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This information chapter addresses the maintenance of the microbiological integrity of sterile product packaging until the time of use of its contents. The scope of application of this chapter includes the container and closure systems of drug products and the sterile barrier packaging of medical devices, including in vitro diagnostic products. Specially designed or novel container–closure and barrier packaging systems, which are generally more complex than classical packaging and delivery systems, are also discussed in this chapter. The establishment of sterile product integrity is necessary to ensure the maintenance of two extremely important product conditions: total product attributes within label claim specifications and product sterility prior to use.
Product package integrity testing continues throughout the life cycle of the product. Generally, this integrity testing should occur during three phases: (1) the initial development of the product packaging system, (2) routine manufacturing, and (3) shelf life stability assessments. Generally, during initial packaging development both physical and microbial studies are conducted to assess integrity. It is at this time that comparative information about physical and microbial challenge methods may be obtained.
During routine manufacturing, physical measurements may be conducted in accordance with an established sampling plan to determine whether the packaging or capping system or both are operating consistently within predetermined performance acceptance ranges. Packaging integrity tests conducted during shelf life stability assessments are physical tests that confirm the integrity of the packaging system supported by acceptance values established during packaging development. Microbial ingress testing may be unnecessary for shelf life stability assessment if comparative physical and microbial testing conducted during the packaging development stage has established physical acceptance values that would preclude microbial ingress. Reconfirmation of product packaging integrity should occur when there are major changes in the package design and materials or whenever there are changes in the manufacturing processing conditions, including sterilization conditions.

Testing during the product development phase is frequently intensive, because it establishes product design limitations before full-scale manufacturing occurs. At this phase, an appropriate product package design relative to the end use of the product is selected, and manufacturing process variables are defined. The effect of the design and process variables on the maintenance of package integrity is assessed. Approximate design tolerances are assessed to ensure sterility of the fluid pathway or contents during processing and prior to usage. Product packaging integrity evaluations should take into consideration the maximum stress conditions encountered during the manufacturing and sterilization processes. Testing should also validate the integrity of the design when exposed to anticipated extreme conditions of storage, shipment, and distribution. During this phase, physical methods are developed to assess the integrity of the proposed package, and they are used later in routine manufacturing testing or marketed product stability testing.

During this phase, maintenance of specified production, engineering, and microbiological conditions is monitored through standard operating procedures. Physical testing methods, on-line or not, may be intermittently used to supplement process control measurements to ensure that product packaging values are maintained within acceptable limits established during the product development phase. During routine manufacturing, monitoring for continuous unit product integrity or finished product release package integrity may be unnecessary when critical production processes are well controlled. Microbiological testing of package integrity is usually not expected during routine manufacturing that operates within specification limits previously determined to produce acceptable packaging.

Physical testing methods may be used to evaluate product packaging systems that are included in a marketed product shelf life stability program. Such systems should be evaluated at stability conditions, at the beginning of the product shelf life as well as at the expiration date of the product, and at other times and intervals defined by regulatory requirements or guidelines. Sole testing of product sterility will not ensure maintenance of product package integrity over the shelf life of the product when performed as part of the packaging stability program.

