Selecting and Verifying Integral Packaging Systems for Injectable Drug Products West Pharmaceutical Services, Inc., Kristine Davidson, Technical Account Specialist, Jessica Mangus, Project Specialist Introduction: Containers for pharmaceutical products must be appropriate for their intended use. One of the most important aspects in choosing a container closure system for parenteral drug products is to ensure an ideal fit between all components to maintain product sterility. During drug product package development, a variety of studies can be performed to support final assembly operations and regulatory filing requirements. Each component material, with its critical dimensional tolerances and physical characteristics, directly affects the intended integrity of the final packaged product. Assurance of package integrity originates from the use of appropriate materials, matching dimensional fit, consistent control of processes and accurate closing parameters used to assemble the final package. There are a combination of variables to be considered when evaluating components, for example, stopper formulations and configurations, glass vial blowback feature and stopper processing (washing and sterilization). The seal quality evaluation was completed based on initial dimensional exercises along with container closure integrity testing for the i) presence of a leak, ii) package leak rate and iii) seal integrity vs time. Data is presented to show evidence of the system fit, acceptable capping pressure, potential for microbial ingress and ability to maintain packaging headspace over time. Objective: To evaluate the fit of different components using a systematic approach ranging from initial qualitative visual and paper-based assessments to quantitative testing. Drawing on the recent proposed revisions to United States Pharmacopeia Chapter <1207> Sterile Product Packaging - Integrity Evaluation1, this study looked at different methodologies that could be used during package development to determine suitability of a container for its potential drug product. The results from these types of initial evaluations will give insight to help drive further testing throughout the phases of component selection (e.g. manufacturing and drug product stability). Samples and Testing The stopper and vial configurations selected for this study are based on currently accepted recommendation practices for the market today. Study #1: Interference Fit Interference fit is the evaluation of the stopper plug diameter with the inner neck diameter of the glass vial. This assessment provides an initial understanding of the amount of rubber in contact with the vial. Too much interference between the stopper and vial could indicate risk of stopper pop out, while not enough could lead to a leak in the package. For example, if the nominal plug diameter of a 20 mm serum stopper is 12.954 mm and the inner neck diameter of the vial is 12.6 mm, the interference with the vial can be calculated, as shown in Table 1. Study #2: Stack Up Assessment A stack up assessment evaluates the appropriate aluminum seal skirt length needed for an acceptable crimp to a vial. = {(mean skirt length-aluminum thickness)-(vial crown height +(flange thickness X percent compression))} Stopper G has a flange thickness of 3.30 mm. The aluminum seal thickness is 0.2032 mm. The vial crown height is 3.6 mm. For this case, the percent compression assumed is 20%. (7.5 mm-0.2032 mm)-(3.6 mm+(3.30 mm X 0.80))= 1.1 Results: In general, an excess seal skirt length of approximately 0.76 mm or greater is required for an acceptable crimp on a vial. Less than 0.76 mm could lead to inadequate material to provide a sufficient crimp leading to potential loss of product sterility. For this study, all stoppers had the same durometer (hardness of material) and the appropriate aluminum seal was used; if a softer rubber was used, a shorter skirt length may have been required. The calculation for this assessment does not take into account the durometer of the stopper. The next study evaluates the visual fit of the different blowback features on both the stopper and vial, since the measurements cannot indicate potential for the seal to be comprised. Study #3: Visual Assessment The fit of the stopper and vial configurations were evaluated visually; the main point of focus was around how the plug of the stopper interacted with the blowback feature of the vial. The methodology used for this section was adapted from a PDA Journal of Pharmaceutical Science and Technology article, “Visualization Techniques for Assessing Design Factors That Affect Interaction Between Pharmaceutical Vials and Stoppers.”2 Results: The interaction of