Originally Published PMPN October
2004
Sterilization
Sterilization
Combination Products
Products
with drug and medical device components are challenging current sterilization
methods.
 |
| Sterilizers are used for Cosmed’s 24-hour turnaround EOExpress process in its Dallas/Fort Worth area location. |
Drugs and devices aren’t the only items on healthcare practitioners’
shopping lists these days. Combination products are becoming just as common.
Drug-eluting stents have certainly grabbed the headlines, but kits and prefilled
syringes are even more popular. Other products include living tissues impregnated
with drugs and devices coated with antibacterial agents. And others are yet
to launch.
With these novel combinations come challenges, especially in packaging and sterilization.
How do you ensure that a drug withstands terminal sterilization, for instance?
Many manufacturers have already answered this question and others. Still, challenges
remain, and sterilization service providers are working on the solutions.
COMBINATION MENU
In December 2002, FDA formed the Office of Combination Products (OCP). It also
outlined this definition in 21 CFR § 3.2(e):
“(1) A product comprised of two or more regulated components, i.e., drug/
device, biologic/device, drug/biologic, or drug/device/biologic, that are physically,
chemically, or otherwise combined or mixed and produced as a single entity;
(2) Two or more separate products packaged together in a single package or as
a unit and comprised of drug and device products, device and biological products,
or biological and drug products;
(3) A drug, device, or biological product packaged separately that according
to its investigational plan or proposed labeling is intended for use only with
an approved individually specified drug, device, or biological product where
both are required to achieve the intended use, indication, or effect and where
upon approval of the proposed product the labeling of the approved product would
need to be changed, e.g., to reflect a change in intended use, dosage form,
strength, route of administration, or significant change in dose; or
(4) Any investigational drug, device, or biological product packaged separately
that according to its proposed labeling is for use only with another individually
specified investigational drug, device, or biological product where both are
required to achieve the intended use, indication, or effect.”
The diversity of such products involves many centers in application reviews.
The OCP attempts to oversee these reviews, assigning them to appropriate centers
and keeping those centers on track. It also aims to help the centers develop
guidance or regulations to clarify FDA regulation of combination products.
STERILIZATION
FDA’s oversight no doubt has involved careful review of sterilization processes.
Methods and processes that have worked in the past may no longer be appropriate
or, at the very least, may require modifications.
“Sterilization is not a straightforward science,” says one medical
device manufacturing professional, whose firm brought a news-making combination
product to market this year. “One method will not fit all devices or combination
products.” Still, he has found that radiation and ethylene oxide (EtO)
continue to be the primary methods. They provide the lethality that is required
for complex devices, he says.
Wayne Rogers is a consultant based in Temecula, CA, who focuses on sterilization
and materials safety for the medical device manufacturing industry. He agrees
that common methods are usually considered first. “Most manufacturers will
continue to use current and traditional methods of sterilization; however, some
will modify them. They may also need new ones and novel approaches, which is
often where I come in. Most frequently I modify traditional or current methods
to overcome limitations or difficulties. But in a few situations I have come
up with some novel approaches.” New options include a combination of approaches
and sterilizing processes from physical, chemical, radiation, and plasma agents.
The medical device professional, however, has found that the “new sterilization
methods have not proven to be as robust as the tried-and-true methods.”
However, he does say that “Some vaporized hydrogen peroxide methods do
work for surface sterilization and for products that do not require significant
penetration.”
CONCERNS
 |
| The interior view of one of the Cosmed sterilizers shown on the previous page. These sterilizers are used for processing all types of healthcare devices including combination products. |
The marriage of drugs and medical devices and others has complicated matters.
Drugs must now cope with terminal sterilization, and stability no longer is
just a physical trait for devices. Each must now face the special considerations
previously reserved for the other.
For instance, “drugs that are processed with any sterilizing agent should
be tested after sterilization to verify that the process has not changed or
converted the drug,” says Brenda Sparks, account manager for Centurion
Sterilization Services (Howell, MI). “Precautions must be taken to
validate the sterilization process and the product when being used on various
drugs.”
Devices with active coatings, such as catheters and needles coated with heparin
or antiinflammatory agents, can typically be sterilized with EtO, says Gary
Benson, manager of sterilization and laboratory sales for Ethox Corp.
