The parenteral drug market has long used 1 mL long glass prefilled syringes. While these syringes have experienced success, they have been prone to, for example, breakage or production inconsistencies. Increased regulatory scrutiny of glass syringes, vials and cartridges, and the way in which they are filled and processed, has led drug manufacturers to search for alternatives.
A few years ago, syringes of Crystal Zenith, a proprietary cyclic olefin polymer from Daikyo Seiko, were introduced. The polymer syringes are not only more resistant to breakage, but is known to have improved manufacturing consistency as well as resistance to extreme temperatures. In addition, they are silicone-free.
Recently, West Pharmaceutical Services and Vetter partnered to offer 1 mL Crystal Zenith syringes to their clients. Drug manufacturers have the option to conduct the syringe filling within their facility, or to outsource to Vetter. To find out more, we presented questions to West and Vetter. Responses were provided by Graham Reynolds, West’s VP for Marketing & Innovation; Mike Schaefers, West’s VP for Marketing in Europe; and Vetter Managing Director Thomas Otto.
PhM: West and Vetter have collaborated to provide customers with the new Daikyo Crystal Zenith syringes. What was the business rationale?
Graham Reynolds: Many of our customers are challenged to find total packaging solutions that are not only high-performance syringe systems, but also suitable for sensitive biopharmaceutical products. Many of today’s sensitive drug products present a host of new challenges: higher viscosity, sensitivity to tungsten and silicone oil, etc. Also, manufacturers are facing increased scrutiny from regulatory agencies while searching for a way to move drug products to the market quickly, maintaining safety and efficacy.
PhM: What do drug manufacturers need to know about the CZ syringes and the polymer of which they’re made? Are there new manufacturing issues or validation challenges to consider?
Mike Schaefers: The Crystal Zenith polymer offers many advantages, including glass-like transparency, which permits visual inspection of the manufactured components and of the parenteral products that are delivered to the end user. In addition, the material is highly break-resistant and forms an excellent moisture barrier. Packaging systems based on Daikyo Crystal Zenith have been used for many years on marketed drug products. The 1mL long insert needle syringe system features new enhancements such as automated cleanroom manufacturing, 100% vision inspection (including the needle), and an insert molding process for the needle that eliminates the need for adhesive or tungsten.
Graham Reynolds: We feel the syringe is ideally suited for biopharmaceutical drug delivery. It is sterile, silicone-oil-free and the plunger is laminated with Flurotec film, which helps to lower protein adsorption and serves as a barrier to leachable substances while enabling effective functionality without the need for silicone oil lubrication. The material’s tight dimensional tolerance and consistency of syringe functionality can help to make a delivery system’s operation predictable, which makes it an easy-to-use, safe option for the patient, as well as enabling consistent performance within a delivery device (such as an auto-injector).
In general terms, the Crystal Zenith syringes are provided in the same basic format as similar glass syringes, enabling filling on existing equipment. West works actively with customers to understand specific equipment needs, and has extensive links with the equipment manufacturers.
PhM: Were the regulatory issues with prefillable glass syringes the key driver for this project, or was performance and patient preference the driver?
Graham Reynolds: These syringes have been developed specifically to meet the needs of sensitive biologic products, and may help to overcome many of the limitations of glass syringes, including breakage and particulates, as well as eliminating materials such as silicone oil, tungsten and adhesive, which could be sources of potential interaction with certain drugs. The FDA is becoming increasingly aware of glass-related quality issues, including breakage, cracks, contamination and particulates (often formed over time due to interaction between the glass and the drug) and there has been an increase in the number of recalls related to glass issues. It was our goal to develop a system that meets the needs of the patient, the drug product and the drug manufacturer, and to be able to fill and deliver that product to the market as efficiently and effectively as possible.
