Parenteral Packages Need Specific Tests for Extractables
Parenteral packaging undergoes scrutiny as FDA seeks information on extractables and drug-package interaction.
by Erik Swain, Senior Editor
Potential interaction between the drug product and the package has always been an important issue for parenterals. Never has it been more crucial than it is currently, as FDA is demanding more and more information about each and every packaging component and its potential to interact with the drug.
Interaction happens mainly in two ways. Extractables from the package can get into the drug product, causing contamination. Or the drug can be absorbed by the package, causing the package to compromise its barrier properties or the drug to lose some of its potency.
An operator at West Pharmaceutical Services uses a liquid chromatograph to detect organic compounds in a drug container.
FDA in June 1999 published a guidance, "Container Closure Systems for Packaging Human Drugs and Biologics," that outlined what information about packaging is needed for a new drug application. For parenterals, the document outlined what kinds of tests must be performed to show that interaction is not a problem.
Since then, the issue has been reinforced by the agency in a draft guidance on stability and a final guidance on post-approval changes. And it is sure to be elaborated upon with regard to making changes in the near future as work begins on PACPAC, the packaging edition of FDA's Scale-Up and Post-Approval Changes (SUPAC) guidances.
The stakes for suppliers could be significant. Those who create components that offer less risk of interacting with drug products, and those who can provide services to customers to help them assess the issue, stand to benefit.
The guidance is expected to have the biggest impact on extractable testing, which determines which extractables may occur as a result of using a particular packaging component, and what kind of effect these extractables may have on a drug product.
Most drug manufacturers already perform two general tests, USP 661 for plastics and USP 381 for elastomers. But the container closure guidance now mandates more-specific tests in addition to those. (USP 381 is itself being revised.)
Fran DeGrazio, vice president of global technical support at West Pharmaceutical Services (Lionville, PA), says she has noticed in recent years that FDA was asking her customers for more information on extractables from specific packaging components. The guidance codifies this, but also goes beyond it, she says. "Not only are they looking for the uniqueness of extractables from a specific rubber formulation, but they're looking for a unique extractable within a customer's specific drug product or placebo," she says. "That's not something you can generate by running a standard solvent."
While the manufacturer can easily provide a list of each component's extractables, the agency wants an analysis of what extractables exist when the packaging material interacts with the specific drug product. That requires extra testing. Liquid or gas chromatography is the usual method.
Vial and bottle stoppers, such as these from American Stelmi Corp., can be supplied ready to sterilize.
"Obtaining this information will not necessarily require different testing equipment, but different methods," DeGrazio says. "Looking for specific extractables from a packaging component is totally different from doing a drug assay analysis, but both utilize liquid chromatography. There will be some additional expense associated with doing the additional testing, which for the most part was not carried out by end-users. The key thing is that budgeting for testing be built into the stability and qualification studies of the closure and the final drug package. I've had discussions with customers who did not realize the need for this until late in the product development cycle."
While the mandate may surprise many at first, in the long run its impact promises to be positive.
"I see it helping organize the way packaging is considered in drug applications," says Roger Asselta, manager of parenteral package development, Comar Inc. (Buena, NJ). "We as packaging suppliers will be able to answer questions from our pharmaceutical customers more completely and earlier in the process."
Also, it is very important, says biopharmaceutical product development consultant John A. Bontempo, PhD (East Brunswick, NJ), that biopharmaceutical companies understand the functions of excipients in terms of their interactions with the active substance and the packaging materials. "The stabilization of many new substances, such as proteins, peptides, and monoclonal antibodies, requires specific excipients, which are well documented in literature, to impart desirable shelf life," he says. "Therefore, the selection of excipients in a formulation has the ultimate specific function with the active substance to ensure and retain its effectiveness during manufacturing, shipping, storage, and usage.
"There is a limited selection of excipients acceptable for parenteral formulations," he continues. "Consequently, when initial preformulations are designed for new drug development, only approved excipients from International Pharmaceutical Excipient Council (IPEC), U.S. Pharmacopeia (USP), and FDA should be used. If other excipients are used they may require considerable regulatory review for acceptable use.
"Initially," he explains, "several preformulations should be designed to determine what excipients are needed, or not needed, to yield potential preformulation candidates for further development. Preformulation is a 'must' requirement to ensure that a potential formulation may arise for marketability. Shortcuts are costly. Management should be advised to do it right the first time, because perhaps that could speed up the drug development."
