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Stopper “Pop-Up” and the Effects on Container Closure of Sterile Vials

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Stopper “Pop-Up” and the Effects on Container Closure of Sterile Vials LIGHTHOUSE The Science of Pharmaceutical Manufacturing Application Note 101 Stopper “Pop-Up” and the Effects on LIGHTHOUSE The Science of Pharmaceutical Manufacturing Container Closure of Sterile Vials LIGHTHOUSE Application Note 101 The Science of Pharmaceutical Manufacturing Stopper “Pop-Up” and the Effects on Container Closure of Sterile Vials Introduction Container closure integrity plays an impor- Prior to sealing finished vials at the end of sec- tant role in maintaining the stability and ondary drying, a lyophilization chamber is sterility of lyophilized products. The in- backfilled to a gas pressure that is specified for creased number of biological products com- the vial headspace. The specified headspace ing to market and the need to extend product pressure varies from product to product. Typi- shelf life has driven the growth of lyophiliza- cally, freeze dried products are stoppered at ei- tion capacity worldwide. Lyophilization is a ther full vacuum (0 mbar absolute pressure) or complex process that presents many manu- partial vacuum (typically 750 mbar absolute facturing challenges one of which is main- pressure). The vacuum level serves the practical taining and monitoring container closure purpose of helping to seat the stopper and to integrity. Recent attention to package integ- facilitate reconstitution. Once equilibrium is rity issues can be seen in both the revised achieved, the gas pressure in the vial headspace aseptic processing guidance from the regula- matches the chamber pressure and the shelves tory agencies (for example, Annex 1 revisions are lowered to seat the stoppers into the vial. At to the European Guidelines for the Manufac- this point the vial closure integrity is estab- ture of Sterile Products) and an increasing lished but not considered complete until the number of package integrity related product aluminum overseal is applied. Once the shelves recalls. Concerns over the number of custom- are raised, the seal integrity must be main- er complaints and the cost of investigations tained for a period of time ranging from min- and recalls has motivated investment in utes to hours to possibly days before unloading container closure inspection systems by the and capping occur. It is possible during this industry as a means of building quality into time for stoppers to “pop-up” allowing gas in- manufacturing operations. gress into the vial headspace. Stoppers can pop up due to a number of reasons including im- LIGHTHOUSE The Science of Pharmaceutical Manufacturing 1 LIGHTHOUSE Application Note 101 The Science of Pharmaceutical Manufacturing proper seating during shelf lowering, out of pressure rises which may impact the ability to specification stopper and/or vial flange dimen- reconstitute the product and would likely re- sions, and stopper coatings. sult in a customer complaint. Second, if the product is oxygen sensitive then air ingress will If seal integrity is lost during this time period result in oxygen exposure and potentially im- then the physical properties of the headspace pact the product stability. Third, if container (gas pressure and/or composition) will change closure integrity is breached then sterility can as gas from the ambient environment outside no longer be assured. the vial ingresses into the vial headspace. Two common situations serve to illustrate the point. In-process monitoring systems, based on laser If the vial is exposed to a nitrogen atmosphere, absorption spectroscopy, now exist that can for example prior to unloading from the freeze nondestructively monitor each vial for changes dryer, then nitrogen gas will enter the head- in the headspace gas composition and pressure. space causing the pressure to rise. If the vial is These systems are in routine use in the industry exposed to an air atmosphere, either because for inspecting container closure integrity in the chamber was vented with sterile air or be- freeze dried product and, in particular, for ad- cause the vial was exposed to room air prior to dressing the stopper pop-up issue. capping, then air will ingress into the vial caus- ing both the pressure and the oxygen concen- Measurement method tration to rise. The practical implications of lost Laser absorption spectroscopy is a nondestruc- seal integrity are threefold. First, the headspace tive method for monitoring pressure, oxygen Container Figure 1. Overview of nonde- (Tubing, Molded, Clear, Amber) structive headspace mea- surement method Laser Detector diode LIGHTHOUSE The Science of Pharmaceutical Manufacturing 1 2 LIGHTHOUSE Application Note 101 The Science of Pharmaceutical Manufacturing and moisture in the headspace of parenteral changes in the headspace condition of a grossly containers. The method was first introduced to leaking vial occur within minutes. A micro-leak the pharmaceutical industry in the late 1990’s (< 1 micron) will exhibit detectable changes in and has been adopted and validated by compa- the headspace after a few hours to a few days