Suitability-for-Use Considerations for Prefilled Syringes

Prefilled syringes have become important options in the packaging, distribution, and delivery of pharmaceutical solution products, particularly biopharmaceuticals. This container–closure system provides several practical advantages, including convenience in simplified drug administration; greater accuracy in filling (i.e., less likelihood of overfilling, which is common in other packaging–delivery options); and reduced instances of misidentification, improper dosing, and contamination (1). These advantages, along with a critical mass of commercially available syringe systems, have fueled a rapid expansion of the market for prefilled syringes, with worldwide sales estimated to exceed 1 billion units and annual sales expected to grow at a rate in excess of 10% (2, 3).

Author

The basic components of a prefilled syringe are illustrated in Figure 1. The syringe barrel is typically either made from Type 1 borosilicate glass or various plastic materials (e.g., polypropylene, cyclic olefin polymer, cyclic olefin copolymers). Other components (e.g., tip cap and plunger) are typically made from elastomeric materials, which may be surface coated. Syringe barrels and plungers are typically coated with an agent (e.g., silicone oil) to facilitate plunger movement. Plunger movement is accomplished by an attached piston rod (typically plastic).

Figure 1

In the US Food and Drug Administration's Guidance for Industry, Container Closure Systems for Packaging Human Drugs and Biologics www.fda.gov/Cber/gdlns/cntanrqa.pdf, the agency defines a container–closure system as "the sum of packaging components that together contain and protect the dosage form. This includes primary packaging components" (4). A similar definition is provided by the European Medicines Agency in its Guideline on Plastic Packaging Materials www.emea.europa.eu/pdfs/human/qwp/435903en.pdf (5). It is clear from these definitions that a prefilled syringe meets the definition of a container–closure system and thus is subject to the associated guidelines and regulations. It is noteworthy that because of its use and nature, a prefilled syringe, as an injectable product, falls into FDA's highest risk category for the likelihood of a packaging component–dosage form interaction.

Foremost among these regulations and guidelines are the regulatory expectations that revolve around suitability for the intended use. As noted in FDA's container–closure guidance:

Every packaging system should be shown to be suitable for its intended use: it should adequately protect the dosage form; it should be compatible with the dosage form; and it should be composed of materials that are considered safe for use with the dosage form and the route of administration. If the packaging system has a performance feature in addition to containing the product, the assembled container closure system should be shown to function properly.

Each of these aspects of suitability for intended use will be considered in greater detail as follows.

Protection

As a packaging system, a prefilled syringe must meet all the suitability-for-intended-use expectations. Only certain aspects of a given expectation may be applicable to prefilled syringes. For example, the expectation of protection of the dosage form is interpreted to mean that the prefilled syringe should protect the dosage form from factors that may degrade the quality of the dosage form throughout its shelf life. Some commonly cited causes of such degradation for prefilled syringes include loss of solvent, adsorption of water vapor, and microbial contamination. Other potential causes of degradation, including light exposure and contact with reactive gases, are less germane to mainstream applications of prefilled syringes because such systems are not currently marketed as light or gas barriers.

Compatibility

Several interactions between the drug product and the prefilled syringe can come into play under the general category of compatibility. In essence, compatibility is achieved if the interaction of the drug product and prefilled syringe is sufficiently limited that the quality of the drug product (or the syringe) is not changed to an unacceptable degree because of the interaction. Examples of potential interactions that could lead to unacceptable changes in product quality include:

• Loss of drug product potency owing to absorption and/or adsorption of the active drug substance or formulation excipient by the syringe

• Accelerated or modified degradation of the drug substance or formulation excipient induced by a chemical leached from the syringe

• Precipitation

• Change in drug product properties (e.g, pH, biological activity)

• Discoloration of either the dosage form or packaging system

• Increase in brittleness of a packaging system component.

