What is the purpose and intent of USP <1207> Package Integrity Evaluation – Sterile Products?

The USP <1207> provides guidance on the integrity assurance of nonporous packages intended to hold sterile pharmaceutical products. The chapter provides background instruction on the topics of leaks, leakage rate, and package sealing/closure mechanisms. Explanation is given as to how packages that conform to specified leakage limits help to ensure the contained product meets and maintains sterility and relevant physicochemical specifications. The integration of package integrity assurance as a key component of the entire product life cycle is stressed. Guidance in the selection, validation, and use of leak test methodologies as well as package seal quality tests are also included. Detailed recommendations are presented in three subchapters:

  • Package Integrity Testing in the Product Life Cycle—Test Method Selection and Validation <1207.1>
  • Package Integrity Leak Test Technologies <1207.2>
  • Package Seal Quality Test Technologies <1207.3>

 What is meant by the term leakage specific to container-closure system?

Leakage is the unintentional entry or escape of matter (solids, liquids, or gases) through a breach in a package wall or through a gap between package components. Leakage can also refer to the leaking matter itself. Leakage flow rate is a function of the absolute and/or partial pressure gradient of leaking matter that exists across the package barrier.

Is Package Integrity the same as Container Closure Integrity?

As specifically stated in the USP <1207> chapter, package integrity is synonymous with container–closure integrity the terms are used interchangeably. In the past, to say a sterile product–package has container–closure integrity commonly meant that the package either had passed or was capable of passing a microbiological challenge test. The new USP <1207> Guidance chapter defines the concept of container–closure integrity more broadly, encompassing the absence of all package leaks that risk product quality. By this definition, a package is considered to have integrity if it allows no leakage greater than the product–package maximum allowable leakage limit. In other words, the largest and smallest leaks of concern are absent.

What is the Maximum Allowable Leakage Limit (MALL)?

The maximum allowable leakage limit is the greatest leakage rate (or leak size) tolerable for a given product–package that poses no risk to product safety and no or inconsequential impact on product quality. The maximum allowable leakage limit for a sterile pharmaceutical dosage form package will ensure the content’s sterility, preserve product contents, and prevent entry by detrimental gases or other substances, thus ensuring that the product meets relevant physicochemical and microbiological specifications through expiry and use. For multiple-dose product–packages, the in-use maximum allowable leakage limit is defined as the degree of protection demanded of the closure to limit microbial ingress and product formulation leakage between and during dosage access.

It is often stated that the USP <1207> outlines deterministic leak testing methods. What are deterministic leak test methods?

A deterministic leak test method is one in which the leakage event being detected or measured is based on phenomena that follow a predictable chain of events. In addition, the measure of leak detection is based on physicochemical technologies that are readily controlled and monitored, yielding objective quantitative data. Common deterministic leak methods noted in USP <1207> include Vacuum Decay, Laser Diffraction, Helium Leak Detection and High Voltage Leak Testing. Deterministic methods provide quantitative measure of analysis. A quantitative measure of analysis for leak testing is a measurement (result) approach based on objective, numeric data that either directly or indirectly correlates with leak presence, leak location, or leakage rate. Examples include the mass-of-gas-per-time reading generated by the helium mass spectrometry tracer-gas leak test, or the pressure reading as a function of test time measurement produced by the vacuum-decay method.

Dye Ingress test methods are acceptable deterministic leak testing methods?

Dye ingress tests not validated, reliable or sensitive enough for whole package integrity verification. Results generated from dye ingress testing tend to be variable and subjective. Even with the use of a spectrophotometric dye detection measurement, the risk of false positive or negative results is not eliminated.

How do Deterministic Test Methods differ from Probabilistic leak test method?

A probabilistic leak test method is the converse of a deterministic leak test method. Probabilistic tests rely on a series of sequential and/or simultaneous events, each associated with random outcomes described by probability distributions. Thus, the findings are associated with uncertainties that necessitate large sample sizes and rigorous test-condition controls to obtain meaningful results. Typically, sample size and test condition rigor are inversely related to leak size and in all cases results are always qualitative. A qualitative measure of analysis for leak testing is a measurement approach based on a subjective evaluation of some quality, attribute, or characteristic of the test sample. Visual inspection is an example of a qualitative measure of analysis.

