One appeal of the blister package is its ability to preserve pharmaceuticals. To prove that it actually does, you've got to perform a successful stability study.
by Daphne Allen, Editor
To preserve tablets and capsules, drug packagers often choose blister packaging over bottles. Unlike bottles, blisters are designed to keep each dose fresh until needed. To ensure that blisters actually do protect their contents from moisture, humidity, and other environmental hazards, drug packagers need to subject the packages to a series of environmental challenges known as product and package stability tests. These tests help engineers determine that they've chosen the right material for the drug formulation and that their package manufacturing processes aren't altering the materials' barrier performance.
Stability tests, however, take a minimum of six months to perform, and during that period the drugs cannot be marketed. Any delay, which can range from an improperly performed test to the discovery that a particular material or package fails to preserve the drug, costs drug manufacturers more than time. In addition to the costs of restarting tests with new or different materials or procedures is the risk of having a competitor market its product first.
Reynolds Metals' blister foils are suitable for a wide range of OTC drugs.
Packaging engineers must therefore perform stability tests with a full awareness of all regulations and guidances to ensure an adequate—and FDA-acceptable—test. To save money and time, engineers should base their choice of materials and package forms on the drug formulation. They should use production equipment to form test packages and make sure the seals of those packages are adequate. Finally, they should enlist the help of material suppliers, many of whom offer reams of data on material performance.
REGULATIONS AND GUIDANCES
In section 211.166 of title 21 of the Code of Federal Regulations, FDA mandates the performance of stability testing. "The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates," reads the regulation.
In June 1998, FDA released a draft guidance designed to help drug packagers through such stability studies. The document includes significant references to stability guidelines produced by the International Conference on Harmonization, a continuing tripartite effort by representatives from FDA, Japan, and the European Union. FDA's draft covers stability studies for new drug applications (NDAs), abbreviated NDAs, and investigational NDAs. It also lists the stability data required to support postapproval container and closure changes. In several places throughout the draft, FDA states that "stability studies should include the drug product packaged in the proposed containers and closures for marketing as well as for physician and/or promotional samples." While the suggestions listed in the draft are not requirements, FDA recommends that any deviations from the guidance should be discussed with the agency prior to stability studies. However, FDA writes that "submission of data not conforming with this guidance is possible with justification." The agency has not indicated when the draft guidance will be final.
Section 661 of the United States Pharmacopeia 23 provides chemical test methods and standards for plastic materials intended for use as drug packaging. Section 671 outlines the test procedures for determining "the moisture permeability of containers utilized for drugs being dispensed on prescription." These standards for permeation are also used by FDA to demonstrate the protective characteristics of market containers used by pharmaceutical firms. These sections are being revised, according to C. Jeanne Taborsky, a former FDA reviewer and USP research scientist who also helped to develop the standards in 661 and 671 and who is now a packaging consultant for both industry and USP. The standards are based upon work done about 15 years ago and are currently under review.
In November 1995, FDA released the guidance, "Immediate Release Solid Oral Dosage Forms Scale-Up and Postapproval Changes" (SUPAC), written for drug manufacturers and packagers who intend to make some sort of change in site, process, or equipment in the production of an immediate-release oral formulation. In January 1999, the agency released an addendum on manufacturing equipment. The documents explain when additional studies are necessary for such changes.
It is important for drug packagers to be familiar with these regulations, says Michael McMaster, senior manager of quality assurance for Packaging Coordinators Inc. (PCI; Philadelphia). Not only will such awareness help manufacturers satisfy FDA requirements, but it will also help companies properly allocate their resources. Without full knowledge of the regulations and guidances, a company could be spending too much time and money on one study and not enough on another.
Before companies can perform any stability study, they need a finished package designed for the market (see sidebar 2). To select appropriate materials and forms for that package, engineers must consider the needs of the product, explains Darrell Morrow, founder and chairman of Leak Detection Associates (LDA; Williamstown, NJ). "The engineer must understand the needs of the product in order to identify candidate materials, but also must have an eye to budget."
Engineers must also determine how the product and the packaging material interact. "There can be a chemical interaction between the plastic and product," says Morrow. That interaction can have an indirect effect on stability. An example of this, he explains, is a dentifrice product that attacked its plastic blister package. The plastic cracked and the product dried out. A material change solved the problem.
However, because time is so critical in getting a new drug to market, many engineers can't spend a lot of time considering a variety of materials. Instead, they often choose blister materials with the highest possible barrier. For instance, one packaging engineer says that 90% of his drugs are overpackaged in terms of barrier properties. "Because it takes so long to do a stability study, you don't want to take a chance by underpackaging. If it fails, it's back to the drawing board. You could lose two years."
New drugs present a special problem. "With new drugs you can't always anticipate their stability. You tend to want to err on the conservative side—you don't want to be the reason the study fails and the launch is delayed," explains another packager.
