The growth of biologics is an important factor for the injectable drug delivery systems market. Prefilled syringes are gaining attention in drug delivery because of the value they offer in improving administration, patient compliance, increased safety, and dosing accuracy. As a result, prefilled syringes are a growing alternative to vials for many of today’s parenteral products. Pharmaceutical companies recognize the advantages of prefilled syringes with specific regard to preventing dose overfill and ease of self-administration.
Prefilled syringes are used to package injectable drugs and vaccines. Some of the therapeutic drug classes which are packaged in prefilled syringes include antithrombotic agents, vaccines, blood stimulants, interferons, and rheumatoid arthritis medications. To date, there are more than 50 drugs and vaccines now available in a prefilled syringe format. It is estimated there will be 2.5 billion prefilled syringes used this year. With countless more pipeline drugs expected to be launched in a prefilled syringe, the market will continue to grow at rates well above 10% per year for the foreseeable future.
As the use of prefilled syringes continues to grow, it has received increased attention. With the passage of the US Needle Stick Safety and Prevention Act of 2000, prefilled syringe manufacturers began incorporating safety elements into the design of the device; these can reduce the risk of needle injuries. As more medications are self-administered at home, safety becomes an important driver. Additionally, some patients are needle phobic; the use of an auto-injector can hide the needle and a patient can easily perform the injection without the fear associated with needles. Usually an auto-injector consists of a staked needle prefilled syringe, the primary container-closure system which contains the exact drug dose, plus other device components. Due to the technological advances in safety, dosing, and compliance, prefilled syringes are one of the fastest expanding growth opportunity areas and stand to make strong market gains.
One of the drivers for prefilled syringe adoption by end users is simplicity. Instead of the traditional vial, which requires up to 8 steps to administer the drug, only 3 or 4 steps are required for a prefilled syringe.
Many injection device manufacturers are working on a range of drug delivery options to meet specific market and customer requirements such as ergonomic and visual enhancements to address end user needs, drug branding and differentiation strategies. Most of the time, the primary container system is the prefilled syringe.
Prefilled syringes act as the primary container for drug products. Therefore, they are required to provide seal integrity, compatibility and drug stability through the shelf life of the drug product. The syringe system should be a clear, transparent, low extractable, low particle, and sterile container closure system, which needs to meet various USP/Ph Eur/JP compendial requirements as well as ISO standards.
The traditional prefilled syringe system is made from glass; it provides good chemical resistance and oxygen and moisture barriers. It is transparent so the patients and caregivers can perform visual inspection to see if there is any color change, or particles inside the syringe prior to the injection; glass is strong and dimensionally stable, easy to clean and sterilize and can tolerate heat for the depyrogenation process.
The traditional staked needle glass syringe is the most popular prefilled syringe system; it consists of a steel needle, a glass barrel, a rubber plunger, a rubber needle shield and a plastic plunger rod. In order to achieve a nearly effortless injection process, it is necessary to apply a silicone oil coating on the inside of the glass barrel to provide lubricity between the plunger and the glass barrel. The staked needle provides the convenience; the user does not need to assemble the needle prior to the injection.
There are some challenges associated with the current staked needle glass syringe system: the rubber plunger is a complex mixture of organic and inorganic chemical compounds which have a tendency to leach into the drug solution and glass is not absolutely inert - there are many inorganic ions that can be leached into drug solutions, especially at high pH. Surface silicone oil has caused protein drug aggregation and residual tungsten from the staked needle insertion process can cause protein degradation. And, glass breakage problems have been the reason for several glass prefilled syringe product recalls.
Recalls have also resulted from other syringe-related causes. Eprex prefilled syringes were recalled due to leachables from the rubber plunger. The leachable caused an effect called PRCA – Pure Red Cell Aplasia in Eprex patients.
An auto-injector product recall was due to the uneven silicone oil coating (dry spot) on the syringe barrel causing incomplete injection. This was due to the fact that the auto-injector was designed to deliver a prescribed fixed force that was not able to move the plunger in areas lacking sufficient silicone oil.
Amgen’s recent recall of 5 lots of Enbrel prefilled syringes on October 25, 2010 and Johnson & Johnson’s recall of 70,000 prefilled syringes of antipsychotic drug on February 15, 2011 were due to glass breakage.
With a long list of glass prefilled syringe recalls, it is time to develop new materials and new designs to correct existing problems. Some recent advances are:
Plastic Syringe Systems
There are COC, COP and CZ (custom formulated COP resin) systems that have been developed. These cyclic olefin copolymers and polymers have excellent transparency, good moisture barrier properties, are chemically clean with very low extractables, break resistant, have low protein surface adsorption, are compatible with wide pH range solutions, have good dimensional tolerance and with high flexibility in design and no tungsten or adhesive is involved in fixing a staked needle to plastic syringes.