During the initial evaluation of product packaging, both physical and microbiological testing are frequently used.1 Physical testing to assess product packaging integrity has a variety of advantages over microbial testing, depending on the test method and the packaging being evaluated. These advantages may include greater sensitivity, ease of use, rapid speed of testing, or lower cost. Physical testing can be used to evaluate product packaging throughout its life cycle to ensure that total product attributes are maintained within optimum predefined limits. Microbial ingress testing in concert with physical testing should also be considered at the initial stages of product packaging development. However, physical testing methods with sensitivity comparable to or greater than that of microbial methods are preferred for evaluating product packaging in a marketed product shelf life stability program. Physical testing methods provide rapid assessment of packaging integrity during routine testing of large numbers of product stability samples.
Comparison of Microbial and Physical Methods
A comparative evaluation should determine whether microbial intrusion or ingress into the product packaging could occur at those physical integrity test value ranges that have been deemed acceptable for the finished product. This determination should be based on a comparison between microbiological data and the values obtained from physical integrity test method. The comparison of physical integrity testing to microbial ingress testing for assessment of product packaging integrity can be obtained either by direct comparison or by studies that demonstrate that the physical test measures defects that are too small for microbial passage.
Due to its design or material composition, a product packaging system may not permit or yield graded physical test responses when a range of defects is created in the packaging. In some situations, even upon creating artificial defects in a product packaging system, the resulting range of physical testing values may remain approximately the same. In other words, the test method may yield a qualitative rather than a quantitative measure of package leakage. Also, microbial ingress may not occur until exaggerated physical defects are created in the packaging. In such cases, a direct correlation of microbial ingress to a series of physical value ranges is not possible. When this occurs, the testing results become merely pass or fail results conducted on packaging with known defects.
Selection of Evaluation Methods
Physical and microbiological methods for product package integrity testing should take into consideration the design of the closure system; the manufacturing method, including the sterilization process; and the intended use of the product. Any particular physical or microbial method may not be applied to all product packaging systems.
During initial integrity evaluations of a packaging system, a number of physical tests may be used. These physical tests may include, but are not limited to, pressure and vacuum decay tests, dye immersion tests, liquid chemical tracer tests, gas ionization of evacuated containers, high-voltage leak detection of plastic or glass containers, visual examination for glass cracks, and gas leakage or package headspace analysis. Other tests that may be valuable in evaluating package seal quality include screw-cap removal torque, elastomeric stopper residual seal force, or heat seal strength.
Microbiological tests may include closure immersion testing for rigid container systems, inoculated shipment testing for certain packaging, and an aerobiological challenge for tortuous path barrier packaging.
Dual Function Container–Closure Systems2
Dual function container–closure systems are characterized by the addition of one or more intended functions to that of a container and require special consideration for integrity evaluation. For instance, in the case of small, flexible or rigid containers with an appended device component that allows direct patient injection and drug delivery, a delivery function is added to the container function. Thus, frequently, one compartment of the dual container–closure system is designed to contain the drug or solution prior to use or activation of the system—product containment compartment. Another compartment, different in function and design, either directly delivers the product from the container portion to a fluid pathway for direct injection of the patient or communicates with a sterile pathway of another access device. For example, a prefilled syringe contains a solution (container compartment) and a device component (delivery compartment) physically separated from the container compartment and used to directly administer the drug to the patient.
Therefore, dual container–closure systems typically have at least two compartments that require microbial barrier properties, and packaging integrity after sterilization and/or aseptic filling should be demonstrated for both compartments. In many cases, different portions of the dual system require different integrity testing methods. The selection of the integrity testing method is determined primarily on the basis of the intended objectives or performance requirements of the particular compartment. For example, the solution or drug-containing compartment of the dual container–closure system must be enclosed or sealed in a manner that precludes leakage of product or microbial ingress during and following the manufacturing process (see Selection of Evaluation Methods). On the other hand, the delivery portion of the dual container–closure system frequently contains a fluid pathway that is empty during the sterilization or aseptic filling process and is intended to remain dry until the product container portion is activated prior to use. A covering, a sheath, or perhaps a cap designed to vent during sterilization and storage protects the delivery compartment from airborne microbial ingress throughout the life of the article. However, this portion of the device is frequently not designed to prevent liquid ingress. Liquid ingress can be precluded by secondary packaging or by the physical design of the system itself. Microbial integrity testing of the delivery portion of such a dual container–closure system may include a nonimmersion microbial method or physical integrity test. Microbial testing would include, for example, an aerosolized microbial challenge under defined pressure changes.

1  A review of physical and microbiological methods related to the evaluation of product packaging integrity appears in Pharmaceutical Package Integrity, Parenteral Drug Association's Technical Report No. 27, 1998.
2  For more information, see ANSI/AAMI/ISO Standard 11607-2000, 2nd ed., Packaging for Terminally Sterilized Medical Devices.

Auxiliary Information—
Staff Liaison : Radhakrishna S Tirumalai, Scientist
Expert Committee : (MSA05) Microbiology and Sterility Assurance
USP29–NF24 Page 3035
Pharmacopeial Forum : Volume No. 27(5) Page 3111
Phone Number : 1-301-816-8339