What role do positive controls play in the USP <1207> Leak Testing Methods?

Positive controls are used during leak test method development and validation. A positive control is a package with a known, intentional defect usually created using a laser technology with the “hole” size being certified to a certain dimension or specific flow rate – for example, a 5 micron positive control defect. Positive controls used for leak test method development and validation studies should duplicate study negative controls in terms of materials of construction, package assembly, and component processing. Some methods require the use of positive controls during routine testing as well.

Positive controls created by inserting needles, tubes, or pipettes into a package are acceptable replacements that can be used in place of laser drilled positive controls?

The simple answer is no. Inserting a wire, needle, tube or pipette into a parenteral glass vial, a syringe barrel or an elastomeric stopper is a less expensive and simple way to create a defect and may be useful for screening leak test methods. But, in many cases, long channels or wires artificially lodged into the package are no substitute for more realistic defects strategically positioned throughout the container, including at critical seal sites. Peer reviewed studies using laser-drilled holes in glass vial walls demonstrated that proteinaceous active substance in liquid product formulations may clog defects making it impossible to use leak test methods that rely on gas or liquid flow through the leak, such as vacuum decay or dye ingress. This observation might have been missed if other types of artificial defects had been used.

While the USP <1207> Chapter outlines numerous test method approaches and technologies, only one method or technology is needed and can be applied to multiple package systems and products?

The simple answer is no. Numerous leak testing approaches are useful, but no one method or technology works for all applications, package and/or product types. As heard numerous times, the “toolbox approach” for leak testing methods is required due to the various product-package applications. As an example, vacuum decay methods are generally effective for testing powder-filled packages and non-proteinaceous liquid-filled packages. High voltage leak detection works well for many package systems containing liquid formulations so long as the product is conductive. Frequency modulated spectroscopy with laser-based gas headspace detection is invaluable for packages requiring vacuum or inert gas headspace. These methods are all nondestructive, leak test methods that have replaced, and improved upon, the reliance on microbial challenge and dye ingress tests.

What is meant by the phrase Inherent Package Integrity?

Inherent package integrity is the leakage characteristic of a well-assembled container–closure system using no-defect package components. Inherent package integrity is first determined during product–package development and qualification and is a measure of the leak tightness of a container–closure system, given anticipated variables of material composition, dimension, processing, and assembly. Inherent package integrity may also be determined as a function of anticipated final product storage, distribution, and use. Acceptable inherent package integrity for a container–closure system conforms to the specific product–package maximum allowable leakage limit. Inherent package integrity is expressed in terms that allow a meaningful comparison to the maximum allowable leakage limit.

What type of information is needed to begin determining the most optimal test method for my container-closure system?

To initiate an effective USP <1207> CCI program on a specific package-system and product, you must provide technical specifications on the container system to include size, material of construction and type of closure system. Next you will need outline specific product information to include dosage form, fill level, headspace information, sterile profile, product protein level if applicable, and reveal is the product is gas (oxygen) sensitive. In addition, assembly process information, storage conditions required, and shipment profile and shipment temperature can play key factors. Collectively this data will held to determine the most optimal test method and technology approach that ensures your CCIT objectives meet all regulatory requirements.

How long does a routine USP <1207> CCI Testing method development and validation program take to complete?

As a general rule of guidance, a standard USP <1207> test method development and validation program will take somewhere between 15-20 weeks from start to finish. The process can be broken down into three distinct phases. Phase One will include consultation to determine the optimal approach and method. A key part of this phase is the development of instrument change parts specific the container-closure system to be tested and the creation of positive control samples (laser drilled and size certified) on actual empty containers. Typically phase one is 6- 10 weeks. The next phase brings the project to method development. Each combination of container system and product requires the development of a method specific to that system and technology being used. Using a trial an errors process, various parameters are investigated that lead to the creation of a robust method. Typically, the method development phase lasts 2-4 weeks. Finally, phase three is validation of the method. This is typically done over a defined time period and across a variety of operators. Method validation typically takes 2 weeks with any additional 2-4 weeks for a complete compilation of all data and the generation of a formal method development and validation report.