Advancing technology and upcoming guidance documents promise to make parenteral packaging more reliable and user-friendly than ever before.
by Karen G. Beagley, Midwest Editor
To protect and ship highly sensitive pharmaceutical powders and liquids, drug manufacturers rely on high-barrier vials, bottles, and syringes. These packages must keep the pharmaceuticals sterile yet allow healthcare practitioners to use them efficiently, safely, and quickly. To ensure that such packages remain sterile, both industry groups and FDA are working on guidances that assist both the manufacturers and the users of parenteral packaging.
Industry is also involved by developing high-tech aseptic systems such as barrier isolators to nearly eliminate contamination associated with the filling and sealing of vials, bottles, and syringes. Industry is also creating systems that help users deliver drugs quickly and efficiently yet minimize accidents such as needle sticks and overdoses.
GUIDANCE DOCUMENTS
The Parenteral Drug Association (PDA) and FDA are both working on guidelines to assist pharmaceutical manufacturers who use parenteral packaging. PDA is currently formulating a guidance document on sterile product filtration processes. "The guidance will affect integrity testing and validation of filter processes," says Edmund Fry, president of PDA. "The technical guidance our expert committee is preparing should be published in the next few months."
PDA has also submitted comments to the European Commission regarding the latter's guidance document on aseptic processing, specifically on sterile medicinal products, requesting that the guidance reflect the benefits of using isolator systems. "In Europe, the initial experience may have been with isolators in hospitals," explains Fry. "Isolators in hospitals are often not used in the same manner that drug companies use them. In the United States, FDA regulates industry's use of isolators under the stringent standards of GMPs."
FDA is producing an updated version of its 1987 "Guideline on Sterile Drug Products Produced by Aseptic Processing." Richard Friedman, consumer safety officer for the agency's Center for Drug Evaluation and Research, explains that "there will be new sections on personnel, design, and endotoxin control. The guideline will also have new definitions and address technologies such as barrier isolation and form, fill, and seal."
NATURAL RUBBER RULE
A regulatory development that will affect the labeling of pharmaceuticals that are packaged in bottles, vials, and syringes is FDA's final rule on latex-containing devices and packaging. Published on September 30, 1997, "Natural Rubber—Containing Medical Devices: User Labeling" will take effect one year from its publication date. According to Michael Gross, director, corporate regulatory affairs for Becton Dickinson and Co. (Franklin Lakes, NJ), "The rule mandates that manufacturers label, using specific statements, all over-the-counter and prescription medical devices, in vitro diagnostic products, and drug-device and biologic-device combination products and their packaging when they or their components are manufactured from natural rubber. The regulation applies to all products manufactured either by dipping molds into liquid suspensions of natural rubber latex particles or by molding dry natural rubber, if they are intended to, or are likely to, contact humans."
FDA has received 62 comments on the proposed rule, and all of them reportedly support it, but differ in their reactions to FDA's proposal to label latex-containing medical devices for the protection of latex-sensitive individuals.
Schott Pharmaceutical Packaging's glass containers feature a high purity, ultrainert inner surface that allows safe packaging of sensitive or aggressive products.
"Drug-device and biologic-device combination products are subject to certain intercenter agreements published in 1991," says Gross. "Through a novel use of two of these intercenter agreements, FDA has also stated that it has the authority to apply the final rule to combination products that contain natural rubber and are regulated solely under drug or biologic authorities. It will require manufacturers of such products to comply after the applicable intercenter agreement has been amended to reflect that prefilled vials, patches, infusion pumps, and prefilled syringes are subject to the final rule, or by the effective date of the final rule, whichever is later."
The regulation requires manufacturers of products containing or packaged with natural rubber latex to include the following statement in product labeling: "Caution: This product (or the packaging of this product) contains natural rubber latex which may cause allergic reactions." For products containing or packaged with dry natural rubber the label must read, "This product (or the packaging of this product) contains natural rubber."
Even though latex is used more for devices than for packaging, parenteral packaging often contains components made of latex. "This ruling affects vial stoppers and syringe plungers," says Edward Smith, vice president of technical affairs, Helvoet Pharma Inc. (Pennsauken, NJ). "The drug and medical device manufacturers will have to label their products with this warning. It is to prevent an allergic reaction in people who are sensitive to the rubber protein."
"The interesting thing about this ruling is that FDA made it based on regulations that apply to medical devices," says PDA's Fry. "Combination products of drugs and devices are falling under this ruling."
SYRINGE ADVANCES
Many parenteral packaging suppliers are devising new ways to hold and deliver pharmaceuticals to help make an end-user's job easier. "Prefilled needleless syringes are gaining popularity," says Ken Muhvich, senior regulatory pharmaceutical consultant for The Validation Group (Baltimore). "Hospital personnel can tap the syringe into an existing IV line. Since the medication isn't drawn from a vial it reduces the possibility of medication error. And because the syringe is needleless, it also prevents the possibility of a needle stick."
