Originally Published MDDI January 2005
Originally Published MDDI January 2005
Extra Effort: Packaging for Combination Products
Producing a suitable package for a combination product requires device companies to understand the regulations, materials, and processes behind drug and biologic packaging.
|Combination-product packaging must incorporate elements of pharmaceutical and
biologic packaging to account for the drug in the device.
You're a packaging engineer at a medical device company. Your firm plans to develop its first combination product, and you've been asked to design and test its package. What do you do? For starters, you do a lot more than you've ever done for a regular device package.
Combination-product packaging presents a new set of challenges for the medical device packaging engineer, because the design must incorporate elements of pharmaceutical or biologic packaging. And that means device companies must consider a number of factors and run a number of tests that they never needed before. Although the same materials that suit a regular device may also suit a drug-device combination product, proving it to FDA is a much more involved process.
To what extent do the requirements for drug or biologic packaging come into play for a combination product? It depends on the product.
If it is a drug and a device combined as a single entity, “this is really where a medical device combination product is treated like a drug,” and its packaging, to an extent, is treated like drug packaging, says consultant Hal Miller, president of PACE Solutions LLC (Warren, NJ).
If the drug and device are not integrated but placed in the same kit, drug-packaging guidelines do not apply as much, Miller says. The same is true for a drug and a device that are packaged and sold separately but intended for use in the same application, he says. In the former case, drug-packaging guidelines apply only to the primary package of the drug inside the kit. In the latter case, the drug and the device are packaged according to their respective regulations, but labeling requirements cross over.
New Sets of Issues
Drug packaging is based on principles that are different from device packaging, Miller explains. “Drug packaging primarily deals with the safety and effectiveness of the product, whereas device packaging is a slightly different concept,” he says. “It's about protecting the product, allowing for sterilization, and maintaining sterility.”
|Oliver Products Co. had to scale down its normal EtO sterilization cycle because the drug involved in the device was very susceptible to heat.|
“The biggest difference,” says Ed Haedt, director of marketing for Perfecseal (Oshkosh, WI), “is that a device coated with a drug or biologic may require more than just physical testing. Drugs and biologics may be unstable under certain conditions.”
Laura Bix, assistant professor at the Michigan State University School of Packaging, agrees. “Device packagers working on combination products will find that the atmospheric environment is much more significant than it has been,” she says. “It may take them a while to get used to issues of shelf life and safety.”
This proved to be the case when Boston Scientific Corp. began developing the packaging for its Taxus drug-eluting stent. “There were different requirements since a drug was in play,” says Tim Mlsna, Boston Scientific's director of packaging engineering. “These ranged from biocompatibility to photostability to integrity to moisture permeation to thermal conditions. Many of the tests we had to do were the same [as for packaging a bare-metal stent], but there were some that we had not done before.”
Mlsna said his team also found that FDA expected a much greater level of detail about the packaging of Taxus than of regular devices. “For example, we had to perform more validations,” he says. “We needed to validate that the temperature extremes in the sterilization cycle were within what the drug could withstand.”
Two guidance documents from the Center for Drug Evaluation and Research (CDER) show how to determine whether the product is safe and effective within its package.1,2 Anyone packaging combination products should be familiar with both of them, says Miller. As a former director of packaging technology for Johnson & Johnson, Miller has experience with both.
The documents offer clues about the kinds of tests that a device package developer normally wouldn't use but that are required for drug packaging. Perhaps most arduous are stability tests. These tests determine how the quality of a packaged drug product varies with time under the influence of environmental factors such as light, humidity, and temperature. Other tests that may be novel to device manufacturers follow United States Pharmacopeia (USP) standards. Those tests include ones for moisture vapor transmission rate (MVTR), gas permeation, adsorption, absorption, and extraction studies.
It is also helpful, Mlsna says, for the package development team to consult with the regulatory affairs team early on in the process. “We needed to understand what additional requirements [FDA] would have,” he says. “Working with regulatory early on was so important, as was bringing in consultants who had relevant experience.”
Container Closure Guidance
|Amcor Flexibles Healthcare found that control of packaging material becomes even more important when a drug product is in play.|
CDER's container closure systems guidance contains information on qualifying packaging components for drug products. It can help packaging engineers determine what tests they need to perform. The tests ensure that packaging materials adequately protect and don't adversely affect the drug portion of a combination product.1
The level of assurance CDER requires depends upon the likelihood of interaction between the package and the drug as well as the level of risk associated with the administration route. For many drug-device combination products, the latter will be high, and the former has a good chance of being high. Inhalations and injections are specified as high-risk routes of administration. Although it is not stated specifically, chances are the agency would similarly classify any product that requires a surgical procedure to be activated as high risk. Tablets, capsules, and powders are the only drug types that are not considered a high risk for interaction with packaging components. Most combination products use drugs in liquid or aerosol forms. Thus, CDER is likely to require extensive proof that a package is suitable for a drug-device combination product.