(Buffalo, NY). “However, these types of products can sometimes be heat
sensitive and require special attention. Standard cycles with high temperatures
may also not be appropriate for some combination products.”
If EtO cannot fit the bill, gamma radiation is another option for these products,
says Benson. “The hurdle is to aggressively control the biocontamination
load of these products before sterilization, because dose is solely dependent
upon bioburden levels,” he says.
Novel drug-delivery products that use thin films may face hurdles with radiation,
however. “Radiation continues to be limited by the degradation of the polymer
materials, especially thin- film materials,” says the device manufacturing
professional quoted earlier.
As with any sterilization process, there is the potential to reduce or impact
the stability of the drug, adds Benson. “A targeted 5-year shelf life could
easily be lessened by sterilization if not designed around the limitation of
the combination product,” he says.
Testing related to sterilization may also need to be modified for combination
products, says Gordon Ely, identifications and packaging section leader for
Nelson Laboratories Inc. (Salt Lake City). These evaluations may include
LAL, bioburden, sterility, and others, he says. “Decisions would need to
be made on a case-by-case basis,” he says.
SOLUTIONS
Most agree that EtO will still be the leading choice for sterilizing combination
products. “Kits will continue to drive the EtO sterilization business.
As devices become combined with kits, this will keep the EtO volume growing,”
says the medical device professional.
Clark Houghtling of Cosmed Group Inc. (Queensbury, NY) also sees continued
growth for EtO. He is vice president, technical affairs, for Cosmed’s healthcare
division. “Of the approximately 20 sterilants known to man, EtO is the
most material friendly. It also has the fastest turnaround time when using our
1-day-turnaround EOExpress process. We are currently sterilizing combination
devices with EtO using this process.”
Rogers says that he has a customer that has validated both EtO and radiation
for its drug-coated stent.
Modifications may need to be made for certain products, however. Says Benson,
“For heat-sensitive combination products, we have used lower-temperature
EtO processes with longer cycle times.” Temperatures of 29°C have been
validated for products such as synthetic materials, tissues of natural origin,
and tissue substitutes, he says.
Bill Young, vice president EO technology, Sterigenics (Oak Brook, IL),
says that when bioburden levels for combination products are low, sterilization
providers are able to use just what is needed to render the product sterile.
In other words, they can redesign the sterilization process to tailor it to
the product’s needs. “Our research has shown that we can use lower
EtO concentrations and reduced gas-dwell times for certain products,” he
says. “For instance, we can minimize the time the product is exposed to
heat during preconditioning and aeration by adding time in the EtO chamber.
You end up with a longer cycle time in the chamber, but a shorter process overall
because preconditioning and aeration is reduced or eliminated.”
Young does say that combination products sensitive to vacuum pressure may require
further process modifications so that the vacuum in the chamber does not damage
the products.
Such tailoring shows that sterilization is no longer a cookie-cutter process.
“There are many variables we can work with,” Young says. Even the
firm’s relatively new expedited EtO process, CyclEOne, which is being used
for combination products, can also be modified to meet individual product needs.
“For kits, we have tried to standardize the process, but we still make
adjustments when necessary.”
Bill South, manager of Steris Isomedix Services’ EtO TechTeam, has
modified EtO processes for combination products. “One of our first challenges
was a product designed by a heart surgeon. The device assisted the heart by
increasing blood flow through the body, helping sustain a patient until a transplant
is available. The left-ventricle-assist device contained a collagen graft that
was sensitive to both high temperatures and elevated moisture, typical components
of EtO processing.” His team was able to design an EtO process that used
low temperature and moisture levels, while still achieving the desired sterility
assurance level.
Rogers says that he has designed, developed, and validated an EtO process with
extremely low EtO concentrations. “It is close to being a combination of
low-temperature steam and EtO, which was a feasibility process I worked on many
years before for the Department of Defense for sterilization in evac hospital
units.”
NEW PROCESSES?
 |
| A laboratory technician performs biological indicator sterility testing (photo courtesy Centurion Sterilization Services). |
Rogers says that most traditional methods will continue to work for combo products,
but in some cases newer methods present an opportunity. “All sterilization
methods have their limitations. Heat will distort or melt plastics and may adversely
affect drugs. Irradiation and EtO commonly react with drugs; but without moisture,
some may be more compatible. Steam, EtO, chemicals with moisture, and radiation
may adversely affect electronics.”