de- nies around the world for both sterile develop- pending on the initial headspace conditions. ment and manufacturing applications. Both headspace pressure rise and oxygen in- Container closure integrity in particular can be gress can be nondestructively monitored by la- monitored nondestructively by headspace gas ser absorption spectroscopy. analysis. Changes in the gas pressure or gas composition are leak indicators. For vials stop- Systems for nondestructive headspace analy- pered under vacuum, a leak causes a rise in sis using laser absorption spectroscopy are headspace pressure towards atmospheric lev- configured as shown in Figure 1. Laser light els. For vials stoppered at or near atmospheric passes through the headspace of a vial and the pressure and exposed to air, a leak causes oxy- laser wavelength is tuned to match the absorp- gen ingress into the vial headspace. The leak tion wavelength of oxygen at 760 nanometers rates that result in pressure rise or oxygen in- or moisture at 1400 nanometers. Oxygen con- gress are dependent on vial volume and pressure differ- Figure 2. Headspace ential. In general the head- inspection systems incorpo- rating the laser measure- space pressure and oxygen ment technology concentration of small vol- ume parenterals (e.g. 3-10mL) packaged under vacuum rise more quickly than the head- space pressure and oxygen concentration of large vol- ume parenterals packaged near atmosphere. Detectable LIGHTHOUSE The Science of Pharmaceutical Manufacturing 3 LIGHTHOUSE Application Note 101 The Science of Pharmaceutical Manufacturing centration is proportional to the amplitude of tions or in-process monitoring of small the laser absorption signal and total gas pres- (<5000) batches of containers. Automated sure is proportional to the width of the laser systems are configured for 100% inspection ap- absorption signal. Systems are calibrated us- plications when batch sizes are large. ing NIST traceable standards with known pres- sure and oxygen concentration. Case study 1 In the case studies described below non-de- The first case study involves an investigation of structive headspace gas analysis systems from container closure integrity for an oxygen sensi- LIGHTHOUSE were used to monitor container tive lyophilized product stoppered with a ni- closure integrity for commercial batches of ly- trogen headspace near atmospheric pressure ophilized product. Systems, shown in Figure 2, (800 mbar). A number of vials from a com- can be configured for manual operation or in- mercial batch showed elevated levels of oxygen line automated operation. Manually loaded during routine QC analysis using a destructive systems are useful for conducting investiga- oxygen analysis method. A decision was made 12 12 10 10 8 8 6 6 4 4 2 Headspace Oxygen (%) 2 Headspace Oxygen (%) 0 0 0 50 100 150 200 250 0 50 100 150 200 250 Sample # Sample # Figure 3. Headspace oxygen content of vials located Figure 4. Headspace oxygen content of vials located in zones 4-6. Vials from this location in the freeze in zones 1-3. Vials in these locations show air ingress dryer showed no evidence of stopper pop up. due to stopper pop-up. LIGHTHOUSE The Science of Pharmaceutical Manufacturing 4 LIGHTHOUSE Application Note 101 The Science of Pharmaceutical Manufacturing to test the entire batch using nondestructive head- sure integrity of two different vial stopper combina- space oxygen analysis. tions under actual in-process conditions. The same A LIGHTHOUSE FMS-Oxygen Headspace Analyzer was vial was evaluated with a grey butyl and a teflon coat- used to test the entire batch for the presence of oxy- ed stopper. The lyophilized product was specified to gen in the vial headspace. Vials with greater than 1% be stoppered at 414 torr (550 mbar) of nitrogen. The oxygen were to be rejected. study evaluated each vial stopper combination for Figure 3 shows the headspace oxygen concentration its ability to hold vacuum. The study used 1000 prod- in vials of freeze dried product that have maintained uct filled vials (500 with each type of closure) distrib- seal integrity. The headspace oxygen levels are all be- uted over 8 shelves (4 shelves with each type of clo- low 1%. Figure 4 shows a very different situation for a sure). set of vials from the same batch of product. One dif- Figure 5 shows the headspace pressure in vials of ference between the two sample sets was their physi- freeze dried product stoppered with a grey butyl cal location inside the lyophilizer. In Figure 4 over elastomeric closure at 414 torr (550 mbar). All of 10% of the vials have lost seal integrity as evidenced by headspace oxygen levels ranging from 1.5% to 10%. 75It0 is Nitrogen Headspace Pressure believed that the root cause of the container closure700 Product samples using rubber butyl stoppers integrity failures was due to stoppers not properly650 750 seated when the lyophilization chamber shelves were600 700 Shelf5 550 650 Shelf6 lowered. This allowed air to ingress at different rates Shelf7 Shelf8 600 UpperSpecification (650 Torr) 500 Target (413.7 Torr, 8psia) resulting in oxygen concentrations over a broad LowerSpecification (350 Torr) Shelf5 550 Shelf6 450 Shelf7 range.
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