The guidance's first requirement is that the proposed packaging system adequately protect the dosage form from factors that degrade its quality. These include exposure to light or reactive gases like oxygen, loss of solvent, water vapor absorption, and contamination.
The need for light protection can usually be determined by USP <661>. Solvent loss can occur from leakage or inadequate sealing. But in the case of some combination products, it also can occur from a poor choice of coating. Water vapor and oxygen can enter a package through a permeable surface or by diffusing past a seal. Both surfaces and seals may need to be tested for these characteristics, depending on the nature of the product and the packaging materials chosen. Device manufacturers likely already have validated procedures to check for microbial contamination and contamination by filth.
The next requirement is that the packaging components and the dosage form must be evaluated. They must not interact sufficiently to cause unacceptable changes in each other. Sometimes such interactions can be detected during qualifications of the packaging materials and components. Other times, they will only show up during stability studies. CDER requires that any change during a stability study that might be attributable to drug-package interaction be investigated immediately.
The package also must be evaluated for safety. It cannot contain materials that will leach harmful or undesirable amounts of substance to which a patient would be exposed when being treated by a drug product.
|When developing the package for its Taxus drug-eluting stent, Boston Scientific found that different requirements were in play since drugs were involved in the device.|
CDER requires a comprehensive safety study for drugs with a high-risk route of administration, which applies to most combination products. First, an extraction study of the package must be performed. That study determines which chemical species may migrate into the dosage form, and at what concentration. Second, a toxicological evaluation of the extracted substances must be performed. For injectable or ophthalmic products, performing USP biological reactivity tests and USP elastomeric closures for injections tests might be sufficient. For liquid drug products, referencing the food additive regulations in 21 CFR 174–186 for the particular packaging material may be enough. However, if the drug is intended for chronic use, such a reference probably isn't adequate. If the product is in clinical trials, FDA considers documentation of no adverse reactions related to the packaging as supporting evidence of the packaging's safety.
The guidance also requires an assessment of whether the packaging system functions in the manner for which it was designed. This has mostly to do with cases in which the package also functions as a drug-delivery system. The document does not specify what tests should be used. But it does say that they should be determined based on dosage form, administration route, and design features.
Also in the guidance is an outline of how to describe quality control measures that will be used to ensure consistency in the packaging components. First, the packaging process must be evaluated for variation in physical parameters that may affect the quality of the dosage form. Second, consistency of chemical composition must be monitored. In many cases, this requirement can be fulfilled by stability studies. However, for inhalation drug products, batch-to-batch monitoring of the extraction profile for the polymeric and elastomeric components is expected.
The guidance also delves into an area with which device packaging engineers may not be used to working: drug master files. These enable FDA to learn about the chemical composition of the packaging components supplied by vendors. They generally contain information that packaging suppliers consider proprietary and do not wish to share with their customers. CDER expects to see this information referenced in an application as a matter of course; CDRH does not.
The other drug packaging guidance that device-packaging engineers should be keenly aware of is on stability testing.2
FDA wrote the document with European and Japanese regulators, and its advice applies to products shipped to all those nations. It does not provide details for sampling and testing of particular dosage forms in their proposed packages. Yet it does cover what sort of stability-related information CDER expects to see in applications.
It is up to each device manufacturer to determine how the stability study should be designed. According to the guidance, Stability studies should include testing of those attributes of the drug substance that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes. Validated stability-indicating analytical procedures should be applied. Whether and to what extent replication should be performed should depend on the results from validation studies.
Photostability testing, if appropriate, should be conducted on at least one batch of the drug product.3
Both long-term and accelerated stability tests are needed. For long-term studies, frequency of testing depends on the proposed shelf life. For example, a product with a 12-month shelf life should be tested four times during the first year of the study, twice the second year, and once each year thereafter. For the accelerated study, testing should be conducted at least three times, including at the starting and end points of the time frame. Reduced designs, where testing frequency is reduced or certain factor combinations are not studied at all, are sometimes permitted. However, the manufacturer must justify these designs to FDA.
For most drug products, long-term testing must be conducted at 25°C ± 2°C/60% RH ± 5% RH or at 30°C ± 2°C/65% RH ± 5% RH. Accelerated-age testing must be conducted at 40°C ± 2°C/75% RH ± 5% RH. The requirements are different for products packaged in semipermeable containers or those that must be stored in a refrigerator or freezer.
In most cases, test results must be analyzed statistically. However, if the data show very little degradation or variability, a formal statistical analysis may not be necessary.
Postapproval stability studies may have to be conducted as well. Sometimes, available long-term stability data do not cover the proposed shelf life granted at the time of approval. In those cases, manufacturers must promise FDA that they will continue the stability studies after approval to firmly establish the shelf life.