There are limitations of the plastic syringe system, such as the risk of scratching during machining, reduced moisture and oxygen barriers and limited high temperature resistance. The CZ syringes may have higher plunger release and travel forces than the silicone oil-coated glass syringes, however, consistent forces can be achieved; this is a great benefit for auto-injector applications.
Fluorocarbon Coatings on Rubber Plunger Surfaces
These provide surface lubricity and chemical barrier. There are two companies that have commercially available fluorocarbon coatings on rubber plungers:
A PVTF coating which is applied by spraying process, can reduce or eliminate the need for silicone oil on the plunger, and it provides some barrier properties. The other is an ETFE film, laminated during molding process, it can eliminate silicone oil on the plunger and minimize adsorption and absorption and reduce extractables and leachables.
In order to achieve consistent plunger release and travel forces, and eliminate potential film wrinkling of the ETFE, vacuum plunger placement is highly recommended. A secondary package may also be required for certain oxygen-sensitive drugs. There are several commercial products such as a high-viscosity hyaluronic acid, a high-value protein/peptide drug of Calcitonin, that are using the CZ syringe with ETFE film laminated plungers and many cytotoxic oncology drugs are under evaluation.
Container Closure System Design
In order to achieve a silicone oil free system, it is necessary to have a very tight dimensional tolerance and interference fit of both syringe barrel and fluorocarbon coated plunger, plus a super smooth surface of the syringe barrel. For unstable drugs, dual chamber cartridges or syringe systems are used for lyophilized drug separated by a rubber plunger from the sterile diluent; the lyophilized drug can be reconstituted right before use. This is a method to reduce the drug solution contact time and reduce drug-container interactions.
Process Modification
Sterilization causes damage to polymeric materials such as polymer chain scission which increases extractables/leachables. A reduced bioburden-controlled manufacturing environment can reduce the sterilization cycle either for steam sterilization, gamma radiation or E-beam sterilization. Plastic syringes, due to their limited high temperature resistance, require a modified sterilization process. “Ready to Use” rubber plungers are provided by several vendors with optimum washing, siliconing and sterilization cycles applied. With these components, there is no need to further process the plungers by pharmaceutical companies. A modification of the existing filling line is recommended in order to prevent surface scratching of the plastic syringes.
In summary, future materials for prefilled syringe components have been identified. They are clear, breakage resistant, chemically clean with low extractables and leachables, compatible with wide pH ranges of drug solutions, silicone oil free polymers. However, it is necessary to have all four elements present; otherwise the new materials will not function.
The four elements are:
- Plastic syringe systems
- Fluorocarbon coatings on rubber plunger surfaces
- Container closure system design
- Process Modification
References
- PDA J. Pharm. Sci. Tech., 2007, 61, 423-432. (December 2007).
- Amgen public announcement to Wholesale/Distributors/Customers titled “URGENT DRUG RECALL” (October 25, 2010) .
- Wall Street Journal “J&J Recall Watch: 70,000 Syringes of Injectable Antipsychotic Pulled” (February 15, 2011).
Author Biography
Patty H. Kiang, Ph.D. is a Pharmaceutical Consultant on Pharmaceutical packaging and delivery devices for liquid and lyophilized products, Prefilled syringe system, and CMC filing for Combination Products.
Prior to the consultant position, she was Account Director for Catalent Pharma Solutions; she was responsible for business development of Analytical & Biotech Services to Biotech and Pharmaceutical companies on the West Coast of USA, Canada and Asia Pacific territory.
She was Head of Device Development for Genentech, Inc. in South San Francisco, CA. She was responsible for the development of a new autopen injector for Growth Hormone; she was also responsible for setting up the Extractable / Leachable program for evaluation of primary container/closure systems and was a CMC leader for a prefilled syringe drug development. Prior to joining Genentech, she was Director, Delivery Device and Packaging Support for Schering Plough, in Kenilworth, NJ. She was responsible for the development of PEG-Interferon dual chamber pen injector and various delivery devices. Prior to joining Schering Plough, she was Director of Technology Development for West Pharmaceutical Services in Lionville, PA, a developer and manufacturer of parenteral drug packaging components, where she coordinated with corporate partners in Japan and Germany in the development of various new products.
She is a member of the faculty of the PDA’s Training and Research Institute, where she teaches courses on Parenteral Packaging, Prefilled Syringe and Injection Devices, and served as a member of USP’s Expert Committee on Drug Packaging, Storage and Distribution. She was the chairperson for PDA Gamma Radiation Sterilization of Polymeric Materials Committee. She is an expert in the area of drug and container/closure interactions and compability issues.
This article was printed in the July/August 2011 issue of American Pharmaceutical Review - Volume 14, Issue 5. Copyright rests with the publisher. For more information about American Pharmaceutical Review and to read similar articles, visit www.americanpharmaceuticalreview.com and subscribe for free.