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Industry awaits the final revision of USP General Chapter and the impact it will have on the evaluation of sterile product package integrity.
A proposed revision of the United States Pharmacopeia (USP) General Chapter <1207>, Sterile Product Package-Integrity Evaluation, calls for a shift to more quantitative, validated test methods. Although there is no set timetable, industry observers expect the chapter to be effective at the end of 2016.
“The first round of proposed revisions were included in the Pharmacopeial Forum (PF) in September 2014,” says Justine Young, project manager, container closure integrity testing (CCIT) at Whitehouse Laboratories. “The comment period has elapsed, and feedback has been received,” adds Brandon Zurawlow, who also serves as a project manager, CCIT at Whitehouse Laboratories. “The expert committee is now in the process of preparing a second revision to be released to PF. If sufficient comments are received, the chapter will need to undergo an additional revision process,” he explains.
According to Oliver Stauffer, chief operating officer at PTI-Packaging Technologies & Inspection, the revised chapter “clearly outlines the various container closure integrity (CCI) test methods fit for use in the pharmaceutical industry. It identifies deterministic methods that are quantitative and definitive in measuring the integrity of a package. It also identifies probabilistic methods that use qualitative information or attribute results derived from human judgment. The document strongly advises use of deterministic methodology to assure CCI.”
“Many of the technologies included in the revisions have been available for decades,” notes Young. “Despite this,” she says, “industry has continued to rely on probabilistic test methods to evaluate the integrity of parenteral packages.” Once the chapter is effective, she predicts, “FDA will become more stringent in its review process of package integrity data.”
Zurawlow adds, “From discussions with others in industry, FDA is already beginning this shift, and companies are beginning to receive pushback when submitting data obtained by the dye ingress method.” Whitehouse Laboratories already employs deterministic leak-test technologies and currently relies on vacuum decay, mass extraction, helium mass spectrometry, high-voltage leak detection, and laser-based headspace analysis systems.
Stauffer explains, “USP <1207> does not necessarily change methods or technologies. It changes the way that organizations relate to those methods and the information they offer [and] … encourages organizations to adopt test methods that provide the highest level of quality assurance. The chapter removes gray areas within CCI, highlighting some methods that have industry-proven capability, and drives industry to deploy solutions that have a higher detection capability.”
Regardless of the CCIT methodology chosen, testing should be quantitative, repeatable, reliable, and validated for each product-package system. Ideally, any test also should be nondestructive to prevent waste and loss of costly product.
As a result, it seems inevitable there will be a shift from probabilistic testing such as dye ingress to more deterministic methodologies. However, Louis Brasten, supervisor, routine and functional analysis/filling services at West Pharmaceutical Services, notes, “Chapter <1207> has become more of a guideline. No ‘one test’ is the key to defining a client’s closure integrity. It is the right combination of testing that shows the complete picture over the lifecycle of the product.” West relies on state-of-the-art equipment and CCIT techniques to paint a complete picture of CCI for the lifecycle of its customer’s products.
Whitehouse Laboratories provides CCI method development and validation services for client-specific product-package systems in a cGMP, FDA-regulated laboratory environment. “We will work with clients to understand their product-package systems and to determine the most applicable CCI technology to employ for integrity evaluation, offering our knowledge and years of experience to optimize the use of these technologies,” says Young.
In addition to contract packaging services, West offers components to help ensure CCI. Ready-to-use Flip-Off PlusRU sterile drug-vial seals help to ensure injectable drugs are sterile and free of contaminants and particulates that could present risks to patients. “In recent years, changing regulatory guidelines have increased the demand for reliable seal solutions in the pharmaceutical industry,” said Mike Schafers, vice-president, global marketing, pharmaceutical packaging systems at West, in a news release. “Using high-quality sterile packaging components minimizes the risk of external contamination, line stoppages, and equipment down-time” (1).