Whatever testing schemes a device company comes up with should “boil down to [the product's] critical needs,” says Mary Czarnopys, converted products market manager for Perfecseal. “For example, we had one customer use a film that, when tested, turned out not to be suitable. We found [the film] needed an additional nylon barrier. Then we did distribution testing and barrier testing to make sure it fit the critical need.”
Sterilization practices may have to change when a combination product is involved. Device manufacturers have to understand what effect their sterilization methods have on drugs or biologics. Drugs and biologics are usually not subject to terminal sterilization like devices are. “Typically, they're manufactured in a cleanroom or by aseptic processing,” says Miller. “You may not be able to take a normal approach with sterilization, especially when it comes to biologics.”
John Ozcomert, director of technology for Amcor Flexibles Healthcare (Mundelein, IL), says those who choose radiation forms of sterilization may need to rethink that when it comes to combination products. “If you are using gamma or E-beam sterilization, it could make a significant impact on the efficacy of the drug,” he says. “Frequently those kinds of products are sensitive to those environments.”
Jeff Murak, director of sales and marketing for Oliver Products Co. (Grand Rapids, MI), says device companies that use EtO may need to adjust cycles for combination products. “We were working with an ophthalmic application where the drug to be injected was very susceptible to heat,” he says. “As a result, sterilization cycles had to be scaled down from the normal EtO cycle.”
Material choices may be affected, too. If the product is particularly sensitive to moisture or oxygen, its package may require materials common to pharmaceutical packaging such as foil or high-barrier films like polychlorotrifluoroethylene (PCTFE). “Specialty packaging for pharmaceuticals and medical devices is being blended together,” says Miller. “You now need to know about options that are available outside of your own sector.”
Peter Giczewski, vice president and general manager of Barger Packaging (Elkhart, IN), also notices that trend. “It seems that a lot of our customers want MVTR to be significantly less where combination products are concerned. In those cases, we may switch from PETG to PCTFE, and from Tyvek lidding to foil lidding.”
Mlsna says Boston Scientific was able to use most of the same packaging materials for Taxus as for its other catheter products, but it took a lot of analysis to reach that conclusion. “Early tests we had done resulted in preliminary findings about the level of protection the existing package could provide compared with the need of the product,” he says. “Then we were able to upgrade some materials to produce the strength that we needed.”
High-barrier materials tend to be nonporous. Yet it is possible to continue using EtO sterilization, for which porous materials are required, if the package is designed in a certain way. For example, some combination products are packaged in a foil pouch with a Tyvek header. They are sterilized through the Tyvek header, which is then cut off and the package sealed, allowing the entire package to be nonporous after sterilization.
DuPont Medical Packaging, maker of Tyvek, has noticed that Tyvek may need to be coated differently when used with combination products than when used with regular devices. “We get more requests for uncoated or zone-coated Tyvek with combination products,” says Miray Peirera, global business manager. “This is to avoid the coating coming in contact with the product. There is a tendency for combination products to be more sensitive to contact with coatings.”
Material suppliers and converters are coming up with other solutions. “Converters are figuring out ways to make a package sterilizable by EtO yet also provide a high barrier,” Haedt says. “We have developed a unique bag that we believe fits that bill.”
Device companies may even have to change how they procure their packaging materials if they begin to develop combination products. “You can keep a device on a shelf for a long time, but a drug may only have a shelf life of three months,” says Ozcomert. “That may mean you need to make smaller orders every few months, instead of one or two large orders a year,” to mirror the inventory of the product itself.
Also, control of packaging materials becomes even more important when working with a product subjected to drug regulations. “We had to build in controls that allowed us to keep track of every label and every package,” he says. “So the manufacturing side brought in additional complexity.”
A number of new factors come into play when device companies package a combination product for the first time. Therefore, not only should packaging engineers expect to face more issues than usual, they should expect the entire package-development process to take longer. But if work is started early enough, the right people are consulted, and a strong development plan is put in place, the results should be more than satisfying.
“The assessment and ultimately the development of the packaging definitely took longer than with a typical product,” Mlsna says of the Taxus project. “But we knew we needed to start working on the package development at the same time the R&D engineers started working on the product. That was the only way to ensure we would have enough time to get everything done properly.”
1. Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics, [on-line] (CDER, 1999); available from Internet: www.fda.gov/cder/guidance/1714fnl.htm.
2. Guidance for Industry: Q1A(R2) Stability Testing of New Drug Substances and Products, [on-line] (CDER, 2003); available from Internet: www.fda.gov/cder/guidance/5635fnl.doc.
3. Guidance for Industry: Q1B Photostability Testing of New Drug Substances and Products, [on-line] (CDER, 1996); available from Internet: www.fda.gov/cder/guidance/1318.htm.
Erik Swain is East Coast editor of MD&DI.
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