For the last few years there’s been a steady stream of new combination products, and deepening trends toward self care appear to be encouraging even more. Home healthcare is growing just as healthcare systems are being encouraged to improve patient outcomes, so devices that ease drug administration and encourage compliance continue to be in demand. And as healthcare systems look to reduce the length of hospital stays and prevent readmissions, pharmaceutical-enabled devices are being employed to shorten procedure times and promote recovery while minimizing the chance for practitioner errors.
Hence the increase in the number of prefilled syringes, pen injectors, inhalers, and drug-eluting stents. Other combination products include orthopedic products, infusion pumps, wound care products, transdermal patches, and more, reports Allied Market Research in “Global Drug-Device Combination Products Market (Product types, Application, and Geography) - Size, Share, Trends, Company Profiles, Demand, Insights, Analysis, Research, Report, Opportunities, Segmentation and Forecast, 2014 – 2020. The firm divides applications for combination products into the following categories: Cardiovascular, Non-Cardiovascular, Urological, Bone Treatment, Antimicrobial Treatment, Cancer Treatment, Ophthalmic Treatment, and Diabetes Treatment.
And it is a growing market indeed. Transparency Market Research (TMR) predicts that the global drug device combination products market will grow at a CAGR of 7.9% between the years 2013 to 2019. It valued the 2012 market at US$66 billion and expects it will reach US$115 billion by 2019. The report is titled “Drug Device Combination Products Market - Global Industry Analysis, Size, Share, Growth, Trends and Forecast, 2013 - 2019.”
WHAT FDA IS SEEING
Anya Harry, M.D., Ph.D. Medical Director for Voisin Consulting Life Sciences (and former FDA medical officer and branch chief), reports that a total of 330 combination products were submitted to the FDA Office of Combination Products for review in FY330, compared with 264 in FY2012. And there were 828 inter-center consulting requests in FY2013, compared with 660 in FY2012.
When asked to explain the difference between total combination products submitted for review and total inter-center consult requests, Harry, who gave an overview of combination products during Pharmapack North America in June, says that the “total combination products submitted are the numbers of applications sent to the FDA for review, while the number of total inter center consult requests are the numbers of requests from one center to the next for consultation. For example, if the combination product is a part of a New Drug Application, then the Center for Drug Evaluation and Research will consult the Center for Devices and Radiological Health to provide input regarding the delivery aspect/component of the application and vice versa.”
Harry says these totals “show there is more interaction between the different centers at FDA for review of these applications,” Harry says. “Not all combination product applications are reviewed necessarily by two centers. If [an application is] very straightforward, one center may review the whole application without consulting another. For example, heparin lock flush solutions are combination products; however, CDRH reviews the application without consulting CDER unless there is a complex or new issue.”
So what role should packaging play in this burgeoning market? The packaging for combination products can be just as complex as the products themselves. Designers need to identify specific product and user requirements for both primary and secondary packaging. And not only must packaging serve the traditional roles of maintaining product integrity, efficacy, and perhaps even sterility, it may also need to be patient friendly by promoting user convenience, safety, and compliance. Package design should therefore be built around both product and end-user needs.
When it comes to designing primary packaging for combination products, Eric Schmohl, Customer & Application Support Manager for DuPont Medical & Pharmaceutical Packaging, explains that considerations depend upon the risk analysis of a product and the applicable standards.
“With regards to vials and syringes, [designers must] protect liquids from any contaminants, visible or nonvisible, as well as [promote safe] handling both by the nurse and the patient,” Schmohl says. Considerations therefore include “usability, biocompatibility, extractables and leachables, and potential sterilization of the content.” In addition, the prevalence of automated filling lines adds “easy processability” to the list of needs, he says.
Inhaler canisters and cartridges for pens need to be easy to handle for patients of varying age and capabilities, says Schmohl, calling it “a very special consideration that rarely applies to a primary package of a mere medical device."
