Protecting Parenterals in Primary Packaging

Issues with glass (the traditional material for parenteral containers) and the complex needs of the rapidly growing biologics market are spurring developments in parenteral packaging. “Ease-of-use for the patient is another concern due to an increasing trend toward self-medication,” says Christopher Cassidy, vice-president of sales and marketing, North America for Schott Pharmaceutical Packaging.

Quality continues to be imperative. “ … the main and most important concern of the pharmaceutical packaging market has always been the integrity of the drug and how to avoid any interaction between the glass and the drug,” says Paolo Golfetto, director of technical and business external relations at Ompi. He reports, “In recent years, with several recalls spurred by container or closure defects (… loss of sterility) or particle contamination, attention has intensified.”

Dr. Nicolas Brandes, director, Market Development at West Pharmaceutical Services, agrees. He says, “From a regulatory perspective, we are seeing increased scrutiny on quality. It’s essential to build in quality from the start.” 

The steady rise in biologics poses additional challenges. “Biologics often require specialized containers,” notes Brandes. Products often are highly concentrated, more viscous, and sensitive to packaging materials such as glass, polymers, elastomeric stoppers, coatings (such as silicon oil), and the traces of tungsten left behind during the syringe manufacturing process.

The higher viscosity and higher volume of many biologics that will be entering the market may not be compatible with some formats, especially auto-injectors and prefilled syringes. Steven Kaufman, global business development lead at Bespak, explains: “In the past, a fill volume of 0.2 mL to 1 mL, using a 1-mL prefilled syringe with a 27-gauge needle was typical. That’s changed. In addition to the 1-mL prefilled syringe, primary containers have grown to include the 2.25-mL prefilled syringe, and needle gauges have diminished in size to 29 gauge. This combination poses a big challenge for injection time and, more importantly, for ensuring completeness of injection. With high viscosity comes concern about the force placed on a glass syringe to achieve a target injection time and guarantee conpleteness of injection. Glide force also must be considered, along with injection time and the risk of breakage. Major suppliers have addressed these needs with biotech-ready prefilled syringes, which offer better dimensional control and siliconization. Many pen systems have difficulty handling formulations above 10 centipoise (cp), but Bespak’s VapourSoft-based auto-injectors and our latest amplification system can easily handle several 100 cp with minimal risk of glass breakage.” In addition, Kaufman says, “Shipping testing and transport are critical parts of any device manufacturer’s program. When delivering high-value biologics, the appropriate level of robustness must be built into the device itself. ISO standards must be followed and tested against to ensure there’s no variability and that key specifications are met.  Now, more than ever, the importance of auto-injectors and similar devices such as wearables is increasingly clear.”

Glass innovations

Glass, a well-established material for vials, syringes, cartridges, and ampuls, has experienced quality issues such as particulate contamination, interaction with high pH products, and subsequent delamination. Glass also has the potential to break and may not be compatible with the cold temperatures some biologics and other novel applications, such  as cell therapy, require. “Extremely cold temperatures pose a challenge to container closure integrity,” explains Brandes.

Suppliers of glass containers for parenterals have improved manufacturing processes to reduce chances of delamination and particulate generation and upgraded testing to provide earlier detection of problems. Ompi, for example, has “completely redesigned manufacturing equipment and introduced new process steps to drastically reduce … particles,” Golfetto reports. He adds, “We operate with a continuous improvement mindset, with a special focus on manufacturing process capability and product quality.” In fact, the company’s quality targets have moved from an acceptable quality level approach to a more stringent parts-per-million defect level.

Cassidy emphasizes the importance of making process improvements within existing validation frameworks. For example, he says, “With Vials DC, we have optimized an established production process [to minimize chances of delamination].” Produced from high-quality Fiolax glass tubing, Vials DC containers undergo an optimized hot-forming process. The result is vials with highly homogeneous inner surfaces. Tests based on United States Pharmacopeia (USP) <1660> showed no delamination or pre-indicators for delamination. He recommends, however, “performing screening studies for each individual case.”

Measures are also being taken during manufacture, fill/finish, and final packaging to minimize glass-to-glass and glass-to-machine contact, which can flaw a container or cause breakage. The expanding use of ready-to-use nested vials, now available from multiple suppliers, prevents containers from coming into contact with each other or the equipment. Nested vials also streamline the fill/finish process. “Ready-to-fill packaging eliminates the need for washing and sterilization by the pharmaceutical company or third-party filler,” says Brandes. Users can load tubs directly onto filling lines. The streamlined, contact-preventing process reduces reject rates and preserves the cosmetic quality of the vials.

Dual-chamber cartridges

Nested vials are not the only recent innovation in glass packaging for parenteral products. Double Chamber cartridges from Schott combine liquids with liquids or liquids with lyophilized drugs to provide stable storage, reliable reconstitution, and convenient and safe administration versus the traditional, multi-step dual vial (drug, diluent) and syringe administration process. “The risk of error, such as a possible contamination of the substances, increases with the number of steps,” observes Cassidy. “In addition, there is the risk that the patient could miss the right mixing ratio or inject the wrong dosage. A Double Chamber cartridge solves this problem because it carries out mixing and application in one go.”

The dual-chamber design addresses approximately 25% of new injectable drugs, vaccines, and biologics that are freeze-dried and have to be reconstituted prior to injection. The Double Chamber cartridge stores drug and diluent in consecutive chambers separated by a plunger (see Figure 1). A bypass in the glass barrel allows the contents to mix before the drug is injected. Turning the pen lock pushes the plunger, leveling it to the bypass and forcing the diluting liquid through a 0.1-mm opening and into the second chamber; the liquid then reconstitutes the drug. Now, the exact dosage of the drug can be injected without risking contamination.

