Scenario one: liquid vial to liquid prefilled syringe
A company markets a contrast imaging agent used in the imaging of major organs. Originally available in 50-mL, 100-mL, and
200-mL single-use vials for intravenous and intra-arterial administration, the company seeks to make the product available
in 10-mL and 50-mL prefilled syringes for intrathecal administration for imaging the spinal cord and nervous system. The 50-mL
syringe also would be used in the previously approved routes of administration and indication.
In this situation, it is important to consider which factors change and which remain the same. The container–closure system
are new, meaning a new size and dimension of container and new functionality of the device are involved. Because the device
would enable administration directly into the spinal cord, the route of administration is new, as is the indication. The formulation
and long-term storage conditions remain the same, however, because the contrast imaging agent was previously available in
a liquid vial.
In selecting a syringe system, the company chooses a device with components similar to those used in the single-use vials.
Because the glass and rubber formulation are identical between vial and syringe, previous extractable and leachable studies
will apply. However, the company must compare all the materials in the container–closure system because some new materials
may be introduced in the components. In addition, the syringe may require additional siliconization to improve the function
of the plunger.
To support the regulatory filing, the company will need to submit three months of comparative accelerated stability data.
Long-term data on at least one batch, possibly three, will be needed at the time of submission. Moreover, the company will
need to commit to placing the first of three production batches on long-term stability and to placing another batch on long-term
stability each year. Additional clinical data also will be needed to support the new indication and the new intrathecal route
Scenario two: lyophilized vial to prefilled syringe
A company producing a lyophilized product packaged with reconstitution fluid for intramuscular injection considers marketing
a prefilled syringe for the same indication, in the management of rheumatoid arthritis. The company must reformulate the molecule
to a stable liquid. The route of administration will remain the same.
The container–closure device, however, will change, which means that some materials and the functionality of the system will
be different. In addition, long-term storage conditions may change because of the new formulation.
When evaluating a syringe system, the company must choose one with components that are similar to those used in the vial and
reconstitution device to best leverage previously conducted extractable and leachable studies. As with other prefilled syringes,
additional siliconization may be necessary. Clinical studies will be required as well if the degradation or impurity profile
Upon submission, FDA will require three months of comparative accelerated data and long-term data on three batches of drug
product. The stability tests will need to focus on appearance, color, clarity, sterility, pyrogens, syringe functionality,
container– closure integrity, impurities, and particulates. The company also will need to commit to placing the first three
production batches and annual batches on long-term stability tests.
The process of moving an injectable therapeutic from a vial presentation into a prefilled syringe or, perhaps, into an autoinjector
format, can be complex, regardless of whether the original product is in a liquid or lyophilized formulation. Companies pursing
a new dosage form must carefully document the sterility and purity of the product and ensure the stability of the molecule
in the new container–closure system. Complexity of the process multiplies when the dosage form is to be marketed on a global
scale. Countries differ in the interpretation of regulatory guidelines established through the International Conference on
To ensure a smooth and speedy transition to a new dosage form, most companies assign responsibility for the change- management
process to a project manager, who coordinates roles and responsibilities of the team involved in the project, establishes
processes and procedures, and manages regulatory submission timelines. Working with team members, the project manager develops
and implements the regulatory strategy to control and properly validate the effect of new processes and materials on the therapeutic
The project manager also helps to select and coordinate the efforts of external partners, including research organizations,
suppliers, and manufacturers. The choice of these external partners is critical, particularly for companies with limited experience
with multiple regulatory authorities or with the formulation or manufacturing of therapeutic molecules. For example, a contract
manufacturing organization with a drug master file on record with FDA for its facilities, processes, or other articles used
in the manufacturing, processing, packaging, or storage can help reduce the amount of paperwork that must be submitted. Moreover,
in some instances, having a fill–and–finish site that passed inspections within the past year may limit the need for an additional
visit by that inspectorate before regulatory approval.
When working with injectable therapeutics, the fastest and most efficient path to market for a new delivery device is one
in which processes are rigorous, documentation is thorough, and team members are experienced and capable. The project manager
can facilitate a smooth transition to the new dosage form by developing and carefully implementing the regulatory strategy
and by choosing qualified, effective partners.
Raul Soikes is senior director of program management at Baxter BioPharma Solutions, 927 South Curry Pike, Bloomington, IN 47403, tel.