Addressing Combination Products

Drug and device combination products impose challenges for packaging and testing.

Combination products offer therapeutic benefits to patients and help caregivers deliver treatments more efficiently. These advantages are driving growth in areas such as respiratory drug delivery systems and prefilled syringes, while spurring innovation in formats such as transdermal patches.

Packaging systems need to protect both the drug and the device, whether the two are combined as a single entity, packaged together in a kit, or separately. Manufacturers and packagers first have to identify the applicable FDA governing center and regulations, based on the product’s primary mode of action.
 
“It is best for the manufacturer to engage FDA at the very earliest stages of development to obtain guidance on what GMPs are applicable and not to make assumptions,” says Alison Tyler, technical director, Beacon Converters (Saddle Brook, NJ).
 
“There is a risk in waiting too long because FDA will determine which of the three centers (CDER, CBER, or CDRH) will preside over the product from a regulatory standpoint. The most important guidance for the packaging supplier will be the guidance that our customer gets as to how the product will be regulated. Then we can work together to develop the most appropriate packaging for the product with the technical support that is needed to bring it to market,” Tyler adds.
 
Combination products may require non-traditional materials, as well as specific sterilization methods. Stabilty testing establishes the compatibility of the container/closure system, and that the drug’s efficacy will be maintained.
 
“Drugs that are injected, inhaled, and, to a lesser degree, transdermally administered—all common routes of administration for combination products—have the highest degree of risk for contamination. Testing for leachables and extractables as well as the characteristics of the packaging materials becomes much more important,” Tyler says.
 
INNOVATIVE SYSTEMS
At Rollprint Packaging Products (Addison, IL), combination product packaging has encompassed drugs and biologics combined with devices and kit packaging for devices and drugs packaged together, says Dhuanne Dodrill, president, Rollprint Packaging Products (Addison, IL).
 
“In medical device packaging, you have to protect the device, while ensuring its sterility. When you introduce a drug in a combination product, the concern is maintaining the drug’s efficacy up to the time of use,” Dodrill says.
“We have seen some very innovative solutions where the device provides the packaging for the drug and the packaging materials that we provide become part of the drug-delivery system,” she says.
 
For a pulmonary drug-delivery system, Rollprint developed a semirigid blister with a flexible lid for packaging unit doses of a liquid drug. Used in an inhaler, the packaging had to provide oxygen and moisture barrier, be drug-compatible, and avoid product contamination from extractables and leachables. “This package had to be designed to peel within a narrow range of applied force to release the drug within a narrow window of time,” Dodrill says.
 
Beacon Converters has developed materials for combo products featuring very high moisture barrier, extreme durability, and UV and heat resistance. “Many biological products that are stored with dry ice require materials that withstand prolonged cold temperatures. The dry ice environment has also required carbon dioxide barrier properties, which is definitely something new,” Tyler says.
 
VENTED POUCHES
Vented pouches provide barrier packaging that supports ETO sterilization. A non-porous pouch is created after the sterilized bag is sealed over. Peelable chevron seals feature easier opening for nurses and clinicians.
Rollprint first developed the foil header pouch for high moisture barrier packaging of absorbable autosutures. Its ClearFoil laminate can be used in instances where the customer wants visibility, says Dodrill.
 
Oliver-Tolas Healthcare Packaging offers the Dispos-A-Vent header pouch for combination devices that require barrier and ETO sterilization, says Jeff Murak, vice president of sales and marketing.
 
“Dispos-A-Vent was developed for packaging combination drug devices such as inhalers, where moisture and gas barrier are an issue. Now we are selling it for other applications including drug-eluting stents and bone screws,” Murak says.
 
The Oliver-Tolas Answer team assists customers with packaging alternatives through the company’s OnSite packaging engineering service. “OEMs don’t always have a clear idea of the packaging alternatives for their combination devices. Our technical team has experience in both the device and the pharmaceutical markets and understands [these products’] requirements,” Murak says.
 
The company has seen a lot of growth in prefilled syringe packaging where the syringes are packaged in a tray with inner and outer Tyvek lids, and the tray is often then packaged in a bag, Murak says.
 
Prefilled syringes are designed as container-closure systems to protect against contaminants and reduce risk of product degradation from interaction with component parts and coatings. BD Medical–Pharmaceutical Systems (Franklin Lakes, NJ; BD) customizes the BD Hypak SCF (sterile, clean, ready-to-fill) prefilled syringe system based on customer applications, says Brian Lynch, marketing manager, BD Hypak prefilled syringe system.
 
“The BD Hypak SCF prefilled syringe is designed for broad applicability, [but] it is pharma-customer-specific based on the drug molecule, a customer’s fill-finish process, and the needs of the patient or healthcare worker,” says Lynch.
 
HANDLING BIOLOGICS
The advent of new biotech drugs has introduced new requirements for prefilled syringes. BD’s Sensitive Drug Initiative (SDI) has enabled the development of protocols and techniques for evaluating compatibility between a biotech drug and a BD syringe.
 
“The latest biotherapeutic products and even some vaccine formulations can be more sensitive to various materials and surfaces inside the container. Each product requires methodical and discrete assessment methods against the different components with which the drug will come in contact,” Lynch says.
Through SDI, BD has developed the BD Hypak SCF for Biotech syringe system. The system addresses drug compatibility with the silicone lubricant, the effect of tungsten residuals that may result in syringe forming, and gliding issues.
 
“We have learned that some of the newer biodrugs are sensitive even to low trace amounts of tungsten, tungsten oxide, and salts. With the BD Hypak SCF for Biotech syringe, we have dramatically reduced the amount of residual tungsten, and we are controlling the quantity and distribution of silicone. We are also addressing improved dimensional control and the physical robustness of the syringe, which are both important when the syringe is used as an auto injector,” Lynch says.
 
Combo products may require alternative sterilization methods. “Ideally, the package is designed to allow for terminal sterilization while allowing the drug to perform effectively. You might be using less robust sterilization methods. Many biologics are temperature sensitive so you may have to perform a low-temperature EtO sterilization cycle. But that means to ensure the same sterility assurance level (SAL), your materials have to be cleaner going in,” Dodrill says.
 
Tapemark (West St. Paul, MN) manufactures and pouch-packages passive and active transdermal patches. Active systems include built-in batteries and electrical circuits for supporting iontophoretic delivery, one of several enhancer
technologies.
 
“For passive and active patches, the barrier properties of the packaging as it relates to the volatility of the API have to be considered. We work with our customers and third-party labs to perform stability studies on the packaged product,” says Steve Larsen, national sales manager.
 
One of the attributes, stability testing measures, is the degradation of the drug over time, and the compatibility of the drug and packaging materials. “You don’t want the drug breaking down the barrier properties of the package, or have the package leaching into the drug. In the testing, we are looking at the substrate of the pouch film itself as well as the heat seal or tie layers,” Larsen says.
 
Patches are manufactured and packaged in Class 100,000 clean rooms. As transdermal patches are applied to intact skin, sterilization is typically not required, “In transdermal patch production, we follow cGMP regulations for pharmaceuticals. Since we are dealing with an API, we default to the more stringent regulation,” Larsen says.
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