Medical professionals and patients favor dual-chamber cartridges because they’re simple to operate. Plus, high dosage accuracy makes the system safe and convenient for patients, especially if a highly concentrated drug is involved. The cartridges are compatible with common pen systems and can be customized. Several major pharma/biotech firms have already adopted the format for a variety of products including human growth hormone.

Polymeric options

Although glass continues to dominate parenteral packaging, it’s not suitable for all products. In those situations, polymeric options are being specified. The most common materials, cyclic olefin copolymer (COC) and cyclic olefin polymer (COP), are tungsten-free and do not leach alkali-ions such as sodium, which can cause the pH-value of the drug to shift. “In severe cases this pH shift may affect the stability of the drug,” notes a Gerresheimer spokesperson.

“COP reduces the risk of breakage and is proven for low temperatures,” says Brandes of West, which offers Daikyo Crystal Zenith COP vials. West licenses this technology from Daikyo Seiko. A clean material, Daikyo Crystal Zenith systems provide very low extractables. As a result, he adds, COPs “help reduce chemical interactions, delamination, protein absorption, and aggregation.” He notes that the material can be formed in custom shapes and designs, which are not possible with glass. “In a crowded market, there’s a need to differentiate products. Custom containment and delivery systems could deliver that differentiation.”

Gerresheimer has offered a range of ready-to-fill COP syringes manufactured by its longstanding partner, Taisei Medical, in Japan. In collaboration with Taisei, Gerresheimer has expanded its ready-to-fill COP syringe portfolio and production capacity by beginning to manufacture the Gx RTF ClearJect syringe at its Gerresheimer Medical Systems plant in Germany. The first Gx RTF ClearJect product to be manufactured is the 1-mL long syringe with staked-in needle. “The Gx RTF ClearJect syringe … allows the use of standard components like plunger stoppers, backstops, and plunger rods,” says a Gerresheimer spokesperson. Under development for approximately 18 months and now in a prelaunch phase, the Gx RTF ClearJect syringe will be available in 2018.

Schott offers a prefillable COC syringe for sensitive drugs. The Schott TopPac SD syringe with pure elastomer components features a reduced extractables and leachables profile. Careful component selection and an optimized processing method result in a significantly reduced level of impurities and decrease the chance of drug/container interaction. Cross-linked silicone for barrel lubrication reduces the amount of subvisible particles while providing optimal functionality. Sterilization with ethylene oxide instead of irradiation further reduces extractables and leachables.

Multilayer containers

Polymeric containers may also be multilayer. The Gerresheimer MultiShell COP/polyamide/COP vial combines excellent barrier properties and glass-like transparency to protect contents from oxidation and water vapor and increase shelf life. A commercial production line manufactures vial sizes from 2 mL to 100 mL. An automated packaging line packages ready-to-use vials or bulkware. Applications include oncology drug products, monoclonal antibodies, osteoporosis treatments, and specialty injection solutions with high pH-value and significant sensitivity to oxygen.

Another multilayer polymer-based container, Wheaton’s DualFusion vial, addresses delamination and leachate concerns. “There are two Fusion layers. The first layer is what we call a ‘protective layer,’ which is an inert organosilicate layer that protects against high or low pH products that can cause delamination via a silicon network hydrolysis,” explains Wayne Brinster, president and CEO of Wheaton. “The second layer is the ‘barrier layer,’ which is a silica layer that is covalently bonded to the COP shell via a plasma-enhanced chemical vapor deposition technology. These layers are less than 500 nm in thickness, so they are not seen with the human eye. When these two Fusion layers are combined with a COP shell it is known as a new material called a ‘Fusion material.’” The outer COP shell provides mechanical strength, protects against breakage, and can withstand a temperature range of -196 C to 121 C without cracking. The inner layer prevents permeation of water vapor, oxygen, and other gases; protects against delamination; and eliminates concerns over leaching of metal ions. Since the lining is so thin, transitioning to the new container would be reportable, but would not require new trials. “It would be a drop-in replacement,” says Brinster.

The base of each ready-to-use, ready-to-sterilize DualFusion vial is laser-etched with a unique DataMatrix barcode for rapid and easy traceability. “This is extremely important when combating the ongoing concern of counterfeit drugs,” says Brinster. In addition, batches can be matched to run size.

Applications include highly toxic drugs like chemotherapy doses where breakage would result in hazardous conditions and an arduous cleanup. Brinster reports, “We are already seeing a shift toward the DualFusion vial in the pharmaceutical industry, specifically in the biological segment. ... There is always a concern with leachates when packaging large protein molecules. For example, if a chemical molecule migrates from the primary packaging component into the end product, it can cause the protein to fold and change its form; this occurrence would result in a drug efficacy [concern]. For example, the folding of the protein will cause the end product to become less potent or even cause it to become dangerous to the patient.” The organosilicate inner lining of the DualFusion vial reduces the concern for leachates because of the high purity of the material. “We are also seeing a shift toward the DualFusion vial in the traditional chemical-synthesized segment due to its protection against delamination. ... The inert organosilicate layer ... protects against delamination from silicon network hydrolysis, which is common for drug products that are in a pH range of 3 to 11,” he concludes.

​Ready-to-use vial trends

According to Gerresheimer, the shift to ready-to-use vials depends on:

Ready-to-use vial benefits

According to Ompi, the benefits of ready-to-use vials include:

Article Details

Pharmaceutical Technology
Vol. 40, No. 10
Pages: 62–67

Citation:

When referring to this article, please cite it as H. Forcinio, "Protecting Parenterals in Primary Packaging," Pharmaceutical Technology 40 (10) 2016.