Ensure Quality, Safety of Prefilled Syringes

By Brian Lane and Timothy Rhines, PhD Significant but manageable technical, regulatory hurdles can be an issue
Although they were introduced more than 20 years ago, prefilled syringes continue to grow in popularity due to the success of parenteral drugs, particularly biologicals. Vaccines, insulin, proteins, anti-coagulants, antibiotics, hormones, small-molecule cancer treatments, and analgesics are among the drugs most commonly formulated in prefills.
A 2010 report from the consulting firm Visiongain estimated the market for prefilled syringes at two billion units per year, at a device value of $2.5 billion. Usage has at least doubled since the mid-2000s and continues to grow by at least 10% per year.1 European prefilled syringe markets are somewhat more mature than U.S. markets. Visiongain notes a trend away from vials toward prefilled syringes for both new and already approved injectable medicines.

Identification of extractables and leachables in prefilled syringes can be achieved through analytical testing such as liquid chromatography/mass spectrophotometry, gas chromatography spectroscopy/mass spectrophotometry, inductively coupled plasma and infrared, and more.

Advantages

The advantages of prefilled syringes include ease of use and lower administration costs, fewer medication errors and higher dose accuracy, greater control over potent or addictive drugs, reduced overfill compared with conventional syringes, the potential to eliminate toxic preservatives in vaccines, lower likelihood of bacterial contamination, and product differentiation.
Convenience and ease of use are beneficial both in self-administration and in formal healthcare settings. Prefilled syringes are rapidly becoming the preferred administration mechanism for diabetics and family caregivers. Peel-off labels on prefills facilitate medication tracking in hospitals, while bar-coding and fixed labels prevent dosing errors common with conventionally filled syringes—those that are filled but not immediately used, for example. A study by Becton Dickinson found that 90% of health care providers preferred prefilled syringes to conventional syringes.²
Prefills require less overfill than conventional syringes. While the United States Pharmacopeia (USP) recommends a 20% to 25% overfill of vials used with conventional syringes, overfill for prefilled syringes can be as little as 2%—a significant savings in drug material per dose that translates into more doses per manufactured batch. Moreover, the increased safety and convenience, particularly with respect to self-administration, allows premium pricing compared with vials.³
Generally, regulatory strategies for prefilled syringes involve evaluating changes in manufacturing, dose filling, packaging, storage, and shipping from the original formulation to the prefill.
Sponsors may adopt a prefilled syringe strategy at any time during the product’s life cycle, but the decision is usually based on time-to-market. Injectable drugs are normally introduced as vialed solutions because development timelines for that dosage form are shortest. The transition from liquid vial to prefilled syringe is generally accomplished in six to 18 months but is somewhat longer for drugs formulated as lyophilized powders.⁴ Consequently, the switch to prefilled syringe is considered a short-term strategy for the former but a mid-term life cycle decision for the latter.

Quality, Stability, and Safety

The scientific rationale for expanded safety testing in prefilled syringes is best illustrated by comparing the materials and manner of construction for these closure types. Where vials are sealed at one end with an unmovable polymer cap, syringe contents touch a movable elastomer plunger, the lubricant used within the barrel, and a removable elastomer tip cap. Thus, prefilled syringe contents are exposed to three separate materials, two of which can be thought of as semi-permeable. The latter point is significant because contact with air will damage parenteral dosage forms through evaporation, oxidation, and other degradative processes.
Because prefilled syringes serve as both delivery device and storage container, drug stability and safety issues arise with prefills that do not with vialed liquids. Prefilled syringe barrels are produced from high-quality borosilicate glass, as are vials, but plungers are made of medical-grade polymer. Medical-grade plastics are gaining popularity for syringe barrels as well, but their use entails considerable investment to demonstrate that the drug and package do not interact unfavorably. Silicone or, more recently, baked-on silicone lubricates the moving parts of the syringe. Lubrication assures that the syringe will operate smoothly under conditions of normal use, while assisting in creating an airtight seal between the plunger and the syringe barrel. However, it may also become a contamination source or a degradation catalyst.
Manufacturers go to great lengths to demonstrate that their construction materials are inert and must do so for an ever-expanding range of injectable drug substances. Nevertheless, the burden of demonstrating safety falls on the formulator and, ultimately, on the product sponsor.

A 2010 report from the consulting firm Visiongain estimated the market for prefilled syringes at 2 billion units per year, at a device value of $2.5 billion. Usage has at least doubled since the mid-2000s and continues to grow by at least 10% per year.

