From The Editor | October 1, 2014

USP General Chapter <1207> Revisions: Industry Experts Offer Best Practices To Avoid Destructive, Unreliable Integrity Testing

By Trisha Gladd, Editor, Life Science Connect

Trisha Gladd

The US Pharmacopoeia released a proposed revision to USP General Chapter <1207> Sterile Product Package – Integrity Evaluation for public comment, which focuses on package integrity testing. This chapter is not mandated but does reflect recommended best practices. To align these recommendations with current thinking on this topic, a panel of experts, including representatives from industry, academia, and the FDA, were commissioned by the USP Microbiology and USP Packaging, Storage, and Distribution Expert Committees to complete the update. This effort took approximately two years. One of these experts, Dana Guazzo, founder and president of RxPax, a consulting firm providing package development support to pharmaceutical and medical device firms, headed the panel to revise <1207>. She believes these change are necessary to better protect not just the product but also the patient.

Dana Guazzo
Dana Guazzo, founder and president of RxPax

A Higher Standard

Better technologies for integrity testing exist and have been evolving for many years, but companies have been reticent to adopt them because of pharma’s tendency to avoid any steps not required by regulation. In the end, the product is left vulnerable and sometimes unreliable. “There are packages that get out into the field that do not provide the proper protection for the product and end up costing industry a lot of money, as well as put public health at risk,” explains Guazzo. “This results in recalls of product, as well as in product decomposition and degradation. We are capable of doing much better than that, so USP’s goal for this chapter is to educate the industry as well as regulatory bodies, so information is readily available that equips them with the ability to work toward a higher standard.”

While it is referred to as an update, Guazzo says the new USP <1207> is a complete rewrite. Prior to this revision, the USP chapter was about two pages long and provided very high level information regarding what package integrity, including brief mention of a few method types. It indicated that if you want to deviate from the more traditional microbial ingress test, a comparison of a microbial test to the alternative method should be completed. Guazzo says this is no longer required.

“You do need to validate the capability of your chosen method to find package defects and/or to measure leakage rates or defect sizes, but the focus is not to compare it to something like microbial ingress, because microbial ingress itself is so probabilistic,” says Guazzo. “In other words, there's a chance you could have an unacceptably leaking package that passes microbial ingress or you could have a package that doesn't leak, but because of laboratory error, fails a microbial ingress challenge.  Such tests are not reliable—and by the way, neither are dye tests—for detecting small leaks that still pose risks to the product. Further, both dye and microbial challenge tests have the disadvantage of destroying the test package, thereby providing no information about the integrity of actual product packages that are distributed to the market.”

The types of methods that are now included in the chapter are largely non-destructive and can be used on the product package intended for distribution. While the tests that are described provide a lot more data, Guazzo notes they represent a big shift in current thinking.

What’s Package Integrity?

Package integrity is not just a measure of a package’s ability to prevent product loss or maintain product sterility.  For certain products that are oxygen sensitive, or perhaps must be sealed under vacuum, package integrity should reflect the ability of the package to prevent oxygen ingress or maintain sub-atmospheric headspace pressures.  Guazzo explains package integrity testing should not be a one-time test or confirmation but an ongoing process that starts in package development and continues for the life of the product. This is a concept the chapter stresses. “There's no one leak test that will take care of all packages, and many packages require multiple leak testing types over the product life cycle,” explains Guazzo.

USP <1207> offers guidance on how to select the right test method for your product and covers several different factors in how to make a proper choice. However, the chapter is not meant to be prescriptive. Because each method has to be uniquely developed for the product-package system, it does not say exactly how to do any of these methods. Instead, it gives a generic description of each leak test technology. These methods are divided into two different sub-groups: deterministic and probabilistic.

Deterministic vs Probabilistic Technology

The difference between deterministic and probabilistic methods is that deterministic methods are less subject to error, especially human error. There's less package preparation involved, the test is performed with instruments, and it offers quantitative outcomes. Examples of deterministic methods would include tracer gas leak testing, such as helium mass spectrometry performed in a vacuum mode, vacuum decay, mass extraction, as well as electrical conductivity and capacitance testing, which is often called high voltage leak detection.

Probabilistic methods include those relied upon more traditionally in the pharmaceutical industry, such as tracer liquid ingress testing—also called dye testing—and microbial challenge ingress testing. According to Guazzo, such tests are very subject to error. However, even these methods may provide valuable information when properly applied. “The chapter stresses that all the methods have pros and cons,” says Guazzo. “The methods that were chosen to be put in the chapter were based on what has appeared in peer-reviewed research articles and methods that are supported by American Society for Testing and Materials (ASTM) with precision and bias data. People can pick from those methods or even one outside the chapter, but what's important is method parameters have to be optimized and the final method validated for the product-package system.”

She says it's important for people to understand that there is a place and a time to use various methods. “Probabilistic test methods should not be relied upon for establishing the inherent integrity of a package,” explains Guazzo. She explains the concept of inherent integrity by saying, “Given the best case scenario with a package that has no defects and it's well assembled, what is the lowest leak rate that that package can achieve? What's the best case scenario for that package? How well does it perform? To do that type of testing, especially when you first qualify and develop a package, you want to understand, ideally, ‘is this package good enough for my product?’ Test methods, such as probabilistic test methods, should not be relied upon for that type of testing.” She adds this chapter is designed to try to help people learn about package integrity and leak testing and to make educated choices in test methods and their validation and use.

An Investment In Accuracy

While Guazzo says a significant investment in expertise and instrumentation will need to be made to obtain the resources necessary to perform these less traditional tests, the long-term savings and security they offer are well worth it. Eliminating the cumbersome processes used today is also a plus. “Microbial ingress and dye testing are very labor intensive,” Guazzo says about currently used methods. “Such methods are time-consuming and require significant human resources. You have to dispose of environmentally hazardous dyes, and you need space for incubating and storing samples that have been exposed to bacteria. If you adopt other tests, yes, initially firms must be prepared to pay an initial cost for equipment and for staff education, but the benefits far outweigh those costs. The financial benefits, over time, will more than pay for that investment.”

She continues with a couple of examples. “A vacuum decay test that's done using a laboratory bench-top instrument can run you $100,000 in equipment. However, you test one sample and it’s done in 30 to 40 seconds, and you could use that sample for other tests or for commercial distribution because it’s a non-destructive test,” says Guazzo. “You have a high voltage leak test that takes one to two seconds to perform, and it can be incorporated online. With a headspace analysis test, you could evaluate the headspace content of a package with a laser light. It takes less than a second to get the data that tells you if the headspace content has changed.” Again, a relatively large investment upfront, but the time and product saved over time offers the ability to obtain quick, accurate results without destroying product.

Guazzo and the rest of the experts, including the FDA, hope that anyone dealing with package integrity testing will not wait for a regulation to take action. Although much of this information was originally included in an earlier print, PDA Technical Report Number 27 (published by the Parenteral Drug Assocation), released in the late 90s, the 2014 USP general chapter <1207> revision was drafted because technology has evolved and improved drastically. “Those of us in the business of package testing, leak testing, and package development understood that it was time for that information to move from a technical report to something with more regulatory muscle.” She adds that because it’s in the USP, it can undergo constant revision and can always be updated.

Those updates can come from feedback from industry experts, and with the USP currently accepting comments on USP <1207>, now is the time to offer any helpful insight. Guazzo notes, “We really want comments back from around the world, so we can learn how this chapter can be made better.”

To read USP <1207> in full and also leave comments, go to and follow the links to the Pharmacopeial Forum, Sep/Oct 2014 issue.