Quality Requirements For Pharmaceutical And Medical Device Packaging
Why Do Sterile Packaging Quality Requirements Matter?
Package integrity maintains the quality and sterility of medical devices and products until their point of use or product expiry. Maintenance of product sterility protects patients from harmful contaminants. For some medical products, the packaging needs to maintain a headspace with non-reactive gases and low water vapor to preserve physical or physicochemical stability for use. Lyophilized products and other products that require reconstitution for use often require gas headspace preservation when packaged. Gas headspace is often needed because gas headspace under vacuum stops moisture from entering the package and prevents reconstitution difficulties upon use.
Nearly all packaging has very low gas flow leakage through gaps between well-fitted closures. Thus, it is not practical or mandatory for packages to be entirely leak-free. However, a packaging system should not permit leakage beyond a maximum allowable limit. This maximum leakage limit differs depending upon multiple factors. For example, low levels of headspace gas leakage will not be an issue for product-packaging systems where sterility alone is the primary objective. However, if headspace gas within product packaging must be preserved to maintain a product’s integrity until use, the maximum allowable leakage limit for a product-packaging system will need to be higher to keep headspace gas pressure above a certain level over time. The maximum allowable leakage limit considers the environmental conditions a package experiences during its life cycle. Such considerations include high-temperature fluctuations, humidity, and pressure changes due to shifts in altitude.
Package integrity testing examines product packaging systems to ensure that any leakage meets regulatory standards and is within the designated maximum allowable leakage limit needed to maintain sterility and product functionality over time. Package integrity test methods vary in detection range, detection limit, precision, and specificity. Thus, the package integrity tests you select depend upon the packaging quality requirements you need to meet for your medical device’s or product’s packaging system.
There are two major categories for sterile packaging quality requirements. The first category is a packaging system where the product’s sterility and functionality are preserved without gas headspace preservation.
The other category is a packaging system where gas headspace must be held to maintain the product’s sterility and functionality. If your product is a multi-dose system, it falls into an additional subcategory of product quality requirements that need to be met. All of these packaging quality categories are discussed in further detail below.
Category #1: Preservation of Sterility & Product Content; Gas Headspace Not Preserved
Most medical devices will use Category 1 packaging quality requirements. Category 1 packaging systems prevent contamination by liquids, solid matter, or microorganisms. Gas headspace pressure changes or loss over time are of no concern for this packaging quality category. Small leaks with a limited gas exchange are of no risk to the product quality in this system.
Leak rates for rigid container-closure systems for Category 1 packaging quality systems are well known. Category 1 products in rigid container-closure systems can safely adopt a maximum allowable leakage limit of less than 6×10−6 millibar liters per second (measured by helium mass spectrometry under vacuum). The probability of microbial contamination with this maximum allowable leakage limit for rigid container-closure systems is less than 0.10. As a result, additional microbial contamination or microbial challenge studies for a Category 1, rigid container-closure system with the maximum allowable leakage limit reference above are unnecessary.
Flexible container-closure systems are not as well understood. Thus, additional testing to evaluate microbial contamination and leakage is needed to ensure the package integrity of flexible packaging systems. Though many package integrity tests are pass/fail, quantitative package integrity tests enable a maximum allowable leakage limit to be established for a given flexible packaging system.
Temperature and pressure fluctuations during transportation and storage of packaging systems significantly impact gas headspace leakage. For instance, low temperatures increase gas headspace leakage, and ultra-low temperatures (-80C) affect the integrity of viscoelastic packaging. Depending upon your product’s storage and transport conditions, gas headspace preservation may be necessary for product quality, even if the product does not require a specific pressure or the presence of a particular gas for optimal stability.
Category #2: Sterility, Product Content, and Gas Headspace Preserved
Most pharmaceutical packaging systems will fall under Category 2, packaging quality requirements. This packaging must prevent contamination from liquids, solid matter, or microorganisms. Additionally, this packaging system keeps the gas headspace content or maintains a particular absolute pressure within the package. Thus, the maximum allowable leakage limits for these products are almost always more stringent than the limits for Category 1 products. Maintaining the headspace content or pressure for a packaging system offers various benefits. Some of these benefits include keeping the stability of physiochemical products, maintaining headspace pressure under extreme temperature fluctuations, and keeping any reactive device materials from oxidizing.
For Category 2 packaging quality, gas permeation through the packaging system will need to be considered when deciding upon the maximum allowable leakage limit as gas permeation can contribute to headspace gas loss in addition to any small leaks. The maximum allowable leakage limit for products in this category is expressed as the maximum allowable package headspace content or maximum allowable pressure change within the package as a function of time.
Multi-dose Product Packaging Systems: Sterility Preserved; Product Access Required
Multi-dose packaging systems are a subcategory of Category 1 and Category 2 packaging systems. For multi-dose systems, packaging must meet an additional set of package leakage requirements. Before initial use, multi-dose packaging systems may fall under Category 1 or Category 2 quality requirements. However, after initial use, multi-dose systems must maintain a “new” maximum allowable leakage limit between the administration of individual doses to maintain product quality and sterility.
An example of such a packaging system is the elastomeric closures of multiple-dose vials. Elastomeric closures are designed to reseal and prevent microbial contamination, and product formulation leakage between dosage draws with a needle. The “new” maximum allowable leakage limit to be maintained by a multi-dose packaging system after initial use is known as an in-use maximum allowable leakage limit.
The in-use maximum allowable leakage limit is defined in terms of acceptable microbial entry and product loss between and during dosage access. A study evaluating the relationship between product access amount, microbial contamination, and product loss is completed to establish in-use maximum allowable leakage limits for unique multi-dose packaging systems. The in-use maximum allowable leakage limit set for one product–packaging system may be used for other systems if they are substantially similar.
Summary
Nearly all packaging displays very low gas flow leakage. Package integrity testing examines product packaging systems to ensure that any leakage meets regulatory standards and is within the designated maximum allowable leakage limit necessary to keep a product sterile and functional over time. Package integrity test methods vary in detection range, detection limit, precision, and specificity. Thus, the package integrity tests you select depend upon the packaging quality requirements you need to meet for your medical device’s or product’s packaging system.
There are two major categories for sterile packaging quality requirements. The first category is a packaging system where the product’s sterility and functionality are preserved without gas headspace preservation. The other category is a packaging system where gas headspace must be held to maintain the product’s sterility and functionality. If your product is a multi-dose system, multi-dose systems must also meet in-use maximum allowable leakage limits. Overall, it is essential to get the suite of package integrity tests you need to ensure your medical device’s or product’s quality over time.
MycoScience is a contract manufacturing organization specializing in sterile syringe and vial filling. MycoScience also offers Preservative Efficacy Testing, Sterilization Validations, Bioburden Testing, Cleaning Validations, Microbial Aerosol Challenge Testing, Accelerated Aging, Microbiology Testing, Cytotoxicity Testing, Bacterial Endotoxin Testing, EO Residual Testing, Package Integrity Testing & Environmental Monitoring services medical devices and allied industries. MycoScience is an ISO 13485 certified facility.
References
United States Pharmacopeial Convention. <1207> Package Integrity Evaluation- Sterile Products. Rockville, MD, USA. 2021. (USPC <1207>).