Immediate plastic packaging for drug products requires different levels of documentation, depending on whether they are for oral or topical products, for inhalation, or for parenteral or ophthalmic administration, adds Schmohl. "And there is further differentiation on whether it concerns a solid or a non-solid dosage form. In essence, the requirements for plastics that are in direct contact with a drug are higher in terms of documentation of chemical interaction, extraction, and toxicological information than compared with a mere medical device. As a rule of thumb, primary packaging of a combination device requires more-sophisticated packaging design and validation than that of a typical medical device. Adding a drug functionality to a standard product such as an intravascular catheter will turn this product’s packaging development into a different story. The different standards for medical devices and medicinal products need to be consolidated, and this results also in different solutions and total costs of packaging."
In addition, "particles and particle burden is of high interest, especially to those manufacturers who handle non-solid drugs. This is less of a concern for a majority of medical devices,” he says.
For combination products that are required to use a sterile barrier system, the sterilization method drives packaging materials selection and design. In some cases, the secondary packaging serves as the sterile barrier. “For pharmaceutical products as well as for products to be used in the operating room, secondary packaging can serve as ‘dust’ protection to allow for moving product from the gray to the white zone,” Schmohl says. “But it can also be a sterile barrier to allow for protection of a product such as a prefilled syringe for use in an ophthalmic surgery, which needs to be sterile on the outside for immediate use.”
If a combination product requires both sterilization and a moisture barrier, the secondary package (e.g., aluminum pouch) can encapsulate the porous primary packaged unit after steam or gas sterilization, Schmohl says. “In this case, secondary packaging serves a need that is in conflict with the sterilization required, but there are solutions where just another conversion step of the sterile barrier system after sterilization can turn a porous package to a non-porous package, too (e.g., vented aluminum bags with a second seal to close the vented area).”
Secondary packaging for combination products may serve as the sellable unit, says Schmohl. As a result, it must support visual needs and labeling requirements such as Unique Device Identification and instructions for use (IFU), which should fit within or be printed on the surface, says Schmohl.
The secondary pack may also include several units.
Unless marketing and the look of a packaged unit play an important role, the protection needs will define the least costly configuration in most cases, Schmohl says. “Functionality of primary and secondary can vary or be exactly the same depending on the case. Unit cost per packaging will usually decrease from primary to secondary and so further as protection requirements do,” he says.
A special function of a secondary or perhaps a tertiary shell can be protection against temperature variations, Schmohl adds. “It can start with a white or reflective box versus a dark-colored one and end up in a box made of insulation material,” he says.
KEEPING THE USER IN MIND
Packaging professionals responsible for developing solutions for combination products should also consider human factors for increased acceptability of the product by patients as well as treatment compliance for better clinical outcomes, says the team at Voisin Consulting Life Sciences.
Some of the market’s best growth opportunities include biotech drugs and advanced therapies with associated devices for a number of user-focused functions. Challenges in design and development arise from the need to ensure completion of such complex tasks as the accuracy of doses delivered and the need to support repeated use and/or cleaning processes, say Harry and her team at Voisin.
In keeping with design control practices commonly used for traditional medical devices, Voisin Consulting Life Sciences advises considering the following:
Develop and Document Input Data: Consider both client requirements for packaging and labeling as well as regulatory requirements along with any such data from previous similar product development and risk analysis. Should also include functional specifications for packaging as well as safety and performance specifications as expected for the intended product use.
Conduct Design Reviews: Meetings should include an interdisciplinary group of professionals (including packaging professionals) and should be held periodically and documented. The reviews should cover package and drug-delivery device design and all development studies. Any deviations and solutions should be identified and documented.
Perform Design Verification: Professionals should evaluate whether output data complies with input data in terms of package and drug-delivery device function and safety.
Perform Design Validation: Professionals should evaluate whether the performance of the package or drug-delivery device design satisfies the requirements of the intended product application.
Document Output Data: Professionals should demonstrate and document conformity to input data and approve the design specifications, ensuring that the package or drug-delivery device design is inline with production and control capabilities. Should consider key features for safe use such as leaflets, labeling, and all marketing and training tools.
When following design control practices as well as working to meet any special circumstances or needs, Harry and her team advise packaging manufacturers and suppliers as well as contract manufacturers to recognize that the drug-delivery device is both a container closure and a device with specific functionality affecting both safety and efficacy of the contained drug. “This should be fully taken into account during development by device manufacturer,” she says. “A close relationship between drug and device developers is highly recommended.”
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