detecting leaks in adrenaline product syringes Created gross leaks in two syringe samples: At needle end (tip cap removed) Through plunger (punctured with needle) Syringes, leak at needle end vs punctured plunger Punctured plunger obviously bigger leak E-2 : worse than 10 µm 10 5 Needle cap removed Plunger punctured O 2 ingress through needle end is slower Time (min) 6.78 E-4 : between 2-5 µm 12

13 Oxygen level (% atm) Oxidation of the formulation Leak removed by placing tip cap back and removed needle from plunger. Bisulfate in adrenaline solution is oxygen scavenger Both syringes show same rate of O 2 uptake from the headspace 25 O 2 uptake by solution after 'removing' leak Needle cap back in place Needle removed from plunger Time (min) 13

14 Headspace oxygen (% atm) Permeation in syringes stored at RT over the shelf life Four glass syringes filled with water: 2 stored in upright position (needle pointing downwards) 2 stored upside down (needle pointing upwards) Monitored headspace O 2 over time: Filled syringes stored at RT in different positions O 2 diffusion rate orders of magnitude smaller than micron defects More permeation than in a vial (3x) Right side up Upside down 5.37 E E Time (months) 14

15 Comparison CCI leaks to permeation CCI leaks (5, 10, 15 micron) ~1 E-3 Permeation thin wall 1ml plastic ~ 1 E-4 Permeation 1ml glass product syringe ~ 1 E-7

16 Influence of storage temp on permeation 16

17 Permeation dynamics as a function of temperature Samples temporarily taken from room temperature to cold storage conditions 17

18 Industry Case Study: Packaging Dev 18

19 Industry Case Study: Packaging Dev OBJECTIVE Customer had new container and fill process for oxygen sensitive product Product containers had passed blue dye so they were confident CCI was good Asked LIGHTHOUSE to measure samples on-site at customer for verifying low oxygen content immediately after filling 19

20 Headspace oxygen (% atm) Industry case study: On-site measurements Headspace oxygen measurements Samples were prepared a day before LIGHTHOUSE visit. All samples showed atmospheric oxygen. 20

21 Headspace oxygen (% atm) Industry case study: On-site measurements Headspace oxygen measurements Samples were also prepared during visit and measured directly after filling 21

22 Headsapce oxygen (% atm) Industry case study: Follow-up studies at LIGHTHOUSE facility Received samples were at atmospheric levels of oxygen Samples placed in a nitrogen glove box for 4 hours. Initial headspace was air diffusion of oxygen out of the headspace was measured Headspace Oxygen levels after storage in nitrogen rich environment t = 0 t = 1 (app. 4 hours) O 2 egress ~6% oxygen over 4 hours: 1.29 E-2 : worse than 10 µm! 0.0 Sample 1 Sample 2 Sample 3 22

23 Industry Case Study: Packaging Dev Syringe headspace studies ongoing Screw-on tip cap is the suspected leak source Currently trying to isolate the difference oxygen diffusion sources: Tip cap Stopper Plastic body 23

24 Industry case study: 100% PFS inspection 1 ml glass PFS Two filling volumes of a new biological product being launched: 0.5 ml and 1.0 ml Headspace purged with N2 during filling Product specification: < 5% oxygen in the headspace 100% inspection performed on validation batches ~ 80,000 syringes inspected for headspace oxygen content Syringes measured 1 to 3 weeks after manufacture 24

25 Results: 100% PFS inspection 1.0 ml filling volume ~ 50,000 syringes All syringes met < 5% headspace oxygen specification Filling/purging process works and is robust And..all syringes are retaining CCI! 25

26 Results: 100% PFS inspection 0.5 ml filling volume ~ 30,000 syringes Approximately 300 syringes found to be out of spec with headspace oxygen levels in the range 10-15%. Root cause: process or CCI? All out of spec syringes result of process issue Air bubble formation in headspace during filling prevented a N2-purged headspace So again all syringes were retaining CCI! 26

27 Results: 100% PFS inspection Stability samples were monitored over the shelf life After two years, headspace oxygen levels from < 5% to 12 15% due to permeation Product stability was demonstrated to still be good 27

28 Managing the risk of CCI failure Zero failures in CCI validation studies Packaging components CCI validation Generate CCI data during scale up, process validation When package is introduced into process, is closure maintained? Zero failures over product shelf life CCI monitoring over the product shelf life Statistical CCI inspection of commercial product samples Is process kept under control well enough to robustly maintain CCI? 28

29 How tight is a syringe? Hopefully this presentation has given some first answers to this question. More importantly..hopefully this presentation has given you ideas for packaging study designs that will give insight into your current syringe and small container CCI questions. 29

30 Thank you for your attention! 30