FDA officially accepts physical integrity testing in lieu of microbial-challenge testing for whole packages

Testing the ability of a package to maintain product sterility has often been a dirty job. Literally. Engineers have stuck a whole package into a microbe-laden bath or overwrap and then tested either the product or a growth medium inside to see whether microbes had penetrated the package. These methods and others were described in Philip Schneider’s “Microbiological Evaluation of Package and Packaging-Material Integrity,” in the May 1980 issue MD&DI.

Using such methods has not been foolproof, however. Some users have reported a high number of false positives. Could recent guidance from FDA leave such testing in the past?

Schneider wrote that “microbiological evaluation of medical device packages and packaging material will produce meaningful results only if relevant test methods are carefully selected and implemented. At the present time, however, no standardized microbiological methods are available for this type of testing. Therefore, physical and chemical testing now provide the primary documentation of medical device packaging efficacy.”

Nearly three decades later, FDA has finalized guidance that concurs. In February, the agency issued “Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products.” The guidance was prepared by representatives from the Center for Devices and Radiological Health (CDRH), the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Veterinary Medicine. The guidance states that physical container and closure system integrity testing or microbiological container and closure system integrity tests “may be more useful than sterility testing in demonstrating the potential for product con­tamination over the product’s shelf life or dating period.” Physical testing includes “bubble tests, pressure/vacuum decay, trace gas permeation/ leak tests, dye penetration tests, seal force, or electrical conductivity and capacitance tests.” Microbiological container and closure system integrity tests include microbial challenge or immersion tests.

Randy Troutman says that such guidance “is the first official FDA document to allow physical testing to support sterility testing. It also addresses the known limitations of sterility testing as compared to the advantages of (more-reliable) physical testing.”

Troutman is technical director of Oliver Medical (Grand Rapids, MI). He explains that “industry wide, there have been a lot of concerns over the past 10 years regarding microbial challenge testing of packaging configurations because of the very high potential for false-positive readings owing to the sensitive nature of the test method. They have been working on this document for 10 years.”

Adds Michael Troedel, president of Michael Troedel & Associates and technical consultant for Mocon Inc. (Minneapolis): “We’ve known for a while that FDA has been behind physical package integrity testing, so this has been a long time in coming. But it is the first time FDA has gone on the record.”

REWIND TO THE ROOTS OF CHANGE

A few years after Schneider’s article in MD&DI, an impressive group of authors led by Anthony Parisi added their perspectives to the mix. “Unlike physical tests, microbial challenges of whole packages rely predominantly on the performance of product sterility tests and are subject to a high degree of false positives that may lead to ambiguous test results.” The article was “Toward a New Consensus on Sterile Device Packaging,” published in MD&DI in January 1993.

Parisi et al. reference the work of ISO Technical Committee 198 Working Group 7. At the time, the committee had proposed a draft standard on packaging. (This standard would evolve into ISO 11607.) “The draft standard states that physical testing is sufficient to demonstrate that seals are impermeable and continuous and that manufacturers should use physical tests to demonstrate the integrity of the sterile package.”

FDA’s guidance “formalizes what the landmark article from Parisi et al. argued,” says Nick Fotis, director of Cardinal Health’s Packaging Technology Center.

In 1995, the Health Industry Manufacturers Association’s (HIMA) Sterile Packaging Working Group published its recommendations in “In Quest of Sterile Packaging, Parts 1 and 2.” (This group included some of Parisi’s coauthors: Curt Larsen, Hal Miller, John Spitzley, and Mike Scholla, all current or former PMP News EAB members.) The articles were published respectively in the August and September 1995 issues of MD&DI. “The chances of establishing a single, properly validated microbial challenge test procedure applicable to a wide range of package designs and packaging materials are very small,” read Part 1. And, quoting industry, “Why not perform just microbial barrier testing for the porous package component, and use physical tests to determine package integrity?”

FAST FORWARD

With FDA eventually recognizing ISO 11607 as a consensus standard, wouldn’t it follow that FDA agreed with the physical-test-method supporters? Perhaps. But the February 2008 guidance means a lot to industry. “It is a blessing for FDA to say this,” says Scott Levy, packaging engineer for DDL Inc. (Eden Prairie, MN). “The four points that FDA make are the gospel truth,” he stresses. Writes FDA in its guidance:

The advantages of using such container and closure system integrity tests in lieu of sterility tests in the stability protocol for sterile products include:

Hal Miller, now with Pace Solutions LLC, details the challenges. “The method typically used for medical devices is to challenge the package with an aerosol of microorganisms; then decontaminate the outside of the package with UV light, alcohol wipe, or something similar; and perform the USP Sterility Test procedure <71> using the Direct Transfer Method. This entails aseptically removing the product from the package, placing it into a growth medium, incubating the culture, and observing any growth organisms. This method is known to produce false positives by not sufficiently decontaminating the outside of the package, or false negatives where there was no growth on the product because the microorganisms that breached the package never transferred to the product.”