Edward Dunn, director of pharmaceutical manufacturing, planning, and support for Nycomed (Wayne, PA), agrees that overpackaging is common. "Some drug packagers start by using materials with the highest possible barrier, like cold-formable foil or Aclar, for their stability studies."
But using such high-barrier materials for all drugs can be a mistake. The amount of barrier needed depends upon the drug. "If drug stability isn't a problem, just put the drug in a container that prevents contamination," says Taborsky. "If you have a sensitive drug, you should measure its rate of dissolution or degradation, then pick material accordingly. There should be science behind the choice of a container."
Kent Sides, business unit manager of pharmaceutical films at Klöckner Pentaplast of America (Gordonsville, VA), agrees. "For a new developmental drug, do a probe study—an unofficial test to determine how sensitive the drug may be to moisture under accelerated conditions. This can help narrow the field of materials used for the formal stability study." He also recommends testing a couple of different material combinations simultaneously.
Michael Franklin, vice president of Tekni-Plex Inc. (Somerville, NJ), says that an interesting approach is the testing of "two or even three different barrier level film types in order to pass the required stability testing on the first attempt using a high-barrier film, while at the same time having product on stability at lower moisture-vapor transmission rate (MVTR) levels." If stability testing is properly conducted, he says, with such an approach, a company can reasonably expect one or both of two results. First, "the testing of product in a very high-barrier film more or less guarantees that rollout of the product will not be delayed because of a failed stability test. Second, one of the stability tests on a lower-barrier film may be successful, and over the life of the product, this lower-barrier, lower-cost film may replace the higher-barrier, higher-cost film."
Sidebar 1: Stable Repackaging
Repackagers do drug manufacturers a great service. They enable drug manufacturers to ship bulk product to various locations, such as hospitals, nursing homes, and pharmacies, which disperse drugs in regimens as needed. If repackagers didn't exist, drug companies would need to predict the supplies that doctors prescribe and then package accordingly.
The drawbacks of such an efficient and convenient system, however, are becoming apparent. "Drug repackagers don't always use patient package inserts or do stability studies on their packaging, and that is a problem," says Edward Dunn, director of pharmaceutical manufacturing, planning, and support for Nycomed (Wayne, PA). The packaging materials and containers that repackagers use might not always be the best choice for a particular drug, so certain drugs may be dispensed in packages that do not preserve them.
"Repackagers may be using a 7-mil PVC blister for a drug when they should be using a 10-mil PVC blister," says C. Jeanne Taborsky, a consultant and former FDA reviewer. "They also may be using a waffle iron—like blister machine, one that may not seal too well and that should be validated."
Taborsky says that drug repackagers should be held to the same standards that drug companies are when it comes to the selection of materials and the validation of processes.
Repackagers, however, aren't breaking any laws by not performing stability studies. Their packaging operations are not subject to FDA's good manufacturing practices. Instead, they are governed by state boards.
Repackagers presently are required to use a beyond-use date (the expiration date applied to the repackaged product). The expiration date is the shorter of two time periods: either six months or 25% of the remaining expiration period on the manufacturer's container if no stability data in the repackaged container exist. Repackagers want a longer beyond-use date, using packaging materials of their choice, without the burden of conducting stability programs.
To this extent, a proposal is being drafted to base the beyond-use date on a performance specification based on a product's particular sensitivity. "It is important for a repackager to understand the relationship between the performance of the formed and sealed container and the particular product's sensitivities to moisture, light, or oxygen, says Rich Hollander, packaging services manager for Pfizer (New York City). Hollander is leading a USP committee charged with writing a general chapter on repackaging practices. Its focus is on solid-dosage forms repackaged into blisters. This same committee is also evaluating revisions to USP 671 Containers-Permeation in order to further divide classes A and B for unit-dose containers. With this new subclassification, more meaningful performance criteria could be made available to the repackager. The committee hopes to have drafts ready some time this year.
Once a drug company has determined the type of material for its blister packaging, it must then decide upon a supplier. Presently, there is little flexibility for a manufacturer to change suppliers from that which was filed in the drug's application. Currently, such a change warrants full product stability and a prior FDA approval before the change can be implemented. However, the manufacturer does have the ability to submit a protocol to FDA for demonstrating equivalence between like packaging materials and, if approved, to notify FDA of the change in an annual report.
The Pharmaceutical Research and Manufacturers Association's (PhRMA) packaging work group has developed an interchangeability monograph for PVC film and foil, based on a collaborative effort with film and foil suppliers, drug product manufacturers, FDA, and USP.
Drug packagers would welcome such a system. "PVC-based films and foils are well understood and widely used. USP monographs already exist for PET, PE, and glass. The industry needs a monograph for blister packaging materials as well," says Rich Hollander, packaging services manager at Pfizer (New York City) and chair of PhRMA's packaging work group.