the blowback features on the vial and stopper create gaps between the glass surface of the vial and the stopper plug. The impact, if any, of the presence of these gaps need to be further analyzed through quantitative test methods. Based on the visual and dimensional assessment, the 12 different combinations of stoppers and vials in Table 2 were used to perform the quantitative container closure integrity testing. Each combination was selected as a bracket representing the range of fit visually and dimensionally. The range in the brackets represent combinations with minimal amount of gaps and spacing between vials and stoppers as well as those that demonstrated the least amount of contact based on sealing surfaces in Picture 1. Picture 1: Primary and Secondary Sealing Table 1: Interference Fit Examples Picture 2: Serum Stopper Stopper Plug Diameter Vial Inner Neck Diameter 1% 2% 3% 5% Actual % Combination D 13 mm Lyo and No Blowback 7.60 mm 7.00 mm 7.52 mm 7.45 mm 7.37 mm 7.22 mm 8% Combination E 13 mm Lyo and EU Blowback 7.67 mm 7.00 mm 7.59 mm 7.52 mm 7.29 mm 9% Combination H 20 mm Serum and EU Blowback 12.954 mm 12.6 mm 12.82 mm 12.69 mm 12.57 mm 12.31 mm 3% Combination G 20 mm Serum and No Blowback 13.2 mm 12.6 mm 13.07 mm 12.94 mm 12.80 mm 12.54 mm 5% 7.44 mm Graph 5: Percent Oxygen in Headspace for 20 mm Stoppers Excess Skirt Length Calculation: Results: The general principle is to target approximately 3-5% interference between the stopper and vial, for lyophilization stoppers the percentage is slightly lower. The 13 mm lyo stoppers exceed the targeted recommendation for percent interference. Therefore, this calculation alone cannot give a complete indication to ideal fit and does not take into account the different blowback features. Theoretical Interference Fit Graph 2: Percent Compression versus Residual Seal Force for 20 mm Stoppers Picture 3: Lyo Stopper 3 Helium Leak Testing3 Helium leak testing was performed to quantitatively evaluate the capping parameters for each of the compression levels. The test measures actual percent of helium filled in the vial along with the rate of helium leak from the vial. Table 2: Sample Combinations tested in Studies #4 and #5 Combination Vial Finish Polymer Type A 13 mm Serum No Blowback Bromobutyl B 13 mm Serum, FluroTec Stopper Size/ Type US Blowback Chlorobutyl C 13 mm Serum EU Blowback Chlorobutyl No Blowback Bromobutyl D 13 mm Lyo E 13 mm Lyo, FluroTec EU Blowback Chlorobutyl F 13 mm Lyo, FluroTec US Blowback Bromobutyl G 20 mm Serum No Blowback Bromobutyl H 20 mm Serum EU Blowback Chlorobutyl I 20 mm Serum, FluroTec US Blowback Bromobutyl J 20 mm Lyo No Blowback Bromobutyl K 20 mm Lyo, FluroTec US Blowback Bromobutyl L 20 mm Lyo, FluroTec EU Blowback Chlorobutyl Results: The data from this testing supports optimal capping parameters for each sample combination. A suitable combination is one that demonstrates the least likely risk for microbial ingress. Graph 3 represents capping parameters of the 20 mm stopper and vial combinations based on plotting residual seal force versus helium leak rates. The graph correlates the optimal percent compression to those with a residual seal force between 10 to 15 pounds of force. Graph 3: Helium Leak Rate Versus Residual Seal Force for 20 mm Stoppers Discussion The five analyses represent the thoughtful and thorough process steps to evaluating a packaging system that is designed to build assurance of integrity throughout the product lifecycle. Not a single evaluation used gave a complete picture to the type of packaging combination that would perform the best. The impact of capping parameters and assembly affect how the components interact together and this cannot be evaluated solely by interference fit, stack up calculations and visual assessments. The focus should be choosing quantitative test methods which qualify that a packaging system functions appropriately and meets the requirements needed by the drug product it contains. Helium leak testing serves as an appropriate quantitative test method for evaluating capping parameters. However, when analyzing the stability of those packaging characteristics over time, laser based headspace analysis may be a more suitable approach. The understanding and recognition of the targeted use of each of these methods for packaging selection allows for the most meaningful and useful evaluations. The samples in this study were assembled and tested under optimum conditions to illustrate the critical factors to consider as an initial, first pass approach. The results generated provided evidence that the different stopper configurations and vial blowback features are capable of maintaining an integral