False positives are troubling. “We all want clean data to file with FDA,” says Levy. “If you fail a traditional sterility test, but pass a physical integrity test, you are in a pickle.”

As an alternative, Miller states that “physical package integrity simply tests for any breach of integrity in or on the package. A package failure is simply that integrity was not maintained regardless of whether any organism gets onto the product or not.”

Adds Levy: “If the package is intact, then it is sterile.”

But does the guidance really change anything? Troutman says no. “The real advantage is that it allows MDMs to reference it as precedent in proving sterility maintenance through performance testing of materials and packaging systems. Instead of sterility testing a package configuration, a packaging engineer can test the strength and integrity of the seals and closures, assuming the materials are proven microbial barriers.”

BENEFITS

Industry response has been favorable. Just as microbial challenge “could be used at any stage,” says Miller, so can physical tests. These stages include “initial package validation, all stability testing intervals, and critical event investigations.”

Troedel points out that physical integrity testing methods are “less operator dependent” than microbial-challenge testing. This can be a benefit to companies struggling with “the personnel challenge,” he says. “The medical device industry is growing to keep up with technology demands for aging baby boomers. And there are a lot of regulations and testing these days. But there are not a lot of qualified people to do this stuff,” he says.

As a result, as staffs are often pushed to their limits, “there is the risk of operator error,” he says. “Physical integrity tests are what you want to rely upon.”

Adds Ed Emerson, business development manager for Mocon: “We hear a lot of sighs of relief from the industry that there is a suitable alternative. We have always questioned whether microbial challenge testing delivers results close to real-world conditions.”

Instead, Emerson says, “Physical integrity methods using instruments are more reliable and reproducible and therefore more effective. We are looking for ways to accomplish high-precision integrity testing.”

As cochair of the AAMI group in charge of writing the ISO 11607 Technical Information Report (TIR) 22, Jackie Daly Johnson says that the guidance “is in harmony with clauses 6.3.1, 6.3.2, and 6.3.3 in ISO 11607 Part 1, as well as with TIR 22 Annex G.” She quotes TIR 22: “The protocol will describe the test methods appropriate for the type of packaging system being evaluated, including methods for seal strength and package (sterile barrier system) integrity.” Johnson is president of Beacon Converters Inc. (Saddlebrook, NJ).

Dhuanne Dodrill, chair of ASTM F02.50, finds that the guidance “allows the manufacturer great latitude with respect to the type of integrity testing performed.” Dodrill is president of Rollprint Packaging Products Inc. (Addison, IL).

“When selecting the appropriate integrity test to perform, ASTM F2097, Guide for Design and Evaluation of Primary Flexible Packaging for Medical Products, is an excellent reference,” she says. “The Package Integrity section of Table 1 provides a brief description of each of the relevant ASTM methods as well as guidance on their applicability.”

But with guidance comes great responsibility. Dodrill advises manufacturers to “take care to validate the integrity test method specific to the product container and closure system or product type.”

Marie Tkacik adds that manufacturers should consider the benefits of using consensus standard test methods. They “provide much needed intralaboratory testing information for these integrity tests. The statements of precision and bias such as those found in ASTM F02 Flexible Barrier Packaging standards provide information on how repeatable a method is within a lab and how reproducible when applied across many labs.” Tkacik serves as director of technology for Tolas Healthcare Packaging, an Oracle Packaging Co. (Feasterville, PA).

Tkacik adds: “Methods that provide a measure of sensitivity and variation based on a multilab study give the user a vital piece of information: How effective the method should be when used in their own labs.”

Packaging experts make some important distinctions. The guidance does not eliminate the validation of a chosen sterilization procedure that is required to prove its effectiveness. “We have to ensure that folks don’t take the guidance too far, thinking that it speaks both to sterility and to package integrity,” says Fotis. “Our company makes a distinction between proving sterility (related to cycle development, selection, and validation) and proving sterility maintenance of the package. The guidance talks about how physical testing can support the proof of sterility maintenance.”

Assessing sterility maintenance is a key part of stability testing, says Johnson. “One of the most critical components of stability testing is demonstrating the maintenance of sterility over time,” she says.

Fotis understands the industry’s worries over false positives. But they cannot be ignored, he says. “The guidance definitely says ‘in lieu’ of sterility testing. If someone does package integrity testing but fails sterility testing, they can’t just say that the integrity testing trumps the failed sterility test,” he advises. “They have to investigate and argue that the whole-package microbial-ingress testing was indeed faulty.”

Johnson worries that some firms may stop looking at the entire packaging process. “A closure seal is not the only thing that can cause a sterility failure,” she says. “Breaches tend to be event related, so packaging engineers need to consider the entire process as well as performance in the field.”

Fotis agrees. “Companies definitely should not think that they can give up performance testing. This a separate part of 11607 for a reason. Performance testing itself is really not testing. Rather, it is another form of conditioning of the package in preparation for testing. This conditioning, rather than temperature or humidity, involves shocks and vibrations. The ‘test’ part comes when one evaluates the package for defects. In this case, the guidance explains that the best approach for evaluation is a physical test versus a microbial test.”