According to West, Flip-Off PlusRU seals are manufactured using its TrueEdge manufacturing process to provide the smooth, even bottom edge needed for high-speed filling and capping. Assembled in a controlled (not classified) environment, seals are sterile and support clean crimping under Grade A air supply to exclude bioburden. A certified bioburden prior to sterilization allows cGMP-compliant sterilization validation, thus enabling clean crimping processes in accordance with the latest quality trends and regulations (1).
Equipment and test methods
Several technologies are used for CCIT. The traditional blue dye test submerges the package in water mixed with blue dye. It’s a destructive test, and pass/fail decisions can be somewhat subjective because the operator is required to analyze the results.
Other CCIT options include camera-based machine-vision systems, headspace analysis (HSA), and leak detection. The latter can be based on vacuum decay, high voltage, or helium. HSA or one of the leak detection systems may be integrated with machine-vision systems or function as standalone units. These technologies are non-destructive, and some can be performed at line speeds to provide 100% inspection.
Christian Scherer, area sales manager, Seidenader Maschinenbau, discussed high-voltage leak detection (HVLD) and HSA in a presentation at the ISPE Manufacturing Solutions Conference at PACK EXPO East (Feb. 16-18, 2015) (2). Either technology can be integrated on Seidenader’s CS series camera-based inspection systems.
HVLD systems position the container between electrodes and detect changes in resistance. HVLD requires a non-conductive container and an electrically conductive liquid product. In addition, the inner surface must be wetted, and the distance between the electrodes and any defect must be relatively short. The container is rotated to scan the whole surface. Vials are held at the top and bottom with electrodes above and below, and syringes are positioned in a vertical orientation, needle down. In an integrated inspection system, containers feed into the vision system to identify visible flaws and are checked with HVLD on the outfeed to locate nonvisible cracks.
Often used for lyophilized product, HSA relies on tunable laser-diode absorption spectroscopy to detect oxygen content, water partial pressure, and absolute pressure in pharmaceutical containers. The laser is tuned over a defined wavelength range, and a photosensitive sensor measures the absorption profile of the headspace gas (3). If a leak is present, the resulting absorption line won’t match the reference reading.
At present, Scherer told the audience, use of HSA and HVLD technology is voluntary except in Russia, which requires machines to have integrated HVLD. “However, the investment in equipment versus the cost of a recall is minimal,” he concluded.
Vacuum-decay systems detect micro-leaks in empty and prefilled syringes, liquid-filled and lyophilized vials, and other liquid-filled packaging (both flexible and rigid). PTI’s VeriPac 455 vacuum-decay leak detector relies on core technology based on the ASTM vacuum-decay leak test method (F2338-09), which is recognized by FDA as a consensus standard for package integrity testing. The system’s patented PERMA-Vac dual-vacuum transducer technology increases test sensitivity and yields consistent, reliable results. The offline system is capable of detecting defects as small as 1.5 µm (4).
PTI also offers an offline laboratory instrument based on HVLD technology. The E-Scan 625 system detects pinholes, micro-cracks, and seal imperfections as small as 1 µm in prefilled syringes, liquid-filled vials, blow-fill-seal containers, and liquid-filled pouches. According to PTI, the HVLD method easily transitions from offline applications to 100% inline testing at high production speeds (5).
1. West Pharmaceutical Services, “West Launches High-Quality Flip-Off PlusRU Seals,” Press Release, February 11, 2015.
2. C. Scherer, “Alternative Inspection Technologies,” presentation at the ISPE Manufacturing Solutions Conference at PACK EXPO East (Philadelphia, PA, 2015).
3. Seidenader Maschinenbau, “Seidenader HSA,” accessed Feb. 25, 2015.
4. PTI-Packaging Technologies & Inspection, “VeriPac Leak Testing,” accessed Feb. 25, 2015.
5. PTI-Packaging Technologies & Inspection, “E-Scan 625,” accessed Feb. 25, 2015.
Article DetailsPharmaceutical Technology
Vol. 39, No. 4
Citation: When referring to this article, please cite it as H. Forcinio, “Evaluating Package Integrity,” Pharmaceutical Technology39 (4) 2015.