Suitability-for-Use Considerations for Prefilled Syringes - Pharmaceutical Technology

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Suitability-for-Use Considerations for Prefilled Syringes
The nature of their application and their mode of use mean that prefilled syringes meet the regulatory definitions of immediate packaging or container–closure systems.


Pharmaceutical Technology


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).


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