Principal quality issues with prefilled syringes include assuring the drug’s potency, identity, safety, stability, and sterility^.5 Additional tests are conducted for extractables, leachables, and syringe integrity, including closure.
Stability testing determines how temperature, light, and contact with the syringe materials affect the drug’s shelf life. The goal is to establish storage conditions and expiration dates for the product.⁶ Stability assays are tailored to the specific drug product and syringe system. As with vialed parenteral drugs, accelerated stability studies are performed at high temperatures and humidity over six months, whereas real-time testing uses standard conditions of 25ºC and 60% relative humidity for up to three years.⁷
The regulatory rationale for stability testing is found in the U.S. Food and Drug Administration’s (FDA) Guidelines on Stability of Pharmaceutical Products, 2007, which states:

Stability studies should include testing of those attributes of the pharmaceutical product that are susceptible to change during storage and are likely to influence quality, safety, and efficacy. The testing should cover, as appropriate, the physical, chemical, biological and microbiological attributes, preservative content (e.g. antioxidant, antimicrobial preservative). Analytical procedures should be fully validated and stability indicating.⁸

Quality of prefilled syringe formulations is covered under several International Conference on Harmonisation guidances:
Q1C Stability Testing for New Dosage Forms: This defines “new dosage form” as “a drug product which is a different pharmaceutical product type, but contains the same active substance as included in the existing drug product … .” Switches from oral to parenteral and new delivery systems are specifically mentioned. The guidance calls for stability testing that parallels the original drug product except in “certain justified cases.”
Q1A(R2) Stability Testing of New Drug Substances and Products: This defines regulatory agencies’ expectations for stability data for new drug substances or products within the European Union, Japan, and the United States.
Q3B(R2) Impurities in New Drug Products: This guidance provides recommendations on the content and qualification of impurities in new chemically synthesized drug products.
Q5C Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products: This covers biologicals, including therapeutic proteins, monoclonal antibodies, vaccines, and gene products and is especially relevant with the emergence of drugs produced from biotechnology.
The FDA requires sponsors to undertake clinical studies if a drug’s indication or administration route changes, and, with reformulation, if tests indicate that the stability or impurity profiles change significantly. A switch from liquid-filled vials or lyophilized products to prefilled syringes requires submission of a supplemental new drug application (sNDA).
Depending on the formulation, a standard set of stability tests for a parenteral drug in a prefilled syringe might include assays for color, clarity, particulates, pH, sterility, endotoxins, particle size (for suspensions), potency, and evaporation.
Compounding pharmacies are a small but growing submarket for prefilled syringe-related services. Compounders add value to drug formulations that are normally distributed in glass vials by providing the same active ingredient in more convenient prefill formats. Compounding pharmacies follow USP General Chapter <797>, Pharmaceutical Compounding—Sterile Preparations. Specifically, USP <797> outlines the workplace environmental requirements for repackaging injectable drugs to maintain their sterility.
For products covered under USP <797>, stability testing requirements are considerably less rigorous than for drug substances filled initially into prefilled syringes. Compounded parenteral drugs are intended for use within a few days or weeks of filling, a time frame in which they are assumed to maintain their original stability profile.
As combination medical devices, prefilled syringes entail quality issues not directly associated with the drug. For example, syringe plungers are designed to move smoothly down the barrel during drug dispensing. It is possible, during shipping or storage, for prefilled syringes to experience high or low-pressure conditions (the latter particularly during air transport), which can cause the plunger to shift from its normal position. Users touching non-sterile regions of the syringe barrel may introduce microbes or air into the active ingredient, causing microbial contamination, oxidation, or degradation. Under low pressure, the solution may expand, pushing the plunger outward. Packaged prefilled syringes should therefore be tested, using standard protocols, for unwanted movement under conditions that duplicate low-pressure transport.
A standard test for closure integrity involves challenging the syringe/stopper interface with very high bacteria concentrations. The contents are then tested periodically to measure bacterial infiltration. Another test uses a dye to measure the penetration from outside the syringe to the clear liquid it contains.

Leachables and Extractables

The quality and safety issues related to leachables and extractables merit a separate discussion. The FDA’s Guidance, Container Closure Systems for Packaging Human Drugs and Biologics, states that a pharmaceutical container should be “suitable for its intended use.” Determination of packaging suitability is based on protecting the drug and ensuring patient safety and compatibility between the container, its components, and the drug, as well as performance.⁹
Examples of incompatibility include loss of drug potency through drug adsorption onto the syringe materials, accelerated drug degradation, alterations in the drug’s physical or biological properties, and unacceptable syringe performance, including plunger sticking, deterioration of barrier performance, and clogging.¹⁰
Among the stipulations of the closure systems guidance are approaches to testing for leachables and extractables. Extractables are compounds that can be extracted from packaging component materials in the presence of an appropriate solvent and under certain defined conditions. Leachables are agents in packaging materials that can potentially contaminate a drug formulation under normal use conditions, e.g., when in contact with the drug substance. Inhaled and injected products are subject to the highest standards with respect to extractables and leachables.
Extraction studies are performed under controlled conditions using multiple extraction solvents and techniques. For example, testing may be conducted in several solvents such as methanol, ethanol, hexane, acetone, dichloromethane, ethyl acetate, iso-propanol, t-butyl methyl ether, toluene, water, buffers, or matrix-matched buffers. Soxhlet extraction, storage at 60°C for 21 days, or other extraction regimes may be used, provided they are scientifically justified.
Analysis of extracted materials should be conducted through two or more orthogonal methods; for example, high performance liquid chromatography using at least three buffers (low pH, neutral, and high pH) and ultraviolet and mass detection.
Extractables testing is founded on the chemical and mechanical characteristics of the specific packaging material and the accepted safety threshold for the product in question, but there is no guarantee that all extractables will be detected. Extractable level profiles may be thought of as a worst-case scenario, however, and should always be higher than the leachables profile, which is obtained under normal use conditions, i.e., with product in the syringe over time.
Analytical methods for leachables should be based on those used in controlled extraction studies, with limits of quantitation guided by the safety concern threshold. Furthermore, drug developers must establish a correlation between extractables and leachables, and all methods must be optimized and fully validated.

