การทดสอบความสมบูรณ์ของแพ็คเกจนั้น เราสามารถกำหนดความสามารถการป้องกันในการสูญเสียของบรรจุภัณฑ์ได้ และยังช่วยรักษาผลิตภัณฑ์ให้ปราศจากเชื้อต่าง ๆ ได้ และในบางกรณีการป้องกันการเข้าออกของก๊าซออกซิเจนหรือรักษาแรงกดดันของพื้นที่ว่างในชั้นบรรยากาศในแพ็คเกจ การตรวจสอบคุณสมบัติของความสมบูรณ์ของบรรจุภัณฑ์จึงแยกออกเป็นตัวอย่างของการรั่วและไม่รั่ว และช่วยให้การตรวจสอบของวิธีการทดสอบเป็นไปอย่างถูกต้องและการทดสอบที่ง่ายมาก โดยทั้งนี้การทดลองและการตรวจสอบความสมบูรณ์ของบรรจุภัณฑ์มีเพียงสองเงื่อนไขเท่านั้น คือ เกิดการรั่วไหลหรือรอยรั่ว และไม่มีการรั่วไหล ซึ่งตัวอย่างที่เป็นตัวแทนของการตรวจสอบทั้ง 2 กลุ่ม จะต้องผ่านการทดสอบ และผลการทดสอบของแต่ละกลุ่มควรจะแตกต่างจากที่อื่น ตัวอย่างที่มีการรั่วไหลหรือมีข้อบกพร่องการรั่วไหลที่รู้จักกันทั่วไปถูกนำมาใช้กับการทดสอบและควรระบุอย่างถูกต้องว่าไม่มีการรั่วไหลหรือมีข้อบกพร่อง
เนื่องจากการออกแบบการทดลองมีสองเงื่อนไขคือ เกิดการรั่วไหลหรือรอยรั่ว และไม่มีการรั่วไหล ตัวแปรนี้มีความสำคัญอย่างยิ่ง ความคิดทั่วไปคือตัวอย่างที่ไม่มีการรั่วไหล (หรือตัวอย่างที่ไม่ใช่การรั่วไหล) เป็นแพคเกจที่มีการปิดสนิท ซึ่งไม่ควรมีการรั่วไหล ตามความเป็นจริงแล้วแพ็คเกจทั้งหมดนั้นมีการรั่วไหลไปในระดับหนึ่ง ซึ่งตามข้อกำหนดของการใช้งานแพคเกจนั้น การรั่วไหลของบรรจุภัณฑ์โดยธรรมชาตินี้เรียกว่า การจำกัดการรั่วไหลสูงสุดที่อนุญาต (MALL) การสร้างตัวอย่างการรั่วของขนาดการรั่วไหลที่ทราบนั้นมีความซับซ้อนมากขึ้นและต้องการทำความเข้าใจอย่างละเอียดเกี่ยวกับบรรจุภัณฑ์ และการเปลี่ยนแปลงการรั่วไหลผลิตภัณฑ์ การใช้วิธีทดสอบการควบคุมในเชิงบวกอย่างเหมาะสมและความรู้เกี่ยวกับวิธีการทางเลือกที่ถูกนำไปใช้เพื่อท้าทายวิธีการทดสอบ ต้องมีความถูกต้องและน่าเชื่อถืออย่างมากที่สุด
Test Method Development, Experimental Design and Positive Controls
Package integrity can be defined as a package’s ability to prevent product loss, maintain product sterility, and in some cases, prevent oxygen ingress or maintain sub-atmosphere headspace pressures. The characterization of integrity separates packages into leaking and non-leaking samples and allows for the validation of a test method to be a very simple experiment. There are only two conditions, non-leaking and leaking. Samples representing both groups are subjected to a test and the results for each should be measurably different from the other. Samples with either a non-leaking circumstance or a known leak defect are introduced to the test and should be correctly identified as non-leaking or defective.
Given that the experimental design has only two conditions, leaking and non-leaking, this variable is extremely important to understand. Conventional thought is that non-leaking samples (or assumed non-leaking samples) are simply sealed packages in which no leak should be present. Realistically, all packages leak to some degree within the requirements of that package application. This inherent package leakage is referred to as the Maximum Allowable Leakage Limit (MALL). Creating leaking samples of known leak sizes is more complex and requires a thorough understanding of package, product, and leak dynamics. Proper use of positive controls and knowledge of how alternative approaches are applied to challenge a test method support the validity and reliability of the method.
