Originally Published MDDI January
2005
Packaging
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.
Erik Swain
 |
| 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.”
Crucial Documents
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.
Stability Guidance
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.
Choosing Alternatives
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.”
Conclusion
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.”
References
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.
Copyright ©2005 Medical Device & Diagnostic Industry