Safety

Safety is a primary aspect of suitability for intended use. Prefilled syringes should be constructed of materials that do not leach harmful or undesirable amounts of substances to which a patient may be exposed. Assessment of packaging systems such as prefilled syringes for leachables has received much attention (e.g., Reference 6) and, as a "hot topic in parenteral science and technology" (7), one can anticipate further developments in the design, implementation, interpretation, and use of leachables assessment. Leachables are a legitimate concern because there are several documented examples in which leachables have caused suitability-for-use issues in prefilled syringe applications.

It is beyond the scope of this article to provide a detailed account of the means by which leachables information is obtained, interpreted, and used. Rather, the reader is directed toward several overviews on this subject (6, 8–10).

Secondary safety effects are important developments in the area of leachables that is particularly relevant to prefilled syringes because of their use in biopharmaceuticals. Although a prime consideration in assessing the safety impact of leachables is the intrinsic toxicity of the leachable itself, recently documented situations related to adverse safety effects have established that secondary safety effects, in which the leachable interacts with a formulation component to produce the agent responsible for the adverse safety effect, are important and necessary to consider when addressing suitability for intended use. An example of such a situation is discussed in "Compatibility case studies" later in this article.

Performance

The performance of a container–closure system refers to its ability to function in the manner for which it was designed. Many container–closure systems perform one essential function: to store the drug product from that point in time at which it is manufactured to the point of time at which it is used. While a prefilled syringe certainly performs this important function, it also serves the purpose of drug delivery, which refers to the ability of the system to deliver the dosage form in the amount or at the rate described in the package insert. FDA's container–closure guidance specifically notes that drug delivery aspects are relevant for prefilled syringes.

Although it is beyond the scope of this article to define and describe all the functional attributes of prefilled syringe systems that may impact their ability to perform the function of drug delivery, in general such attributes include:

• Tip cap or needle shield removal force

• Piston release force (break force)

• Piston travel force (glide force)

• Piston seal integrity (leakage)

• System integrity (sterility).

Compatibility case studies

Instances of incompatibilities between drug products and prefilled syringes have been documented in the pharmaceutical literature. Three specific examples, including protein aggregation related to leached tungsten, interactions with silicone oil, and an adverse effect caused by a leachable–drug product interaction are discussed.

Tungsten. The presence and impact of tungsten in products stored in prefilled syringes has been widely reported. During the manufacture of glass syringe barrels, a tungsten pin is used to form the inner needle channel. Under the high temperature conditions of contact, tungsten can oxidize in the presence of air and interact with the glass to form residuals. Because these residuals may not be removed from the syringe during subsequent washing, they come into contact with the drug formulation, allowing the opportunity for interactions to occur between the tungsten residuals and the drug product (11).

These tungsten residuals have been reported to have a marked effect on drug products stored in prefilled syringes. Lee et al. examined the aggregation of proteins resulting from leached tungsten (11). They report that concentrations of tungsten as low as 1 ppm in the drug product can produce measurable protein aggregation. Analysis of 500 syringes from various manufacturers indicated that, in general, the level of leached tungsten is well below this critical concentration. These authors suggest that tungsten speciation in solution is an important factor in protein aggregation, with large tungstate polyanions (the dominant aqueous species at low pH) having a greater potential impact on aggregation than the smaller tungstate anion that dominates tungsten speciation at higher pH values.

Similarly, Osterberg reports a situation in which tungsten leached from a syringe caused the oxidation of the contained drug product, resulting in drug degradation and aggregation (12). This interaction ultimately led to an unacceptable drug product. Rosenberg and Worobec also report the tungsten-induced aggregation of a protein arising from oxidation mediated by leached tungsten (13), and Markovic documents a case where leached tungsten oxide triggered protein oxidation followed by aggregation (14). In the latter case, the aggregation was mitigated by switching from a tungsten to a platinum filament. Finally, Wen et al. report a case in which protein aggregation results from small particles of tungsten that were present in the drug product as a result of its storage in a prefilled syringe (15).

Siliconoil. Silicon oil is a common lubricant used in many container–closure systems, including prefilled syringes. The potential influence that silicone oil can have on the viability of protein-drug molecules is well documented.