Numerous Benefits

Prefilled syringes provide numerous benefits to pharmaceutical developers, caregivers, patients, and the healthcare system as a whole. Developers readily recognize these advantages, including life cycle extension, but can just as easily overlook the significant but manageable technical and regulatory hurdles of transferring successful products to prefilled syringe delivery formats. A development program, which may take up to two years, must account for all possible changes in the drug product brought about by the syringe, and vice versa.
Many sponsors will farm out parts or all of the development phase for prefilled syringe-based products to a contract research organization. A best-in-class development partner should possess the full line of analytic expertise for quantifying leachables and extractables, as well as experience in validating methods for volatiles, semi-volatiles, oligomers, antioxidants, polyaromatic hydrocarbons, and nitrosamines, and should be capable of conducting a full range of stability assays. Finally, the contract partner should possess the expertise to file all relevant sNDA submissions and supporting documentation and, if necessary, represent the sponsor before regulatory agencies.
Selecting an appropriate development partner requires a sponsor to first take inventory of its in-house competencies and available resources. Second, the sponsor should honestly assess whether internal development efforts are better spent on extensions of existing products or on the next blockbuster. Lastly, it should calculate time-to-market advantages of outsourcing to experts compared with managing projects internally, particularly when resources are already stretched thin
Dr. Rhines is director at CMC Pharmaceutical Development Service North America, Covance; reach him at tim.rhines@covance.com or (608) 242-7043. Lane is principle investigator, CMC Pharmaceutical Development Services, Madison, Covance; reach him at brian.lane@covance.com or (608) 310-4042.

References

1. Visiongain. Prefilled syringes and related systems: world market outlook 2010-2025. London, U.K.; April 22, 2010.
2. Thorpe GA. Prefillable syringes: trends and growth strategies. In: ONdrugDelivery. Prefilled syringes: innovations that meet the growing demand. 2005. Available at: http://www.ondrugdelivery.com/publications/prefilled_syringes.pdf. Accessed Sept. 24, 2010.
3. Borlet M. Financial model for converting from a vial to a pre-filled syringe. Presented at: 2008 Parenteral Drug Association (PDA) Universe of Pre-Filled Syringes and Injection Devices conference; October 6-7, 2008; San Diego.
4. Soikes R. Moving from vial to prefilled syringe: a project manager’s perspective. PharmTech website. Sept. 1, 2009. Available at: http://bit.ly/a8SvmI. Accessed September 24, 2010.
5. Karras L, Wright L, Cox L, et al. Current issues in manufacturing and control of sterile prefilled syringes. Pharm Technol. 2000;24:188-193.
6. Soikes R. Moving from vial to prefilled syringe: a project manager’s perspective. PharmTech website. Sept. 1, 2009. Available at: http://bit.ly/a8SvmI. Accessed September 24, 2010.
7. DeGrazio F. Parenteral packaging concerns for biotech drugs. Innovaro Pharmalicensing website. Available at: http://bit.ly/cZwtEm. Accessed September 24, 2010
8. Government of Nepal. Ministry of Health and Population. Department of Drug Administration (DDA). Guidelines on stability of pharmaceutical products, 2007. DDA website. June 15, 2007. Available at: http://bit.ly/bhSioB. Accessed September 24, 2010.
9. DeGrazio F. The intricacies of selecting and evaluating plungers for prefilled syringe systems. In: ONdrugDelivery. Prefilled syringes: innovations that meet the growing demand. 2005. Available at: http://www.ondrugdelivery.com/publications/prefilled_syringes.pdf. Accessed September 24, 2010.
10. Jenke D. Suitability-for-use considerations for prefilled syringes. PharmTech website. April 1, 2008. Available at: http://bit.ly/ckykvR. Accessed September 24, 2010.