Medical Device Link.

PARENTERALS

In addition to EtO processing, Ethox International manufactures and packages medical devices.

Glass or plastic, prefilled syringes or vials—what is the latest packaging for injectable pharmaceutical products, loosely termed parenterals for this article? Manufacturers of primary packaging, as well as contract packagers, are offering a full range of options rather than marketing one single approach.

GLASS GROWS UP

Almost all parenteral drugs continue to be packaged in glass. Even manufacturers developing the newest plastic alternatives, such as cyclic olefin copolymer (COC), envision such plastics serving a limited market of products with special glass-compatibility issues. Glass packaging, however, is not static. New options are available, and glass handling has become more sophisticated.

Schott forma vitrum Pharmaceutical Systems (Lebanon, PA) is both a major worldwide producer of pharmaceutical glass packaging as well as a leader in the development of COC components. Gary Waller, director, North America sales and marketing, for Schott, describes recent advances in glass packaging. Schott, he says, now offers three levels of quality in glass vials: Standard line, Clear line, and Top line.

“Standard line continues to be the majority of product manufactured in the U.S. market with limited-to-no-inline monitoring of dimensional or cosmetic control.” Schott’s Standard line provides inline dimensional control but no cosmetic inspection of the glass.

“We’re focusing our operation here in Lebanon, PA, on a move toward complete vision technology,” Waller adds. Clear line is manufactured under 100% camera inspection, he explains. “When a customer requests Top line, we review their requirements and tailor the process to meet the mutually agreed expectations.”
Glass handling is another avenue for innovation. Minimizing glass-to-glass contact, from the raw tubing stage through the converting process to the container’s final packaging, is key.

“In the past, pharmaceutical manufacturers would accept glass-related process issues, either cosmetic, functional, and minor dimensional. Today, we see an increased pressure from the pharmaceutical companies on their suppliers to provide a product that minimizes those three areas,” Waller explains. “You have to invest in your machine base and vision technology to accomplish that.” Schott, he adds, has almost eliminated glass-to-glass contact and is in its fourth generation of internal vision system development. It has become a standard within Schott to continually evaluate its process and develop new process and or technology to meet customer needs.

Minimizing glass-to-glass contact during the manufacturing process may ensure that components reach the pharmaceutical manufacturer or contract packager in pristine condition, but how are they handled after that point? Traditionally, vials are placed unceremoniously into the washing process and pass into the sterile core through a depyrogenation tunnel, then accumulate on various collection tables prior to and after filling. It’s at these points, when the vials jostle one another, where damage often occurs, manufacturers agree.

“At sterilization temperature, the surface of the glass scratches more easily than it does at ambient temperature,” Waller points out. One option, he says, is to eliminate this accumulation step, synchronizing the speed of the fill operation with the speed of the wash operation, and minimize other glass-to-glass contact areas within their filling process.

Jörg Bengelsdorf, director, pharmaceutical projects, Groninger USA LLC—a manufacturer of complete filling production lines for both syringes and vials—agrees that the sterilization process is hard on glass. “In the conventional oven, the glass is heated and cooled fairly quickly. This can cause a lot of stress in the glass.

Then when the vials come onto an accumulation table, they are more likely to crack,” he explains. Groninger redesigned the equipment for this step, lengthening the depyrogenation tunnel so that the glass is heated and cooled more gradually. “We still have the accumulation tables,” Bengelsdorf says, “but we don’t see problems anymore with cracks and damaged glass.”

While Baxter Biopharma Solutions, Baxter Healthcare, has invested in a number of technologies and processes to minimize glass breakage during manufacture, the company is also working to ensure that the product remains intact through transit and use. This is especially important with cytotoxic molecules, says Tom Polen, senior director of marketing, because a broken vial can mean exposing the pharmacist or healthcare provider to very harmful compounds. “At our Halle, Germany, facility we’re developing a new vial coating technology to minimize breakage and contamination risk,” he says.

SYRINGES, VIALS, OR BOTH?

Glass-to-glass contact is much less of an issue for syringes, Bengelsdorf points out. “Nowadays, this washing and sterilization process is usually done at the glass manufacturer’s site,” he says. The BD Hypak SCF (sterile, clean, and ready to fill) from BD (Franklin Lakes, NJ) is the leading example of this packaging option in the United States, and Schott offers a similar system. These manufacturers pack 100 syringes in a nested configuration. For higher-throughput processing, BD offers Litepak, which offers a condensed tub containing 160 syringes.