Experimental Design and Control Samples
A simple well-designed experiment contains two types of control variables; positive and negative. Negative controls (non-leaking samples) are used to verify that there is no effect when subjected to testing. Positive controls (leaking samples) are used to draw out unique experimental results differing from the results of the negative controls. Positive and negative controls can be statistically identified as two separate groups. While this case study does discuss negative control packages, the primary focus is on creating positive control leaking samples for package integrity testing.
Positive controls are used to capture the test results that should be expected from defective package samples. When developing a test method, a minimum target leak size is typically identified. This target minimum defect size only identifies the smallest defect that should be detected, when in fact all package integrity defects should be challenged. Experimental design using artificially created defects should capture an array of defect types and sizes. This assures that the experiment will encompass all naturally occurring leak sizes, not simply one target leak size. Below are the various technologies and considerations for control sample creation.
Negative Controls
Negative controls are assumed non-leaking samples, they represent the status quo. An ideal negative control population should consist of packages from different lots or production lines to account for natural variation. These populations are determined to be negative controls after they have undergone a test cycle to assure there is no outlying condition to the samples. Statistical analysis is used to observe the negative control populations, therefore, a significant quantity of negative control samples should be tested. Testing 30 samples is the absolute minimum requirement, with a typical population of negative controls reaching 100 samples. Non-destructive testing provides capabilities to perform multiple testing cycles and select negative controls. Destructive test methods are limited in the ability to pre-screen for a representative negative control population.
Choosing Leak Sizes
Determining the appropriate leak size is based on a holistic assessment of risk and the MALL associated with the application. The end use requirements, product and package characteristics form the crux of selecting a leak size. Smaller leak sizes are necessary for oxygen, moisture and bacterial critical products. Positive control sizes that encompass the full range of potential defects should be selected. Defects should be created down to the MALL and should also include a range of natural defect modes. Using the right approach to create the required size is just as important as determining a leak size.
Actual vs. Simulated Positive Controls
Actual positive controls are the packages with known or intentional leaks. Although these packages serve the purpose of positive control in a good experimental design, they are prone to error and are dynamic (product inside the package may clog the hole or defect). Reliability of a test result may come into question with dynamic positive controls. Therefore, it is also critical to incorporate non dynamic positive controls to obtain reliable and valid test results with actual dynamic positive controls. Simulated positive controls are used to remove the concerns associated with dynamic defects.
For vacuum based test methods, a microflow meter (microcalibrator or MC) fills the role of a simulated positive control in vacuum decay package integrity testing. It creates an exact air flow rate inside the test chamber and measures the differential pressure at that flow rate. The principle is to simulate a leak in the package by adding flow. The MC is set to a certain value to create specific flow rates. A flow rate chart with the assigned MC value is given below. Use of a microcalibrator gives a correlated representation of the detectable gas flow rate (leak size) that is traceable to globally recognized standards.
Methods for Creating Positive Controls
Laser Drilling
Laser drilling is the most effective method for creating positive controls in the package wall. A laser drilled hole closely resembles natural defects such as microcracks. An added advantage to laser drilling is that the product around the defect is evaporated so that excess package material does not interfere with testing. Laser drilling can produce certifications of the nominal ‘hole’ size leak, although the actual defect created is not a perfect hole. Making defects in the range from 3 microns to 50 microns requires the use of laser drilling. Making defects below three microns is more probabilistic, but can be performed using thermal shock cracks mentioned later in this article. Laser drilling is ideal for most package formats and materials. The measurement tolerance of a certified defect is ±10%, producing relatively accurate defects to the target size.
Thermal Cracks
Certain package applications are more susceptible to cracks, specifically glassware such as vials and syringes. Cracks in glassware can be created, but the result is often not too consistent in defect size. By scratching the surface of the glassware, heating the glassware for a few seconds, then applying a drop of cool water to the surface of the glass will produce a crack. Proper safety precautions should be taken into place when doing so. Thermal cracks can produce extremely low leak rates and are the most similar real-world defects. This approach will produce a wide range of sizes and need to be independently certified using other qualified methods such as Helium.