Considering prefilled syringes specifically, Sharma notes that silicone oil has been implicated in the induction of protein aggregation, although evidence in large changes in the protein in the presence of the lubricant is limited (16). Jones et al. report a significant induction of protein aggregation (of four proteins of various molecular weights) occurred in the presence of silicone oil and suggest that the most likely explanation for aggregation is that the silicon oil directly affects intermolecular protein interactions or exerts an effect via a solvent (17). Markovic documents an instance in which the drug product developed thread-like, gelatinous particles when stored in syringes for only a short period of time (less than one hour) because of product interaction with the silicone oil (14). Alternatively, Overcashier demonstrated that the degradation profiles two proteins of varying size were similar when the stored in either glass vials or prefilled syringes (18).

Leaching. One of the most widely documented instances of an unanticipated incompatibility between a container–closure system and a protein-drug product is that of "Eprex" (epoetinum alfa) (Janssen-Ortho, ON, Canada) and its prefilled syringe packaging system (19–21). At some point in its product lifetime (1998), Eprex, a product containing recombinant human erythropoietin, was reformulated with polysorbate 80, which replaced human serum albumin as a formulation stabilizer. Shortly after this change, there were increased incidents of antibody-mediated pure red cell aplasia (PCRA) with Eprex use by chronic renal failure patients. The cause of PCRA was directly linked to the formation of neutralizing antibodies to both recombinant and endogenous erythropoietin in patients adminstered Eprex.

A considerable, crossfunctional technical effort was undertaken to establish the root cause of this phenomenon. One potential root cause involved leached substances. The presence of previously unidentified leachables was suggested as new peaks in the tryptic map of Eprex. Leaching studies determined that the polysorbate 80 extracted low levels of vulcanizing agents (and related substances) from the uncoated rubber components of the prefilled syringe. This leaching issue was addressed by replacing the rubber components with components coated with a fluoropolymer. Because the fluoropolymer is an effective barrier to migration, the leaching of the rubber components was greatly reduced. Since the conversion from the uncoated to the coated components, the incidence of PRCA has returned to the baseline rate seen for all marketed epoetin products. This is strong circumstantial evidence that leaching of the vulcanizing agent was, in fact, the root cause of the observed effect. The circumstantial case against rubber leachables as the root cause was further strengthened when the adjuvant effect of the leached vulcanizing agent (and related substances) was confirmed in animal models. Nevertheless, it is noted that the link between the extracted vulcanizing agent and the adverse patient effect has not been conclusively established and there are alternate proposals as to the root cause of this phenomenon.

Closing observation

The issue of suitability for use of container–closure systems in general and prefilled syringes in particular is complex and multidimensional. This is especially true for prefilled syringes, because of the nature of the syringe system and the functional sensitivity of the biopharmaceutical products that are the most significant potential market for these systems. A high degree of diligence must be used when examining the product quality and safety aspects of drug product–container closure compatibility. Given the complexity of establishing suitability for use, it is clear that no single approach or method is adequate and that an effective and efficient suitability-for-use assessment requires the use of multiple and orthogonal strategies and tactics.

Dennis Jenke is a senior research scientist at Baxter Healthcare Corporation, Technology Resources Division, 25212 W. Illinois Route 120, Round Lake, IL 60073, tel. 847.270.5821, fax 847.270.5897, dennis_jenke@baxter.com

References

1. D.E. Overcashier, E.K. Chan, and C.C. Hsu, "Technical Considerations in the Development of Prefilled Syringes for Protein Products," Am. Pharm. Rev.9 (7), 77–83 (2006).

2. M.N. Eakins, "The Design and Construction of Prefilled Syringes", Am. Pharm. Rev.10 (6), 47–51 (2007).

3. B. Harrison and M. Rios, "Big Shot: Developments in Prefilled Syringes," Pharm. Technol.30 (5), 42–48 (2007).

4. Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics (US Department of Health and Human Services, Food and Drug Administration, Rockville, MD, May, 1999).

