The choice of a syringe system should be a critical part of the regulatory strategy and must be considered at the outset,
perhaps even with product reformulation. The syringe system is important because a packaging system that is acceptable for
one therapeutic will not necessarily work for another because of differences in dosing ranges, patient populations, and in
how individual molecules react to surrounding materials and conditions. Evaluation of the proposed syringe system must consider
these factors, and regulatory submissions must support the suitability of the proposed packaging and storage conditions.
An analysis of proposed syringe systems should take into account their appropriateness, functionality, and materials. First,
the dosing device has to be suitable, and its graduations appropriate, for the intended patient population. At a basic level,
the syringe must deliver the dose in the amount and rate stipulated in the package insert. In addition, the physical characteristics
of the liquid drug formulation must be appropriate for the dosing device to ensure accurate dispersion of the drug through
Second, the proposed system must function correctly throughout its shelf life. The results of coating integrity testing, effect
of viscosity, and syringe-ability must be considered. Moreover, scale intervals on the syringe must represent the labeled
dosages, and gradations in dose must be easily read. The type should be embossed or printed and legible throughout the shelf
life of the product. These markings cannot fade or become dislocated during the use or life of the product. In addition, stopper
movement during use, as well as the effect of shipping on stopper movement, must be considered to ensure sterility of the
product and to avoid particulate contamination.
Third, materials in the proposed syringe must be compared with those of the current vial. The analysis should consider whether:
- The material in the proposed syringe, including in the container, plunger device, and closure system, protects the drug product
- The syringe system introduces a new material
- The system will require any changes to the drug product formulation.
Choosing a container and closure system made of the same materials as the vial will eliminate the need for additional extractable
and leachable studies. Any new materials, including those in the hub or needle, will need to be evaluated in stability testing.
Extractable studies also must include proposed labels, adhesive, and ink if the barrel of the syringe is not made of glass.
FDA rules governing current good manufacturing practice (GMP) stipulate that companies develop and thoroughly document a
testing program to assess the stability characteristics of the drug product (9). Consequently, a company must define stability
testing requirements related to the container–closure system. These requirements include how temperature, humidity, and light
influence the shelf life of the drug and help to determine appropriate storage conditions and expiration dates for the product.
A stability protocol that is specific to the molecule and the proposed drug-delivery device must be written, implemented,
and evaluated to assess the stability characteristics of the molecule in the container–closure system (9).
Although some extractable and leachable studies related to the dry or liquid vial presentation may be transferable to the
new format, some new stability testing is required when moving an injectable therapeutic to a prefilled syringe (see Table
III). The long, narrow dimensions of a syringe increase the molecule-to-surface-area ratio from the previous vial presentation.
As a consequence, accelerated and long-term stability studies are necessary to determine whether the change affects the extractable
and leachable parameters and to understand the impurity and degradation profile of the molecule in the container–closure system.
Table III: Filing requirements for prefilled syringes.
The stability protocol should detail the sample size, test intervals, storage conditions, validated analytical methods to
be performed, the container–closure system, test specifications, and number of batches required. In addition, reconstitution
studies will be required for parenteral products offered in a kit with a prefilled diluent syringe or in a dual-chamber prefilled
lyophilized syringe. Tests and specifications must be based on knowledge of the degradation pathway for the particular molecule,
use validated and stability-indicating methods, and specify limits appropriately.
Clinical studies are required when there is a change in indication or new route of administration for the drug. However,
movement from a dry or liquid vial to a prefilled syringe also necessitates clinical testing if the reformulated drug's degradation
or impurities profile change.