Capillary Tubes
Capillary tubes are practical, simple and cheap to create defects in dry applications. This method can be used for applications with dry fill or gas only. It is not a suitable approach for use with liquid products due to capillary forces that liquids exhibit with the tubing. Capillary tubes create a structured flow rate in a package. Flexible packaging such as pouches and some pharmaceutical products are acceptable for inserting capillary tubes. In flexible pouches a capillary is inserted in the seal of the package and resealed with the capillary tube in place. For rigid containers a capillary is inserted through the container barrier. A larger hole is first created, capillary is inserted through the hole and an epoxy creates the hermetic seal between the container and the capillary. Length and internal diameter of the capillary tube determine the flow rate from the package. This target flow rate can be calculated to cut capillaries to the desired length. It must be emphasized that this method is not appropriate for liquid filled containers with liquid impacting the flow dynamics of a capillary.
Micropipettes
Pipettes are similar to capillaries in that they are a leak component inserted into the package barrier. Pipettes follow a similar process as the capillary tubing but are far more delicate and susceptible to breakage. While a capillary restricts flow through the elongated nature of the capillary, a pipette creates a fine orifice restriction at the tip of the pipette and flutes open to a larger diameter capillary. The restricted flow is isolated at the tip. Defects created with micropipettes are cumbersome due to the delicate nature of the pipette, which becomes larger if the tip is impacted. Once the tip is broken the accurate flow rate is no longer achieved and the leak becomes much larger. The use of pipettes is the least representative defect to naturally occurring defect. The fluted shape of the pipette creates a more detectable circumstance due to air flow dynamics. However, the use of pipettes with liquid applications is even less representative of leak dynamics. The liquids are more likely to be drawn into the pipette due to the fluted shape. This creates a large surface area for the liquid to be detected by a vacuum based method. Use of pipettes does not simulate naturally occurring defect effectively, and their use with liquid container contents is a clear misrepresentation of leak dynamics and test method effectiveness.
Laser Drilled Disc
Laser drilled discs are patches with a certified defect drilled into the material. This is similar to laser drilling into a package barrier. To create certified defects using discs a reliable double-sided adhesive is applied to the package surface. A hole is then created on the area of the adhesive and the disc is applied to the adhesive such that the laser drilled defect aligns with the hole. This is often a practical approach to laser drilled defects if drilling the samples becomes too challenging.
Mechanical Drill
Mechanical drilling involves using a micro-drill to create a defect in a package. The package can be anything with a flexible or semi-flexible barrier, such as a blister pack or foil pouch. Different drills are used to create defects of different sizes. Defects of 50 microns or larger are created using mechanical drilling needles. Pictures below show a mechanically drilled sample as well a mechanical drill needle. This method is preferred over the act of simply puncturing with a needle. Drilling actually removes material while puncturing often leaves package material behind that may obstruct the defect.
Needle Piercing
Needle piercing is similar to mechanical drilling, but in this case the defect is created by puncturing rather than drilling. An acupuncture needle is the smallest available needle that can be used to create defects. This is not considered as reliable as drilling because material is left behind in the defect that may obstruct the leak.
Wire Pull
Pouch seal defects can be created by sealing foreign material into the seal and removing the material after sealing. This is often performed using a wire or thread to create a channel defect. Depending on the sealing substrate, this may be acceptible. Some sealing processes such as Tyvek pouch seals use glue, and pulling foreign material from these seals is often less effective as the glue obstructs the defect after the wire is pulled from the seal.
Summary
There are a variety of methods capable of creating positive controls. Defects that best represent the true circumstances of naturally occurring defects should be used. Some methods for creating positive controls are more effective, reliable and representative than other methods.
Positive controls are dynamic and can always be impacted by outside influences, especially the product. Whether the product is a dry fill powder or a liquid there is always a possibility that a positive control becomes plugged. Liquids are more likely to react in unique ways with positive controls and the method of positive control creation becomes more critical. Simulated flow rates using a microcalibrator allow for a more accurate measure of leakage but this ignores the product interaction. Using both the microcalibrator and positive controls provides the most reliable path for validating a test method. The type of positive control used to challenge a test method will ultimately determine the validity and reliability of that method.
สนใจข้อมูลเพิ่มเติมเกี่ยวกับการออกแบบการทดลองความสมบูรณ์ของบรรจุภัณฑ์และการพัฒนาวิธีทดสอบการควบคุมในเชิงบวก ติดต่อทาซาเทคได้ตามช่องทางด้านล่างนี้เลยค่ะ