“The customers do the filling and stoppering while the syringes are sitting in that nest, so there is no glass-to-glass contact,” Bengelsdorf explains. This system, he says, has been available for a while (according to BD, BD Hypak was first launched in 1954, and the SCF version in the early 1970s.) “It really took off over the past two to three years. The speeds have increased on those lines, and this is now a well-established process. Nowadays, it is the standard operating procedure,” he says.

Glenn Thorpe, BD’s director, strategic marketing, backs up this assertion. He notes that “we are seeing double-digit growth in demand for prefillable syringes, and for the BD Hypak SCF in particular.” He says that the actual driver behind SCF is its flexibility for filling lines. “Several product presentations can be produced on one machine, and the efficiencies in processing result in an overall lower finished-goods cost.” Prefilled syringe use itself is being driven by such factors as ease of use, less chance of medication error or contamination, faster to use in emergencies, and a higher yield from bulk vaccine or drug due to lower overfill requirements, he says.

BD added a new facility a few years ago in Columbus, NE, to complement its worldwide manufacturing presence, which will be capable of producing more than 500 million Hypak syringes per year, according to Thorpe. “The plan now is to expand total global capacity to upwards of 2.5 billion syringes at our four plants in the next few years,” he adds. These four BD manufacturing facilities are in Mexico, Nebraska, France, and Japan.

“A lot of the improvements recently have been processing improvements,” Thorpe says, echoing Bengelsdorf. “We have made improvements to our packaging to facilitate processing and accommodate higher-speed machines and the use of isolators or RABS [restricted-access barrier systems].” To this end, BD has recently introduced its TSCF product line for introduction of syringe components into isolators or RABS systems.

Baxter sees the global syringe market growing at about 15%, says Polen. “We see BioPharma customers not only launching new molecules directly in syringes, but also see customers creating new product iterations as a lifecycle management tool, offering their molecule in both vial and prefilled syringe formats.” Baxter has the capability to fill more than 800,000 syringes per day. “With a brand new facility going live now, we offer the latest manufacturing technology available,” he says.

Vetter Pharma-Fertigung, a company headquartered in Ravensburg, Germany, is a full-service provider specializing in the aseptic filling of prefilled syringes. It has adopted RABS for most of its production lines. The lines are almost fully automated and require no human presence in the Class A areas. “Ever since the introduction of RABS, we have accelerated our production processes tenfold,” explains Jeffrey Turns, president of Vetter Pharma-Turm Inc. (Yardley, PA). “But there is more to it. By clearly separating humans, machines, and the filling area, we can offer our customers the highest degree of sterility assurance in the filling of prefilled syringes.”

This year, the company will be inaugurating its third manufacturing facility, called Ravensburg Vetter South (RVS), and it has decided to add vials to its program. The new facility will allow Vetter to increase its current production capacity of 300 million prefilled syringes per year by a third. By the same token, it will now be adding vials for liquid and lyophilized drugs to its product portfolio, which already includes dual-chamber systems and cartridges.

“As a full-service provider, we would like to offer our customers genuinely comprehensive service – so vials are part of it. This means that our customers will have access to all the relevant application systems currently available on the world market,” said Turns.

Newer classes of therapeutic products have created a different paradigm for drug packaging. Historically, pharmaceutical manufacturers launched some injectable products in lyophilized form in a vial while still working to attain the ultimate goal of a liquid-stable product that could be supplied in a prefilled syringe. Some biotech protein and peptide products, however, are much less likely to ever be stable in liquid form, explains Graham Reynolds vice president, Reconstitution and Transfer Systems, West Pharmaceutical Services (Lionville, PA). “Some of the protein and peptide products must be reconstituted immediately prior to use,” he explains. West has identified the field of reconstitution and transfer systems as “a real growth area for us,” adds Reynolds, who relocated to the United States to focus on this aspect of West’s business.

Reynolds emphasizes the possibilities of synergy, rather than competition, between vials and syringes. “Often there is a combination between some of the technologies. If it’s not possible to put the product in a liquid form in a prefilled syringe, often the next-best option is to have the product lyophilized in a vial and package it with a diluent in a prefilled syringe. Then the product can be reconstituted into the prefilled syringe for administration,” he says.

