Importance of container closure integrity testing


As there is no one solution that solves the different challenges related to specific products, Pfeiffer Vacuum offers a wide range of different leak-testing methods to address all the challenges within the pharmaceutical industry.


The quality and effectiveness of drugs signif- icantly depends on their proper packaging. Sterile products and moisture/oxygen sen- sitive drugs require excellent barriers during the shelf life of the product – up to a couple of years – to protect them from biological contamination, water and oxygen ingress. Otherwise, serious consequences might occur – this was proved by a grave incident in the 1970s. During this period, contami- nated intravenous fluid packs aged in glass bottles, which were typical at the time for packaging such dosage forms, caused an estimated 2,000 to 8,000 episodes of blood- stream infection, resulting in the deaths of about 10% of the patients. This severe pack- ageintegrity failure incident has triggered a heightened awareness of package integrity in the life science industry.


The key risks for contamination are from humidity, oxygen or microbiological ingress, which can impact the drug stability through- out the product life cycle. To prevent the risks of stability failure of highly moisture- sensitive drugs – for example, dry powder for inhalation – or the risk of biological ingress of sterile parenteral drugs, integrity tests with a high sensitivity are required.


Regulated market The high risk in regards to pharmaceutical container closure integrity (CCI) testing leads to a strictly regulated environment. Key authorities are the FDA (US) and the EMA (Europe).


In 2008, the FDA published a new guideline for the whole life science industry (pharma- ceutical companies, veterinarian drugs and companies that manufacture sterile medical products) that obliges the sector to perform reliable physical measurements to ensure proper CCI.


What the official regulations often do not describe in detail is how the CCI testing should be performed. They usually only stipulate using appropriate methods and procedures. The US Pharmaceopia, the gov- ernment body in charge of standards and guidelines for the pharmaceutical indus- try – which, typically, are internationally accepted – dealt with this issue and in 2016 presented a new guideline: the USP <1207>. This guideline focuses on sterile and critical pharmaceutical products; for example, vials and syringes.


Test methods and detection limits An initial list of the various test methods used for package-integrity testing was already published in the late 1990s. The report back then was very narrow in scope and recommended to validate chemico- physical leak-test methods by comparing them directly with a microbiological ingress test. This probabilistic test method relies on a series of sequential and/or simultaneous events with random results. The findings are associated with uncertainties that demand


large sample sizes and precise test condition controls. Some publications on microbio- logical ingress tests show that the method detects leakage pathways the size of a single microorganism.


A portfolio of leak-testing methods Pfeiffer Vacuum offers a wide range of dif- ferent leak-testing methods to address the multitude of challenges within the pharma- ceutical industry, as there is no one solution that fits all different challenges connected to a specific product. Pfeiffer Vacuum can support its customers during the complete CCIT process definition and integration, and also provide GMP support in regards to Installation Qualification/Operational Qualification (IQ/OQ), including the needed documentation for all its test methods. Furthermore, ATC by Pfeiffer Vacuum Mass Extraction leaktesting process meets FDA standard F3287 for leak testing. This short- ens the FDA approval process for pharma- ceutical products that require leak testing significantly. Companies that utilise the ATC leak-testing process will save hundreds of hours of paperwork for the approval application.


Pfeiffer Vacuum’s portfolio of leaktesting methods includes, for example, the helium mass spectrometry, the mass extraction technology and the optical emission spectroscopy instrument.


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