Nycomed's Dunn also looks forward to interchangeability. "You could go from one type to another without having to redo stability studies and file another submission to FDA."
Taborsky is currently conducting a study to pave the way for such a monograph. Working with PCI's McMaster and Hugh Lockhart, a professor at Michigan State University's School of Packaging, Taborsky and her team are currently evaluating more than 40 materials for their barrier performance in relation to one another. These materials represent what industry is using, says Taborsky. "We are evaluating materials from a number of suppliers and plan to complete the study after testing the newest Aclar."
One common mistake drug companies make during stability studies is that they don't always use production equipment to form the blister packages intended for the study, says PCI's McMaster. "When we arrange to produce the packages that will be studied for stability, we recommend that clients wait for the appropriate production unit that will eventually be used to package product. The danger is the difference in sealing methods." McMaster notes, however, that SUPAC does allow for equivalent equipment to be used to form packages.
It is important to test marketing packages because material forming—both thermoforming used for plastics and cold forming for foil—has an effect on the barrier properties of the material. This is so, says Taborsky, because "the thinner you make the material across the blister cavity, the more moisture can penetrate it. What you need to determine is the point at which the thinning allows too much moisture to penetrate."
|Conditions||Minimum time period at submission|
|Long-term testing||25°C ± 2°C/60%RH ± 5%||12 Months|
|Accelerated testing||40°C ± 2°C/75% RH ± 5%||6 Months|
Long-term/accelerated testing conditions, per FDA's stability guidance.
Klöckner's Sides agrees. "How well the package is formed and sealed is critical to passing a stability study." Unless the seal quality is known, the ability to develop package and seal specifications, based on stability test results, is next to impossible.
Sandra Luciano, healthcare market specialist for AlliedSignal (Morristown, NJ), even says that the MVTRs for flat-sheet films don't really help packagers and that instead the MVTR of formed sheets should be considered. Luciano says that AlliedSignal is considering a study that shows the MVTR of certain formed materials. LDA's Morrow indicates that such a study is under way and that more project sponsors are being sought.
Another mistake in setting up a stability study, says McMaster, is that "companies don't always target the best conditions for forming and sealing. If the package looks sealed, they then think it is OK." Sealing parameters and processes should be considered during operation qualification prior to stability studies.
Leak Detection Associates' Morrow says that industry has long used the ASTM method D 3078, a vacuum bubble test, to determine the quality of seals. During the test, packages are placed in a chamber of water. Chamber air is then evacuated via vacuum, which pulls air bubbles out of package holes if they are present. "The problem is that the test isn't very sensitive, nor is it quantitative," he says.
Instead, Morrow's firm came up with another leak testing system, called the seal integrity monitoring system (SIMS), which uses helium as a tracer gas. The technology is currently being used in some sectors of the pharmaceutical and medical device industries for design and development, tooling validation, packaging line setup, and quality monitoring. "Helium is one of the smallest molecules," he says. "It challenges the integrity of seals more than anything else. Helium leak testing is an old technology, but our methods and applications are new."
When using SIMS, operators aren't looking for air bubbles in a vacuum chamber. Instead, filled packages are saturated with helium before they are sealed. An operator places a sample package in the test chamber, where a sensor measures any escaping helium. The test measures leaks at a rate as low as 1 x 10–9 cm3/sec, compared to the vacuum test's lowest leak rate of 1 x 10–4 cm3/sec. "The SIMS unit is designed to test the seals as well as the overall barrier properties of the package," says Morrow.
Material suppliers also assist packaging engineers with their stability studies. Reynolds Metals Co. (Richmond, VA), like a lot of other suppliers, provides stability samples at no charge. Hueck Foils (Wall, NJ) offers a special program for two-week turnaround on blister foils for stability testing. "Most stability runs are small, but we have no minimum order for this program," says David Sciubba, Hueck's healthcare sales manager. "It is very helpful for companies performing stabilities to get material quickly."
Some suppliers even set up their own testing facilities to generate data that packaging engineers can use for such a study. Klöckner has a blister research center dedicated to the dynamics of blister package manufacturing, which Klöckner's Sides says is critical to passing a stability study.
Klöckner, AlliedSignal, VPI Mirrex, and a number of other material suppliers have sent Taborsky materials for her study. Suppliers also routinely conduct and publish studies of their own, so it is important to ask them for such results.
A successful stability study will offer more than just a particular shelf life date—it will also ensure that drug consumers are taking effective regimens. To make sure this happens, drug manufacturers need to keep up with regulations and guidelines and watch for material study results. Care in materials selection, tooling design, and integrity testing is critical to the success of a product launch.
Need more information? See Sidebar 2, Selecting Blister Packaging Materials.
Photo courtesy of Leak Detection Associates and Packaging Coordinators Inc./Photo by Zave Smith