In 2005, West purchased the Israeli firm Medimop, acquiring its range of systems for the transfer, mixing, and administration of injectable pharmaceuticals. One of these products is the MixJect, which is used on commercially available products for the treatment of multiple sclerosis. This system helps patients with MS or their caregivers to reconstitute and administer these drugs, primarily in the home care setting. West provides the sterile device for reconstitution, which can be combined by the customer—either a pharmaceutical manufacturer or a contract packager—with the drug product and with the diluent, either in a vial or in a prefilled syringe, and any other necessary items into a single kit.

THE PROTEIN PROBLEM

Protein and peptide products, the offspring of the biotech revolution, present other packaging challenges in addition to their lack of stability in liquid form. Their notorious propensity to adsorb onto glass is the driving force behind the development of plastic alternatives, particularly COC. (For more on this subject, see “Injecting Excitement into Parenteral Drug Packaging,” Pharmaceutical & Medical Packaging News, April 2005.) In January, Daicel Chemical Industries Ltd., Polyplastics Co., Ltd., and Topas Advanced Polymers (TAP) jointly announced the acquisition of the Topas COC business of Ticona, a wholly owned subsidiary of Celanese Corporation. Schott, Owens-Illinois Healthcare Packaging Inc. (O-I; Toledo, OH), and Alcan Packaging (Millville, NJ) are among the converters developing Topas into vials and syringes.

“We are expecting some projects to start commercializing by late 2006, and that’s when we should see a significant jump in sales,” says Deven Patel, market development, Topas (Florence, KY). “In the syringe market, products are right now going through FDA validation for several customers. Some are in clinical trials, others are doing FDA validation right now on the production facilities. The COC has shown good enough results for them to move forward with the manufacturing operation.”

Like other manufacturers interviewed, O-I sees continuing opportunities for both vials and syringes. “We see strong demand in the future in the prefillable syringe market,” asserts Roger Smith, O-I’s director of technology and innovation. “That’s why this year we are expanding our MLX technology to include syringe barrels that will be prefillable. We intend to have those products ready for stability testing by the end of 2006.”

O-I’s MLX technology incorporates multiple polymer materials in a layered structure. “The reason for that is that polymers are generally good at one thing,” Smith explains. “So one may be good at moisture barrier, and another may be good at oxygen barrier. We combine those to custom build a multibarrier system.”

RESEARCH AND DEVELOPMENT

When introducing new medications to the market, pharmaceutical companies are faced with the challenges of identifying the best combination of packaging material and drug formulation. Internal coatings are another way to minimize adverse interactions between container components and product. Schott introduced its Type I Plus coating technology as a way to assist pharmaceutical developers with protein-based product. “As we moved forward with Type I Plus,” Waller recalls, “we realized that we needed to continue developing other coatings, which we are currently working on, that would increase our offering to minimize protein adsorption. We have also developed a screening process that allows us to mark proteins and then quantify loss from solution because of binding on the surface. We can suggest the type of packaging that will be well suited for the stability of a drug formulation at a development stage.”

Many of the manufacturers interviewed are nurturing similar research partnerships with pharmaceutical manufacturers. Vetter Development Services, for example, is a self-sufficient pilot plant with a dedicated staff of 20. “They can do all of the ‘what if’ scenarios,” Turns says, including compatibility, pumping, and lyophilization studies.

Similarly, West Monarch Analytical Laboratories—a recent acquisition by West Pharmaceutical Services—conducts extractables and leachables testing, drug stability testing methods development and validation, and more. “FDA’s Quality by Design initiative, introduced about two years ago, says the packaging component, the delivery system, the reconstitution system, all those things that really have intimate involvement with holding or delivering the drug product, that’s all a piece of the final package,” stresses Fran DeGrazio, West’s vice president, quality assurance and regulatory affairs. “With the understanding that these delivery systems are a key part of the overall drug product, and the awareness of the potential impact of the system to both the chemicals and functionality in actual use, there’s more of a drive to ensure that those things have been qualified.”

Baxter has brought some the world’s leading lyophilization scientists together at the Baxter Lyophilization Center of Excellence at its Bloomington, IN, facility. “We have scientist experts in both biomolecule and small molecule parenteral product formulation, as well as processing solution, lyophilized, and dispersed-system dosage forms. The center also has a team of analytical development scientists who specialize in developing and validating analytical methods that meet regulatory requirements and assure product quality,” reports Polen.

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