Armed with the knowledge of the specific MVTRs required, packaging engineers can design a package that optimally meets product protection levels.
by John M. Bitner, manager, Package Design and Development, Searle Technical Operations (Skokie, IL)
A combination of corporate and government efforts in recent years has lowered the average span of the drug development cycle by some 18 months. This shortened cycle has accelerated the race to bring new drugs to market first, making it difficult for packaging engineers to do what they do best: optimize the performance and economy of new drug packaging.
Traditional industry resistance to change may be to blame. If a packaging system has worked in the past, why risk failure with something new?
Storage and stability testing of new ethical drugs in their proposed packaging is one of the final steps before submission of a New Drug Application (NDA) for FDA review. Failure of the packaging to protect the product adequately at this stage would require development of new packaging, time-consuming and costly retesting, filing delays, loss of sales from delayed market entry, and perhaps significant damage to a brand's chances of future success.
To avoid such packaging failures, companies typically take either of two approaches. One is to produce an overprotective package. Overpackaging does increase the chances that a product and its packaging will pass stability tests, but it is costly. The other approach is to test multiple packaging options in the hope of finding at least one lower-cost option that provides sufficient barrier and optimum performance.
In the latter approach, there is still no guarantee that a successful package provides the optimum balance of cost and performance. And, at a time when most companies are removing any unnecessary costs from their processes, either approach can add costs during the development process, subsequent manufacturing, or both.
Because most manufacturers are reluctant to spend additional time and money to reduce packaging costs for products already on the market—and reluctant to divert attention and resources from higher-priority launches—both overpackaging and less-than-optimal designs will add incrementally to costs for the remainder of a drug's life.
|DCP Team Functions|
|Phase II–Phase III:|
Determine appropriate packaging materials.
Develop packaging materials for ICH stability studies.
|Phase III–Phase IV:|
Develop final commercial packaging.
Make postapproval packaging changes.
To find the optimum package, it may be tempting to complete stability tests on a wide variety of packaging options (called cells). But stability testing on too many cells can add significantly to package development costs. Depending on the number of dosages tested, estimates of total costs for staff, materials, manufacturing, and laboratory testing range anywhere from $50,000 to $200,000 per cell.
There is an alternative to such expensive guesswork and overpackaging—one that is completely consistent with every firm's current emphasis on compressing time frames and reducing costs. Essentially it involves enabling packaging engineers to make their best scientific, engineering, and business contributions to their segment of the drug development process.
CUTTING TIME AND COSTS
At Searle, a Monsanto Co. (Skokie, IL), a system called Manage Process Technology (MPT) provides a framework for improving the efficiency of each process within the drug development cycle and for facilitating communication and coordination among all disciplines involved. It accelerates the pace at which a product moves from the initial discovery phase to commercialization. A subset of MPT, Develop Commercial Packaging (DCP) focuses on improving package development and its impact on the final stages of drug development.
DCP's charter is "Identify the optimal packaging materials available for a drug product and develop the appropriate specifications, equipment, tooling, stability testing instructions, and final packaging." Under MPT, DCP team members begin their involvement relatively early, toward the latter part of Phase II clinical trials and nine months prior to International Committee on Harmonization (ICH) stability testing.
The DCP team finds that taking a more scientific approach at the earliest stage of involvement results in the greatest time and cost savings for package development and in the ultimate package.
With the drug form decided—shaped tablet or capsule—the DCP team subjects the product to open-dish testing to determine its critical moisture level. The data will be used along with proprietary software to project the minimum moisture vapor transmission rates (MVTRs) required from materials to achieve the desired shelf lives. This immediately enables the team to eliminate a number of materials from consideration.
The ICH protocols stipulate testing under the conditions shown in Table I.
However, Searle's packaging development group selects five relative humidity levels to ascertain whether product instability manifests itself gradually or rapidly. This process generates a more precise profile of water vapor uptake on which the group can base its decisions.
|25°C||60%||52 Weeks (real time)|
|30°C||60%||52 Weeks (real time)|
|40°C||75%||26 Weeks (accelerated)|
Searle chooses different humidity level ranges at the three ICH protocol temperatures, depending on the projected humidity sensitivity of the product. A moisture-sensitive product might react significantly at relative humidities ranging from 20 to 75%. On the other hand, a less-moisture-sensitive product might provide a sufficient profile at relative humidities ranging from 40 to 97%. Whatever the humidity range, packaging engineers at Searle test packages at a relative humidity condition beyond the upper limit stipulated in the ICH protocols during the open-dish testing.
The products are left in the chambers until they reach moisture equilibrium. Following open-dish testing, moisture isotherms are prepared, physical inspection occurs, and R&D performs assay and dissolution analysis of the products. Inputting data generated from the Open-Dish Initiative, including the proprietary shelf lifepredictive software developed by Kenneth S. Marsh & Associates Ltd., Searle engineers are able to predict the MVTRs that a material possesses and to eliminate candidates for stability packaging based on intended shelf life.
The total time to perform open-dish testing, generate isotherms, and perform assays and dissolutions is five weeks.
The phrase "Back it up with cold form" makes DCP team members cringe. But armed with the knowledge of specific MVTRs that the packaging must possess, the packaging development group can design a package that optimally meets product protection levels, as well as consider other factors such as material cost or ease and economy of manufacturing. Furthermore, the team now has the data to back up its recommendations.
The first products to emerge from the Open-Dish Initiative procedure have completed or are now finishing 12-month ICH stability testing and have validated the open-dish shelf-life predictions. Searle engineers have been going back through the company's product portfolio to generate a history of available optimum packaging recommendations for future reference.
"Every product we've performed the open-dish testing and shelf-life predictions on has passed stability testing," says Mark Dressel, Searle's associate director of packaging and equipment.
The DCP team's work has helped move Searle away from traditionally relied-upon forms of packaging that are proving to be overprotective and unnecessarily expensive. In some cases, packages incorporating lower-barrier, less-expensive thermoplastic materials that generate a better heat seal are passing stability tests that package structures with stronger barrier materials previously perceived as better are failing.
As well, the new DCP procedures are helping Searle reduce the number of packaging options it prepares for stability testing. The team conceivably needs to prepare only one fail-safe design in addition to the optimal design it recommends. For some products, this presents a tremendous advantage.