A MATTER OF PARTICULATES
The demand for assurance against interaction naturally is leading to development of products, such as stoppers and coatings, that guard against it. "With more people demanding more information on extractables, you might try to make rubber more inert, but that is difficult," says consultant Edward J. Smith, PhD (King of Prussia, PA), the chairman of the Parenteral Drug Association's (PDA) Packaging Science Interest Group. "There are only so many ingredients you can use. So you coat or shield them. You will see more of that until we see a quantum leap in rubber technology."
In a presentation at PDA's annual conference in December, Smith outlined the coatings, films, and other treatments that are available to decrease extractables and particulate matter or otherwise enhance product-closure compatibility. These include the Abboclad and Deposition Coated Stopper from Abbott Laboratories Inc. (Abbott Park, IL), Coated Stopper from Itran-Tompkins Rubber Corp. (South Plainfield, NJ), Flurotec from West Pharmaceutical Services, and Omniflex Plus from Helvoet Pharma (Pennsauken, NJ). Abboclad and Flurotec cover the plug area of the stopper, while the others cover the entire stopper.
These treatments decrease particles either by increasing the ability to clean the stoppers or by smoothing over the "abradable and volatile" rubber surface, Smith says.
There is also a movement to find alternatives to natural rubber, which causes severe reactions in some people. Robert G. Hamilton, PhD, associate professor of medicine at Johns Hopkins University (Baltimore), is studying whether natural rubber—containing stoppers used in parenterals have enough latex allergens to cause reactions. That work is still in progress. Nonetheless, West Pharmaceutical Services has introduced thermoplastic closures.
"You cannot to date say it is an exact replacement for all characteristics of synthetic and natural rubber formulations," DeGrazio says. "In certain applications, you can apply thermoplastic elastomeric technologies. But you must thoroughly understand the application and its material and design requirements."
Other projects are being developed to cut down on particulate matter. Particles were one of the driving forces behind the development of Comar's Harmony system, which has an all-plastic closure to eliminate risk of aluminum dust and silicone contamination. Asselta says the product has been well received and notes that it has received as much interest for its ease of manufacture and needleless application as for its particulate properties.
READY TO GO
In addition to helping with testing, suppliers can obtain an advantage if they help reduce the pharmaceutical company's processing. Ready-to-use and ready-to-sterilize products and components are attracting interest.
"If companies can buy something that's half-assembled or three-quarters-assembled and already sterilized, they will," Smith says.
Frank M. Keim, managing director of American Stelmi Corp. (Princeton, NJ), says he has noticed an interest in products that are already washed and depyrogenated because drug companies don't want to do much washing and siliconizing themselves. "There seems to be some regulatory interest in looking at end-users' stopper-washing and siliconizing procedures to see if they are validated and duplicable," he says. "That leads to the use of ready-to-sterilize products."
There is also room for innovation in plastics, as newer drugs tend to be more biosensitive than their predecessors and may need extra protection.
"We find that more-complex and -sophisticated drugs require integrating new materials into the container area," says David Bacehowski, vice president—advanced technology development of the corporate research and technical services organization at Baxter Healthcare Corp. (Round Lake, IL). "Better gas barrier, water vapor transmission rate, and other properties are needed, and often conventional materials cannot meet those needs. Also needed are ways of manipulating and processing materials into a new container system. One area of focus is multilayer polyolefin-based containers. We want to investigate creating coextrusions of materials and converting them into multilayer films for specific applications."
The container closure guidance could have a great impact in functional packaging. The guidance states that where the packaging doubles as a drug delivery system or other function, the ability to function in the manner for which it was designed must be demonstrated throughout the product's expected shelf life.
That is of great concern to Michael A. Gross, PhD, director of corporate regulatory affairs at Becton Dickinson & Co. (Franklin Lakes, NJ), who is chairman of PDA's Drug/Device Delivery Systems Interest Group. "FDA put the requirement in the guidance, but no detail about what we're supposed to do," he says.
He hopes that FDA will provide such detail. "It is desperately needed," he says. "It is very important to have clarity from a regulatory standpoint." While functional packages such as drug-device delivery combinations have safety and performance issues that are under the responsibility of the Center for Devices and Radiological Health (CDRH), they are nonetheless still packaging for injectable products and are regulated by the Center for Drug Evaluation and Research (CDER). Therefore, Gross says, he hopes CDER seeks the input of CDRH so that parenterals that are drug-device combinations can be covered thoroughly.
As parenteral technology continues to evolve, it will be more important than ever for industry and FDA to maintain constant contact to keep up with each other's changes. And it will be important for suppliers to keep up with the trends and figure out how to capitalize on them.
"The trend is to eliminate the packaging, or the influence of packaging, as much as possible," Smith says. "But some parenteral products are not simple packages and you can't eliminate them. I empathize with FDA. It is very difficult to learn what a package does and how it functions."