Recent developments around the use of polymeric materials for drug containment have allowed delivery system companies to work closely with drug manufacturers to develop novel systems designed specifically to meet patient needs. The design and manufacturing flexibility of a polymeric drug container, combined with the ability to create patient-friendly devices designed with human factors engineering, enables the design of more innovative overall delivery systems that may aid in patient compliance through ease of use and enhanced technology.
PhM: When will commercial-scale filling be available? Do you expect manufacturers of commercialized products to look to switch syringes, or will the CZ syringes be used primarily for drugs in clinical trials?
Graham Reynolds: Syringe manufacturing capacity is in place today to support customer stability trials and initial activities, which will be required prior to full-scale commercial launch of a drug. West has sufficient capacity to meet these requirements, as well as initial scale-up, and has plans to introduce more capacity within our Scottsdale, Arizona, facility in the near future. Infrastructure is in place, and additional manufacturing cells will be added to ensure customer needs are met.
Thomas Otto: Vetter has installed capacity to meet initial customer needs for technical trials, stability fills and early-phase clinical fills.
PhM: The CZ syringes have the same outer dimensions of glass syringes. If so, what equipment/operational changes were required?
Graham Reynolds: The Daikyo Crystal Zenith syringe has been designed to meet ISO requirements, and to be compatible with existing devices such as auto-injectors and safety systems. The improved dimensional tolerance of plastic over glass has the potential to enhance functionality and reduce variability.
PhM: The solution promises “automated cleanroom inspection and 100% vision inspection.” Tell us a little about the technology behind this.
Mike Schaefers: West applies 100% vision inspection of the syringe at various stages, including inspection of the needle to ensure integrity. Robotic handling in a classified cleanroom, with minimal operator intervention, contributes to a product of extremely high quality and low particulate levels.
Thomas Otto: Vetter will apply the same high standards and systems as used for the filling of glass syringes. In our European facilities, we have adapted a cleanroom especially for filling the Daikyo Crystal Zenith 1mL long insert needle syringe. Using RABS technology to minimize contamination risk, the line is operating with two filling needles. Meeting cGMP specifications, it has a capacity of up to 3,000 units per hour. All syringes are 100% visual inspected following the filling process.
PhM: What are the major pain points that drug manufacturers are experiencing today regarding drugs administered via prefillable syringes?
Graham Reynolds: Traditionally, the market has used 1mL long glass prefilled syringes. These systems have been successful, but they have notable limitations, including:
- Breakage – Any glass product runs the risk of breakage during storage and shipping. Additionally, glass syringes may break under the pressure of an auto-injector system.
- Performance Issues – Studies have shown that silicone oil, used to increase lubricity in glass syringe systems, can be distributed unevenly, leaving surface areas with insufficient lubrication. This will greatly increase the force required to operate the auto-injector and may lead to delivery of a partial dose to the patient.
PhM: How does the prefillable syringe market look for 2012? What are your conservative expectations?
Graham Reynolds: Pharmaceutical and biotech companies are working closely with drug delivery device manufacturers at an early stage to ensure that there is efficient development of an overall system to enable cost-effective drug delivery. Cost factors may include the ability to move the product to market as quickly and effectively as possible; reducing in-process rejects due to breakage or lack of function; and the overall cost of quality, which has to be built into a system from the start.
The FDA is placing extra scrutiny on the area of combination products, such as auto-injector systems that use a prefillable syringe, and there is uncertainty about how this may impact the drug development process. Clearly, regulatory factors will continue to have a key impact on the future development of delivery systems.
Mike Schaefers: The prefilled syringe market, estimated at around 2.5 billion units, is likely to continue to grow close to 10% per year, driven by trends in vaccines, hematology products and biologics. Within the biologics segment, significant growth will continue for therapies to treat chronic conditions such as autoimmune diseases (RA, MS, etc.). Novel systems to enable the effective treatment of chronic conditions such as high cholesterol and allergies will also grow. In addition, understanding the importance of the drug container as it relates to the integration into the overall drug delivery system will continue to be a key factor.