Response to the Publication of USP ‹1207›

MICAH YOUELLO (WWW.ISTOCKPHOTO.COM)

The BioPhorum Operation Group’s (BPOG’s) Container Closure Integrity Testing (CCIT) workstream would like to congratulate the United States Pharmacopeia’s committee for its latest revision to USP chapter <1207> Package Integrity Evaluation: Sterile Products. Generally, we believe it provides a comprehensive overview of the available methods for container–closure testing and outlines many important elements for consideration in establishing a successful CCIT strategy. We first responded to the USP <1207> draft when it was released for comment in 2014. And from our perspective, some of the changes that were proposed and concerns that were raised in 2014 clearly have been addressed. We are grateful to see that.

The purpose of this letter, however, is to highlight specific areas that cause us concern as a crossindustry group. We are aware that USP’s “informational” chapters are not compulsory. As end-users of such guidances, though — and as representatives of companies that receive the scrutiny of regulators — we recognize that informational chapters often evolve in practice to establish expectations. So any lack of clarity or any bias introduced toward specific methodologies is of concern. It is in this context that we would like USP to consider our further comments here.

These concerns center on the description, perception, and treatment of probabilistic and deterministic analytical methods — specifically dye and microbial ingress methods. We would like to see our concerns considered at the earliest possible opportunity, ideally precipitating an update to USP<1207>.

Areas of Concern
This team’s major concern with the published version of USP<1207> relates to ingress methods and the continued implication that dye (and other) such methods are inferior, along with aspects of their controls. Like the draft version from 2014, the published guidance implies that dye ingress is an inferior method by stating a “preference” for other methods. Further, it is implied that the supposed inferiority of such methods lies with their belonging to a probabilistic and qualitative grouping rather than a deterministic and quantitative group of methods. We do not agree that such a distinction between different types of analytical methods should be made because it serves to imply a superiority that may not be true for all container–closure configurations or all leaks of concern. Nor do we feel that it is appropriate or correct to express a preference (or the opposite) for a given method or group of methods in a USP guidance document.

Individual companies can apply a range of tools and tests throughout the lifecycle of their products. But over several decades, the biopharmaceutical industry has successfully validated and routinely used dye-ingress testing methods as its “go-to” method for CCIT. USP<1207> fails to recognize this important point of practice: that such methods are the prevailing — and sometimes the only — test methods at some stages of development/manufacturing. With that in mind, a test such as dye ingress does not simply become obsolete. It may be replaced by an alternative test, of course, but that does not necessarily imply that the original test is substandard (1).

Dye-ingress methods are still in use because they actually do demonstrate CCI and can adequately demonstrate integrity or nonintegrity when risks involve microbial and/or liquid ingress, loss of solvent or product, and so on. Selected container–closure materials and/or final product configurations require an ingress test method — the only option in some cases — for practical reasons.

That has been the experience of BPOG member companies using autoinjectors and combination devices. Dead-air space in such devices, lack of final access to their primary containers, and/or component off-gassing have made deterministic methods impractical. Along those lines, the increased sensitivity of deterministic methods may be unnecessary when microbial ingress or product leakage are the only concerns. Discounting the dye-ingress test as an option may not be in the best interest of patients because such methods can represent the most appropriate and practical method for CCIT.

Regardless of the analytical method and whether it is deterministic or probabilistic, proper validation is key. Any method that is not properly validated is inadequate, whether it is probabilistic, deterministic, qualitative, or quantitative. However, the implication throughout USP <1207> is that this is not the case and that certain methods are “preferred.” The chapter claims that ingress methods tend to be “less effective.” The fact that such methods have been applied successfully for many decades — and continue to be readily validated across the pharmaceutical industry — is largely ignored in favor of commercially available tools and methods. In fact, ingress methods have been exposed to regulatory scrutiny with success throughout their history and continue to be used for many commercial products.

The sensitivity of ingress methods also is called into question in USP<1207>. Text and charts in the new guidance imply that such methods cannot achieve certain levels. However, dye-ingress methods have achieved sensitivities of ≥20 µm in methods used at a number of laboratories. Without substantive reasoning, the chapter has dismissed dye ingress as “not preferred,” even though it is still the most widely used method in the industry for liquid products and has been demonstrated repeatedly as fit for that purpose.

A Proven Approach
Properly validated ingress test methods (dye, microbial, and otherwise) should be regarded as acceptable and should not be distinguished from other methodologies. The basis for any such distinction must be the proven capabilities of a method (not its means for determining results). Therefore, we respectfully request that USP<1207> be updated to remove all suggestion that other methods are “preferable.”

The newly published monograph effectively discounts dye ingress as a tool for CCIT even though it is proven to be effective, robust, and well understood. Whether a tool is used must depend on the industry’s ability to demonstrate that it is effective for its intended purpose and fit for that use. Any tool that meets those criteria deserves to be afforded appropriate consideration. Making CCIT unnecessarily dependent on higher-level technologies would have a number of negative effects, including increasing the cost burden on patients and reducing ready accessibility of new medicines to the marketplace.

The members of this BPOG workstream on CCIT remain grateful to USP for making a concerted effort to improve its guidance on CCIT through USP<1207>. It is our hope, however, that the relevant committee recognize issues that have been identified herein and that they will address our concerns promptly. We are committed to improving CCIT from an industry perspective and welcome all opportunities to engage with organizations such as USP to develop or clarify guidances and/or improve practices across the biopharmaceutical industry.

Reference
1 Ewan S, et al. Container Closure Integrity Control versus Integrity Testing During Routine Manufacturing. PDA J. Pharm. Sci. Technol. 69(3) 2015: 461–465.

Brian Vanness is with Abbvie, which is headquartered in Chicago, IL; Stephen Yi is with Biogen, which is headquartered in Cambridge, MA; Steve Klohr is with Bristol-Myers Squibb, which is headquartered in New York, NY; Lauren Smith and Doug McNeill are with Cook Pharmica, which is headquartered in Bloomington, IN; John Kirk and Chris Levick are with Ipsen Biopharm, which is headquartered in Paris, France; Stefanie Adler and Klaus Wuchner are with Janssen-Cilag, which is headquartered in Schaffhausen, Switzerland; Cindy Lake, Josh Lance, and Sean Fadden are with Merck & Co., Inc., whose headquarters are in Kenilworth, NJ; Tony Polomene and Brian Lee are with Pfizer, which is headquartered in New York, NY; Miteshkumar Acharya is with Regeneron, which is headquartered in Tarrytown, NY; Harold van Deinse and Kamran Simani are with Shire, which is headquartered in Dublin, Ireland. Corresponding author Scott Ewan is a facilitator for the BioPhorum Operations Group (BPOG), 5 Westbrook Court, Sharrow Vale Road, Sheffield, S11 8YZ, United Kingdom; [email protected], www.biophorum.com.