Get with the ProgramGet with the Program
FDA concerns regarding terminally sterilized medical products are based on years of data that implicate failures in primary packaging. Approximately 47% of failures occur due to inadequate package validation programs.1
May 5, 2010
During the packaging validation process, one of the tests that must be performed is a peel test. Images courtesy of MICROTEST LABORATORIES. |
This article provides insight into the general requirements in a microbiological and physical testing program. It discusses how combination products pose a unique set of challenges to package validation engineers. For example, one key issue involves the requirement for a pharmaceutical or biologic component to meet International Conference on Harmonization (ICH) guidelines for stability in a flexible pouch under normal conditions.2 The United States Pharmacopeia (USP) provides information about ambient storage conditions of storage and shipment. Unfortunately, medical device package testing is not standardized in terms of shelf life requirements because the variation of device materials requires the manufacturer to modify ASTM conditions to bracket shipment, storage, and use conditions. FDA has yet to support and standardize an accelerated aging program and microbiological procedures. Physical testing is probably the best indicator of adequate sealing parameters. However, these tests do not give technicians the ability to extrapolate to real world microbiological ingress limits. These limits may have little benefit to the medical device manufacturer. This article discusses some of the options for testing. The Challenges of Packaging ValidationAll medical device materials and drug products have a finite life span. Materials such as plastics, adhesives, polymers, and films degrade with time. Most medical devices have a primary and a secondary packaging system. Both packaging systems require validation programs. Historically, medical devices have been tested for degradation (forced degradation studies) by heating in a hot air oven at 55° to 60°C from weeks to months. This procedure, generally called accelerated aging, is based on the following formula (Q 10 coefficient): a 10°C rise in temperature doubles the chemical reaction rate. Extrapolating the rate to time gives a set point that can be used to indicate aging at room temperature and in real time. After treatment, the devices are tested for various material characteristics. These characteristics include ASTM D2240 durometer, form, fit, and function. The testing of plastics can require infrared scans, gel permeation chromatography (GPC), and gas chromatograph/mass spectrometry (GC/MS) testing for leachates. Typically, the validation program will cull out tertiary testing based on a suitable product risk analysis. Tertiary or release testing programs are typically added after the validation program to determine which analytical procedures would be required for product release. Combinatory products require strict adherence to ICH guidelines for stability of the drug and biologic throughout the shelf life of the product. For products that have a delivery system (such as needleless injection systems), storage and shipping parameters are critical to maintaining required potency. For other products that have a drug coating or scaffolding application, the validation program requires a unique perspective into both medical device shelf-life studies and the ability of the drug and biologic formulation to maintain stability throughout all phases of the manufacturing and sterilization process. Formulation issues are very important prior to FDA filings, and these considerations will be a major portion of the final regulatory filing. It is important to note that this article does not address formulation. Medical device packaging validations are performed with baseline products that have not been subjected to normal warehouse storage. Nonsterile samples are required for initial fingerprint seal analysis. These data give essential background seal analysis information that is essential for comparison studies on sterile packaging. These samples reveal data changes with sterilization. All sterile samples sent in for package seal analysis measurements allow the tester to determine physical seal changes during accelerated or real-time aging studies. Transportation samples are taken from both real-time and aged products. Packaging testing guidelines are listed in ISO 11607. This document describes the available ASTM packaging tests. It also brings together many other key aspects of packaging validation (i.e., material qualification, validation of seal process, and whole package seal integrity). However, it does fall short in not speaking to a definitive validation regimen for all to follow. Physical tests that are performed may include burst, creep, creep to fail, peel, and leak. Packaging validation specialists can help manufacturers choose the most appropriate tests based on its packaging materials (see Table I). A robust packaging validation program should include transportation simulation testing with concomitant sterility testing.3 Some device manufacturers bracket the potential storage and shipment temperatures and conditions (such as air cargo) during their initial studies. The steps in the packaging validation process include the following:
Select appropriate package material and design, qualify equipment, validate sealing process, and produce test samples.
Perform burst test and peel strength creep testing on both sterile and nonsterile, nonaccelerated aged product.
Place an appropriate number of samples into accelerated aging for the required period.
After aging, the packaging is tested for physical testing. Device samples are tested for material problems and whether or not they meet product specifications.
A portion of the accelerated samples are culled for transportation simulation tests, including International Safe Transit Association and ASTM shipping tests.
Packaging samples are tested for physical parameters as above. A visual exam is performed to look for holes caused by vibration testing. Device samples are tested for specification requirements.
Combination products require a second-tier approach to package validation. Appropriate prevalidation questions may contain concerns over active pharmaceutical ingredient potency; biologic activity; medical device polymer, drug, and biologics interactions; and ICH stability issues.4
FDA has also published a guidance document titled 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 CDRH, the Center for Biologics Evaluation and Research, the Center for Drug Evaluation and Research, and the Center for Veterinary Medicine.
Drug and biologic interactions with polymers can be an issue with respect to emitted dose and stability. Some medical device polymers may cause changes to small and large molecules. These changes, such as emitted dose variabilities during product use, can be critical to product launch. The testing regimen must flush out the variables for stability and concentrate on the criticality of the studies and assays in terms of experimental design and robust method development studies. Some of these issues become prominent during production scale up.
Cell therapy products such as xenografts, allografts, and stem cell products create unusual challenges for the package validation engineer and FDA offers very little guidance on these issues. Cells must be able to withstand shipment and storage during a finite and defined period. Evaluation of cell lines and tissue implants during a stability program is required prior to FDA submission. There are several points to consider during package validation studies for cell therapy products, including:
Bacterial, fungal, and mycoplasma sterility testing (USP sterility and FDA mycoplasma test).
Viral sterility test (FDA virus assay).
Particulate test (USP).
Cytotoxicity (USP).
Container integrity testing (MBD immersion test).
pH analysis.
Buffering capacity (container) USP.
Leachate testing (container) GC/MS analysis.
Conclusion
Medical device stability package validation programs should be designed to encompass the overt product storage and shipment conditions. Performing accelerated aging studies does little to address damage during shipment and storage. Damage can be caused by many factors such as aberrant conditions, stress, and overt handling, to name a few. In the future, FDA may require companies to perform similar ICH-type stability studies. In the 1991 FDA guidance document, Shelf Life of Medical Devices, by Geoffrey Clark, much needed guidance was posited. Today, however, new guidance documents are needed to address combination products and to move the medical device industry closer to ICH compliance.
The necessity to develop a robust packaging validation regimen cannot be overstated. A comprehensive regulatory approach to validation during early product development can save many weeks of redevelopment and testing activities. Ideally, as FDA and the global community move toward harmonization, a stability guideline for combination products would emerge and provide a path forward for validation specialists. Combination product GMPs are also in the final review process.5 These GMPs will be the first step toward compliance issues and clarity.
In conclusion, all device and combination product manufacturers are required to have a robust package validation program. The testing that was presented in this article is not all encompassing. It is presented to give one a starting point for package validation programs.
References
1. M Sherman, Medical Device Packaging Handbook (New York, CRC Press, 1998).
2. USP Volume 32, Section 1079, “Good Storage and Shipping Practices: Statements/Labeling of the Immediate Containers or Package Insert” (Rockville, MD) 540-541.
3. Test Series, The International Safe Transit Association, available from Internet: www.ista.org.
4. S Richter, “Combinatory Products: Navigating Two FDA Quality Systems,” available from Internet: www.microtestlabs.com/combinationpaper.
5. Federal Register 74, FR: 48423, September 23, 2009.
Steven Richter, PhD, is founder, president, and chief scientific officer of Microtest Laboratories Inc. (Agawam, MA).
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