5. Guideline on Plastic Immediate Packaging Materials (European Medicines Agency, CPMP/QWWP/4359/03, EMEA/CVMP/205/04, May, 2005).

6. D. Jenke, "Evaluation of the Chemical Compatibility of Plastic Contact Materials and Pharmaceutical Products; Safety Consideration related to Extractables and Leachables," J. Pharm. Sci.96 (10), 2566–2581 (2007).

7. M.J. Akers, S.L. Nail, and W. Saffell-Chamber, "Top Ten Hot Topics in Parenteral Science and Technology," PDA J. Pharm. Sci. Technol.61 (5), 337–361 (2007).

8. K. Nicholas, "Extractables and Leachables Determination: A Systematic Approach to Select and Qualify a Container Closure System For a Pharmaceutical Product," Am. Pharm. Rev.9 (3), 21–27 (2006).

9. I. Markovic. "Evaluation of Safety and Quality Impact of Extractable and Leachable Substances in Therapeutic Biologic Protein Products: A Risk-Based Perspective," Expert Opin. Drug. Saf. 6 (5), 487–491 (2007).

10. D.J. Ball, D.L. Norwood, and L. Nagao, "Utility and Application of Analytical and Safety Thresholds for the Evaluation of Extractables and Leachables in Drug Products," Am. Pharm. Rev.10 (5), 16–21 (2007).

11. H. Lee et al., "Tungsten Leaching from Prefilled Syringes and Impact on Protein Aggregation," poster presented at the PDA Extractables/Leachables Forum, Confronting Extractables and Leachables Issues in an Evolving Industry, Bethesda, Maryland, November 6–8, 2007.

12. R.E. Osterberg, "Potential Toxicity of Extractables and Leachables in Drug Products," Am. Pharm. Rev.8 (2), 64–67 (2005).

13. A.S. Rosenberg and A.S. Worobec, "A Risk-Based Approach to Immunogenicity Concerns of Therapeutic Protein Products, Part 2: Considering Host-Specific and Product-Specific Factors Impacting Immunogenicity," BioPharm Int.17 (12), 34–40 (2004).

14. I. Markovic, "Challenges Associated with Extractable and/or Leachable Substances in Therapeutic Biologic Protein Products," Am. Pharm. Rev. 9 (6), 20–27 (2006).

15. Z.Q. Wen et al., "Investigation of Contaminants in Protein Pharmaceuticals in Prefilled Syringes by Multiple Microspectroscopies," Am. Pharm. Rev.10 (5), 101–107 (2007).

16. B. Sharma, "Immunogenicity of Therapeutic Proteins Part 2. Impact of Container Closures." Biotech. Adv.25 (3), 318–324 (2007).

17. L.S. Jones, A. Kaufmann, and C.R. Middaugh, "Silicone Oil Induced Aggregation of Proteins," J. Pharm. Sci.94 (4), 918–927 (2004).

18. D.E. Overcashier, E.K. Chan, and C.C. Hua, "Technical Considerations in the Development of Prefilled Syringes for Protein Products," Am. Pharm. Rev. 9 (7), 77–83 (2006).

19. B. Sharma et al., "Technical Investigations into the Cause of the Increased Incidence of Antibody-Mediated Pure Red Cell Aplasia Associated with Eprex," Eur. J. Hosp. Pharm.5, 86–91 (2004).

20. K. Boven et al., "Epoetin-Associated Pure Red Cell Aplasia in Patients with Chronic Kidney Disease: Solving the Mystery," Nephr.Dialy. Trans.20 (suppl. 3), ii30–ii40 (2005)

21. J. Pang et al., "Recognition and Identification of Leachables in EPREX Prefilled Syringes: An Unexpected Occurrence at a Formulation-Component Interface," PDA J. Pharm. Sci. Technol. 61 (6), 423–432 (2007).

For more on this topic, see "Big Shot: Developments in Prefilled Syringes" in the March 2007 issue of Pharmaceutical Technology.