Quality control test for parenterals

Quality control test for parenterals - a guide to choosing a compliant leak tester


One of the main drivers behind any leak testing equipment purchase is to ensure regulatory compliance. But how do you know that the machine you are buying has everything you need to meet regulations and guidance such as USP 1207, ASTM standards and 21 CFR Part 11? What design features should you look out for to ensure compliance? Do all leak testers on the market have the capabilities to meet regulatory requirements or do some fall short?

This post aims to answer these and other questions that pharmaceutical and medical device manufacturers might ask when buying an off-line leak tester for vials, ampoules, bottles, syringes and other rigid containers.


Q: Do I need an off-line leak tester?

A: There are several reasons for investing in an off-line leak tester. The main reason large pharmaceutical operators have off-line as well as in-line testing is for R&D and validation purposes. An off-line tester can be used to confirm that an in-line leak testing station is operating as it should as well as to test and/or validate a new container-closure-content combination. For pharmaceutical products that don’t require 100% in-line testing, off-line leak testers can also be used to perform testing on a sample of each production run, thereby satisfying regulatory demands without the costly investment of an in-line solution.


Q: Does an off-line leak tester need to be affiliated to an ASTM standard?

A: Some providers of leak testing technologies cite ASTM standards – which are recognised by regulators as a consensus standard for pack integrity – in their marketing. This should provide a guarantee that the machine will perform CCI testing in line with this standard, thereby giving the pharmaceutical manufacturer peace of mind that they are meeting approved standards.

That is not to say that a leak tester has to be affiliated to an ASTM standard to ensure compliance. Not every accepted test method has an associated ASTM standard (HVLD, for example, doesn’t). Also, it is a misconception that only the system that was used in the development of the ASTM standard is compliant with that standard. This is not true. Take, for example, vacuum decay testing (ASTM F2338-09). There are many systems on the market that are capable of carrying out these tests to ASTM standards, but weren’t used in the development of the original protocol.


Q: What is USP 1207 and how can I be sure that a leak tester meets this guidance?

A: USP 1207 is the latest guidance on CCIT (Container Closure Integrity Testing) for parenteral products. The chapter provides an overview of common CCIT tests and categorises them as being deterministic or probabilistic. It states a preference for deterministic tests on the basis that they are non-invasive, produce repeatable and predictable results and are suited to 100% testing. It is recommended that you consult the guidance in USP 1207 and ensure that your proposed leak test technology and product combination will adhere to the guidelines.


Q: How can I tell whether a leak tester can meet the appropriate ASTM standard?

A: The most common and reliable way to determine whether a machine will meet a standard is to conduct feasibility studies. The goal of these studies is to confirm if a test method protocol is in alignment with a standard relevant to your particular pack-product combination. Say, for example, you want the system to use vacuum decay testing (F2338-09) to identify holes down to 1µm, a feasibility study should confirm the system is capable of that performance on your product.


Q: What is 21 CFR Part 11 and what are the benefits of a 21 CFR Part 11 compliant leak test solution?

A: CFR Part 11 is part of Title 21 of the Code of Federal Regulations that establishes the FDA regulations on electronic records and electronic signatures. Put simply, it sets out how a pharmaceutical company can use electronic quality records and digital signatures in place of paper based documentation.

Basic machines that don’t have 21 CFR Part 11 capabilities will still satisfy QA/QC requirements, as test results can be printed out and filed to create a paper trail. However, there are numerous advantages to electronic record keeping – not only does it eliminate the scope for human error, it is also more efficient and makes it easier to store, manage and interrogate test data. Companies wanting to use electronic records and signatures will need a leak tester that is 21 CFR Part 11 compliant, to meet the FDA’s requirements for electronic documentation.

Whilst not a legal requirement, having a PC-based system with a relational database management system is beneficial for 21 CFR Part 11 and traceability purposes. Some leak testers are PLC-based. This means they have limited internal memory and can only store, say, the last 100 test results. On a PC-based system operating with a database all data that the system generates can be stored and accessed, giving users a full library of test data and trending capabilities as well as full batch and system traceability, right down to the name of the operator who performed the test.


Q: Do I need to purchase a dedicated off-line leak tester for each container type?

A: Not necessarily. Recent years have seen the development of off-line systems with interchangeable test heads, enabling multiple test methods eg vacuum decay and pressure decay to be performed on the same unit. That said, the tooling that holds the pack in the vacuum chamber is container-specific, so switching between sizes or formats would require different tooling. Also, some CCIT technologies are so fundamentally different that they can’t be performed on the same unit. Laser-based gas headspace analysis, vacuum decay and HVLD, for example, cannot share a unit.  


Any test technology requires method development specific to the product-package system to maximise sensitivity. Once a set of parameters has been established as optimal, validation is a critical step before employing the method for routine use.


Sepha Solutions

Founded in 1980, Sepha has established a global reputation for innovation and development of specialised, high-quality equipment for use in the manufacture of pharmaceutical blister packs, parenterals, medical devices and healthcare products.

We have developed two innovative CCIT machines that offer non-destructive & deterministic leak detection utilising vacuum decay or pressure decay.

  • The Multi-Q is a multi-functional system that offers the flexibility to test different container types by use of interchangeable tooling and test methods, including vacuum and pressure decay.
  • The Multi-Q HD has been developed for parenteral applications that have a lower Maximum Allowable Leakage Rate (MALL) and require a higher level of sensitivity. Advanced sensor technology enables ultra-sensitive detection of micron defects as low as 1µm.

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About the Author

Philip Cooper, Head of Technology & New Product Development for Sepha has been with the company for 20 years. He has a BEng (Hons) in Mechanical Engineering, over 20 Years Packaging and Leak Testing Experience and has been an ASTM F02 Primary Barrier Packaging member for 13 years and the F2:40 Package Integrity sub chair for 7 years. Sepha has established a global reputation for its extended portfolio of innovative solutions developed to improve procedures to leak test, deblister and package pharmaceutical products, medical devices and healthcare products. The UK based company has been working with pharmaceutical companies worldwide since 1980.

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