Given these concerns, Rogers has suggested and devised a number of alternatives
for medical device firms. “I helped validate a diagnostic material/device
with the use of a liquid sterilant and filter, because the diagnostic material
was adversely affected by EtO, hydrogen peroxide, radiation, and heat.”
Dry heat is another option. The use of low-temperature dry-heat methods to sterilize
materials and surfaces has proven effective for medical prostheses and implants,
he says. “The process involves exposing the product to hot air circulated
in a chamber,” explains Rogers. “The effectiveness of the process
is based on both temperature and duration of exposure, so parametric-release
process control is possible. The method has been shown to be well suited for
electronic materials that are heat stable, but are sensitive to moisture, resistant
to penetration by steam heat, or prone to radiation damage.”
Dry heat can be used to treat products with less heat than traditionally recommended,
below 160°C (e.g. 120°–160°C), he says, when adequately developed,
qualified, and validated as a new process. “Reducing the sterilizing temperature
allows many more polymers, materials, and electronics to be processed and sterilized
than can be through more traditional methods. Silicone prostheses have long
been dry-heat sterilized at low temperatures, because radiation cross-links
the silicone, and silicone retains high levels of EO residuals if EO sterilized.”
One of Rogers’ clients designs sophisticated medical electronics that can’t
withstand EtO, steam, peroxide plasma, or irradiation, so he is considering
dry heat. “But before we do use it, we will modify our radiation approach
and see if we can make the electronics more compatible, and then provide dry
heat in sequence to come up with a synergistic process.”
Though not a new method, steam sterilization is another option for combination
products. Rogers is helping design and validate a sterilization process for
a prefilled syringe using steam. “We are modifying a very old method so
that the device and drug are compatible with the process.”
Steris’ South is also using steam, but in combination with EtO and gamma.
“I am working with a new drug-delivery device that consists of a drug vial,
syringe, and water for injection (WFI). The challenge is to sterilize the device
without contaminating either the drug or the WFI.” Contained in a closed
syringe barrel, the WFI is sterilized by steam. The drug vial was purchased
sterile from the manufacturer. The remaining syringe components were presterilized
using gamma irradiation. After assembly and packaging in a controlled environment,
the finished kit is then sterilized with EtO.
“By presenting the device in this fashion, we are able to design an EtO
process that will sterilize all remaining surfaces,” says South. “The
process is performed using very shallow vacuums, low temperatures, low gas concentrations,
and very short exposure times. In summary, it is a very mild [but effective]
process, making possible a new drug-delivery device that otherwise may not be
available.”
THE FUTURE
Providers of currently popular methods are often confident that they will continue
to prove themselves for novel products. “EtO appears to be the sterilant
of choice, since it is compatible with most materials,” says Houghtling.
“Combination products are more diverse in nature. That makes it hard for
niche sterilization methods to be able to handle the various materials that
are often present in these types of devices.”
Benson is equally confident. “Ethox is convinced that EtO will have its
share of the market for many years to come.” Two months into a long-term
expansion, Ethox is increasing its capabilities and capacities and is considering
additional locations to better meet the needs of our customers. The expansion
involves a mix of current capabilities in EtO and test services. For combination
products, it involves design modifications to the cycle so that the methods
will “perform as effectively and more efficiently, while avoiding product
and packaging impact,” he says.
Nonetheless, providers are on the lookout for new ideas. “We are evaluating
and investing in exciting new technologies that have potential to change the
future of sterilization,” Benson adds.
South says that sterilization service providers have been fairly successful
in meeting the challenges presented by devices that contain drugs. “However,
device design engineers are becoming much more creative. New drugs are being
manufactured that will enhance the function of existing devices or allow design
of a whole new family of devices. It’s only a matter of time before EtO
will not be an option due to its limitations. Alternate methods must be pursued.
Any new technology or combination of technologies that would replace EtO is
not only desirable, but will be necessary to meet the demands of device engineers
in tomorrow’s manufacturing environment.”
But will it happen? “The discovery of a new or existing technology that
provides a safe, effective method for sterilizing device/drug combinations would
be accepted within the industry with open arms,” says South. “However,
in 20 years of sterilizing medical devices, I am unaware of any such technology.
To my knowledge, it just doesn’t exist.”
Copyright ©2004 Pharmaceutical & Medical Packaging News
