Risk Mitigation Of Parenteral Packaging With Container Closure Integrity (CCIT)

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Pharmaceutical parenteral delivery systems are the highest risk packaging application concerning container closure integrity. Leaks that register in the single micron range can introduce a significant threat of bacterial ingress as shown in research by Kirsch et al. in 1997. To manage this risk, the industry has continued to pursue leak detection methods that are more sensitive and reliable for vials, ampoules, cartridges and syringes.

Dye ingress was long thought to be a simple method, but since then studies have shown a lack of reliability for this leak test method (Wolf et al. 2009). In the past, the microbial ingress method was viewed as the gold standard, but the outdated method remains probabilistic and is challenged by uncontrollable circumstances. For both dye and microbial ingress methods, there are no harmonized standards that are globally recognized, despite their decades of use. The pharmaceutical industry has shifted direction towards newer measurement technologies. Using deterministic test methods that have defined controllable inputs is the primary focus of the United States Pharmacopeia (USP) Chapter 1207 on container closure integrity (CCI).

Practical Solutions

Vacuum decay is a test method that has been tried and proven over decades of use in the food, pharmaceutical and medical device industries. Technological innovations have greatly improved sensitivity and testing capabilities. This test method is simple in principle, practical in application and challenges container integrity based on fundamental physical properties. Vacuum decay involves drawing vacuum on a package within a test chamber and monitoring the vacuum level for any decay, which would indicate a leak. This standard vacuum decay leak test method (ASTM F2338) was developed using PTI’s VeriPac instruments. This method is recognized by the FDA as a consensus standard for CCI testing, is listed in ISO 11607 and referenced in the USP Chapter 1207 on CCI.

When testing parenteral products this method uses a deep vacuum, vaporizing the liquid contents in the presence of a leak to generate a decay in vacuum. While this method is sensitive into the single digit micron range, the challenge to detect even smaller defects more reliably has been ever-present.

PTI’s latest research and technological advancements for PTI’s vacuum technology has earned a reputation for being the most sensitive vacuum-based leak detection method available on the market. Gage R&R studies have established an exceptionally reliable leak detection performance below the 1 micron defect size.

The ability to detect leaks below the 1 micron level is not just about achieving a pinnacle of sensitivity, it is about widening the margin of detection. PTI’s vacuum measurement is extremely stable providing excellent repeatability and reproducibility. The stability of test measurement is the most important aspect to consistently and reliably detecting such small defects. As with all test methods, if the method is not reliable it is not a true test method.

PTI’s Scientific Principles

Competitive leak test system sensitivity claims are often broad reaching or not reflective of real-world operation. To appropriately challenge the repeatability of a test method realistic defects must be used. Appropriate statistical analyses are then applied to verify any sensitivity claim.

PTI regularly uses laser drilled defects and cracks as challenge samples. Alternatives such as micropipettes and capillaries create a false sense of sensitivity due to the geometry and physics of the leak that do not reflect normal leak circumstances. Good scientific principles are applied in collecting and analyzing the resulting data. Repeatability tests to challenge a method are performed over days and under various ambient conditions to account for routine operation. The PTI value “Sound engineering through good science” is never more critical than when challenging our technologies to deliver accurate results.

Effective leak detection is driven by the ability to differentiate the measurement from defects to known good samples. The defect is a signal calling for attention within a sea of noisy data. The best test methods produce non-noisy data so that any signal can standout clearly. The signal to noise ratio (SNR) determines the ability for the test method to accurately determine pass-fail results.

Any test method that produces a high enough SNR provides a heightened level of detection performance. PTI defines the Noise as 3 times standard deviation and the Signal as the difference between the good results and defect results. A common standard in the pharmaceutical industry is one false-positive or false-negative per 10,000 results. To achieve this level of test method reliability there should be a separation of 4 times standard deviation between good samples and defect sample results. This translates into a SNR of 1.33. For leaks below 1 micron PTI’s latest technology produces a SNR beyond the 1.33 standard.

The Most Sensitive, The Most Reliable

Parenteral leak testing requires the detection of both liquid and gas leaks and demands the highest level of reliability in producing accurate test results based on the high impact of the data. PTI’s VeriPac has been a work horse in the field of parenteral and high vacuum leak testing. It is considered one of the most reliable leak detection methods based on its simplicity, sensitivity and ability to produce highly consistent test data.

The VeriPac 465 is PTI’s latest addition to the VeriPac line-up with the development of Active Volume Control (AVC). AVC has redefined what is achievable with a vacuum-based leak detection technology. The AVC application addresses vacuum leak detection at the very core of the physical test measurement, maximizing the SNR between good and defective samples.

Based on extensive testing the VeriPac 465 has now established a new baseline for the smallest reliably detectable leak size using a vacuum based leak test. Repeatability and reproducibility studies have established the VeriPac 465’s sensitivity to reliably detect defects down to the 0.7-micron level.

This latest technology innovation provides the VeriPac series with the most stable test measurement ever achieved through vacuum decay. Container closure integrity is a high-risk aspect to pharmaceutical delivery systems. Many conventional methods suffer from uncontrollable probabilistic circumstances. While the microbial ingress method was a gold standard, data from the newer technologies assert the need to reassess leak detection strategies. The sensitivity and reliability of the VeriPac 465 test system and the overall level of performance it provides in high stakes testing applications makes this model an essential consideration when assuring container closure integrity.


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