seal. Additional steps would be needed to determine suitability for the specific drug product being packaged along with larger scale manufacturing conditions. Conclusion Study #4: Capping Analysis Sufficient compression is essential for seal integrity. A capping study was performed in collaboration with Genesis Packaging Technologies, as the first stage to evaluate the stopper, vial, seal combinations and ensure they represent an integral packaging system. Each of the combinations were assembled and capped using three different levels of compression. In order to determine and verify the targeted percent compression of each combination, the samples were tested initially and 48 hours after capping for residual seal force. The integrity of the capping parameters chosen were further evaluated by helium leak testing. Residual Seal Force Residual seal force was measured in conjunction with capping to verify the forces of the compressed stopper on the neck of the vial. This measurement allows a pharmaceutical manufacturer to evaluate the consistency of the force. Results: The more the stopper is compressed, the greater the force exerted on the glass vial by the stopper flange. This results in an increased residual seal force value with increased percent compression of the stopper. Graphs 1 and 2 provide representative results of the combinations by plotting the different percent compression values from the capping versus the residual seal force measurements. Graph 1: Percent Compression versus Residual Seal Force for 13 mm Stoppers Study #5: Stability and Critical Headspace Non-destructive, laser-based frequency modulated spectroscopy (FMS) analysis4 performed using Lighthouse Instruments FMS-760 Headspace Oxygen Analyzer measured changes in the internal headspace of vials using the optimum capping conditions established in Study #4. The vials were capped at atmospheric conditions then placed in nitrogen chambers for four weeks. The level of oxygen in the atmosphere is typically 20% and was measured at three different time points, time zero, two weeks and four weeks. Laser drilled vials of known, targeted leak sizes served as positive controls. This demonstrated that the storage conditions would allow for ingress of nitrogen gas and the resultant change in oxygen concentration in the vial head space was capable of being detected. Results: All positive controls tested showed a significant decrease in the percent oxygen in their vial headspace. This indicated that leaks within a range of 1µm to 25 µm would be detected. Based on the data in Tables 3 and 4, all sample combinations show no sign of nitrogen ingress over four weeks. Graph 4: Percent Oxygen in Headspace for 13 mm Stoppers The studies above have shown there is not a single assessment to ensure an integral packaging system. The evaluation of packaging systems is a step wise approach to ensure that the components work together and meet the requirements of the system over time. A thorough understanding of the components fit and function along with their critical characteristics will ensure container closure integrity over the product lifecycle. Next Steps This study evaluated a few common parameters to consider when beginning the selection of primary packaging components. Future studies will include evaluating variables that exist and understanding their impact to container closure integrity. Further evaluation is needed to understand the following: 1. Rubber formulations, polymers and ingredients 2. Extreme storage conditions, e.g. cryogenic storage 3. Dimensional and lot to lot variability 4. Vacuum Retention prior to capping Acknowledgements Roger Asselta, Genesis Packaging Technologies, Exton, PA Dave Markoch, Genesis Packaging Technologies, Exton, PA Barbara Jacobs, West Analytical Labs, Exton, PA Tom Millner, Lighthouse Instruments, LLC, Charlottesville, VA Florence Buscke, Schott Mainz, Germany References 1. <1207> Sterile Product Packaging-Integrity Evaluation; United States Pharmacopeia, PF 40 Pharmacopeial Forum, Inc. Rockville, MD 2. Lam, P., Stern, A. (2010). “Visualization Techniques for Assessing Design Factors That Affect Interaction Between Pharmaceutical Vials and Stoppers,” PDA J Pharm Sci and Tech, pg. 64, 182-187. 3. Container/Closure Integrity of Parenteral Vials, PDA J Pharm Sci and Tech, 41, 145-158 4. West Analytical Test Method, Selblty-12 Rev 5 Helium Leak Testing on Pharmaceutical Packaging 5. Lighthouse Instrument Measurement Services SOP 10G-00-0004 FluroTec®, and West and the diamond logo are registered trademarks of West Pharmaceutical Services, Ltd., in the United States and other jurisdictions. FluroTec® technology is licensed from Daikyo Seiko, Ltd. 9029