Needleless or not, prefilled syringes are convenient for end-users. Because they eliminate the need to draw medication from a vial, they ensure that the correct dosages are given.
"Prefilled syringes cut down on medication errors and the chance of infection," says John J. Racik, senior product manager, pharmaceutical systems division, Becton Dickinson. "They also increase the efficiency of the manufacturer's production line. When filling a prefilled syringe, the manufacturer doesn't have to compensate for overfill as you do in a vial. The overfill is 50% less in a syringe than it is in a vial."
Currently in the United States, vials are still used more than prefilled syringes. But, says Racik, "as more companies are looking to stand out in the marketplace, prefilled syringes will become more prevalent. We did a study that showed that 85% of healthcare professionals prefer prefilled vaccine syringes. In the future, the delivery system will become more of the selling point."
"More manufacturers are making prefilled syringes because of the ease-of-use factor," agrees Jeff Turns, vice president of sales and marketing at Pharma-Turm Inc. (Yardley, PA). "Healthcare providers appreciate that they do not have to manipulate the syringe to ensure the correct medication."
VIALS AND STOPPERS
To protect highly sensitive substances, vials are often lined with a coating to prevent interaction between vial and pharmaceutical. "We have lined the vial with pure, fused silica to eliminate the interaction between the glass surface and the contents," says Robert Swift, scientific services manager, Schott Pharmaceutical Packaging (Cleona, PA). "In addition to the essential inertness, the vials are completely compatible with existing depyrogenation and filling processes."
Some pharmaceuticals degrade, depending on the moisture content of the finished formula. But the use of packaging materials that absorb moisture can significantly stabilize pharmaceuticals. "Calcium oxide and molecular sieves are known to have good desiccating capacity, and both will absorb water at relatively low humidities," says Val Romberg, director of Westar, multimaterial product development, at The West Co. (Lionville, PA). "We are developing stoppers that contain molecular sieve powder, and they effectively act as desiccants for injectable drug formulations."
BARRIER ISOLATION TECHNOLOGY
Many companies are at various stages of developing barrier isolator systems to fill parenteral packaging. Barrier isolation involves using a closed filling and packaging environment, which some consider to be superior to aseptic processing. "People are the greatest contaminant in an aseptic process," says Ben Webb, associate engineering consultant, Eli Lilly & Co. (Indianapolis). "We all want to produce a sterile product. FDA requires media fills to prove that a process is aseptic. We plan to submit media fill data later this year proving that our system is equivalent, if not superior, to conventional aseptic processes."
FDA does acknowledge the potential benefits of a barrier isolation system. "If the isolator is properly designed, maintained, and controlled it should offer a tangible advantage over classic aseptic processing," says Friedman. "But the jury is still out. FDA will wait until we see the data."
Another factor creating the need for barrier isolation technology is the advent of biochemical drugs, which cannot be terminally sterilized. "For products that can't be terminally sterilized, barrier isolation technology gives users the confidence that the package maintains its sterility," says Ron Filipski, director, Pasteur Merieux Connaught (Swiftwater, PA). "Biologicals cannot be terminally sterilized, so barrier isolation technology gives users a better confidence level of sterility."
Jack Lysfjord, vice president of technology and international sales, TL Systems Corp.—Bosch Group (Minneapolis), agrees. "Biological products are becoming more prevalent, so the industry needed to create a system for them. Barrier isolation technology answers this need."
Products that cannot be terminally sterilized will most likely continue to be handled in an aseptic system. And further, companies that use aseptic processing may benefic from using barrier isolation.
"What we have to prove now is that barrier isolation technology works properly. We are doing this through validation and documentation," says Paul Chimino, sales engineer, Bausch + Stroebel Machine Company, Inc. (Clinton, CT). According to Friedman, some of the key issues to developing barrier isolation technology are finding suitable construction materials, maintaining adequate positive air pressure from the isolator to the surrounding environment, meeting Class 100 standards for the interior of the isolator, and at the very minimum maintaining a Class 100,000 environment in the surrounding room.
"Companies should examine whether or not they have products that can be terminally sterilized. If a product can be heat sterilized it should be, because heat sterilization is the more reliable, robust process," explains Friedman. "It comes down to product safety. Ultimately, both industry and FDA agree that product safety is the most important issue."
CONCLUSION
With product safety in mind, both industry and FDA are working to improve parenteral packaging. Designed to protect latex-sensitive patients, a new FDA ruling regarding the labeling of latex-containing packages affects pharmaceutical manufacturers, who will need to either institute the new labeling or find nonlatex alternatives. New guidelines from FDA and PDA along with developments in barrier isolation technology should help industry refine filling and packaging processes. And industy is devising safer, more reliable ways to package and deliver drugs. As much as these developments affect pharmaceutical packagers, their impact will be felt most by healthcare practitioners, who will be able to deliver drugs more safely and efficiently while minimizing nosocomial infections and allergic reactions.
Photo courtesy of Becton Dickinson, Pharmaceutical Systems Div.
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