Pharmaceutical product development activities are highly interconnected in nature. For parenteral drug products, the prefilled
syringe is generally considered a challenging container closure system, particularly in the case of vaccines with complex
product design requirements. The authors describe a holistic and integrated approach to focus on the linkage of the prefilled
syringe with the four phases of product design, development, operation, and control.
The product design phase involves integration of prefilled syringe as a crucial part of the target product profile (TPP) when
considering the complex health policy and user requirements imposed by different global geographic regions and regulatory
authorities. The product development phase focuses on the prefilled syringe as an integral part of the vaccine drug product.
Particular attention needs to focus on multiple syringe component attributes such as silicone oil and tungsten that may create
potential interactions with the diverse molecular properties of antigens. Emphasis of the product operation phase is to link
prefilled syringes to the product performance per design requirements and supplier process capability and quality control.
Lastly, processing and supplier quality control must be implemented within regulatory compliance framework to ensure delivery
of quality vaccine product to patients.
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Vaccine product development in prefilled syringes—drivers and complexity
The goal of pharmaceutical product development is to design and establish the formulation composition and its manufacturing
process to consistently deliver a drug product with all the appropriate quality attributes required for its intended efficacy
and safety profile. A systematic approach according to the quality-by-design (QbD) concept is applied to achieve both the
information and material deliverables during the product development lifecycle (1). Before work begins on the development
of a new product, it is crucial to clearly define the quality attributes of the product with consideration of the end user’s
needs in mind, commonly referred to as the target product profile (TPP) in the pharmaceutical industry.
A TPP can be used to facilitate discussions with regulators regarding the anticipated label claims for a product (2). It can
also be used for the private sector market, to help determine competition and associated pricing strategies (3, 4). Alternatively
in the case of vaccines, a TPP can be used as a tool to engage and align with public health policy organization by working
together to achieve the intended health impact (4, 5).
The definition of TPP according to the target disease/health policy and user requirement drives the design of the dosage form
with selection of the primary container-closure system as an integral aspect to meet the delivery requirement. Drug products
packaged in prefilled syringes essentially remove the withdrawal step from another container, such as a vial or ampoule, prior
to administration. As a result, prefilled syringes offer a more convenient alternative to vials for the preparation and administration
of injectable drugs. This results in improved provider/patient convenience and compliance, as well as product differentiation
when combined with auto-injector delivery devices.
There are many drivers and good reasons to have vaccines in the prefilled syringe presentation. First and foremost vaccines
are complex biological entities; therefore, they must be administered by injection due to the lack of significant advance
in alternative delivery technologies. From the technical point of view, one can imagine it is absolutely crucial to reduce
the risk of wrong dose and also better dose precision; therefore, one can see the advantages of prefilled syringe as compared
to vials. From a practical point of view, vaccines are sometimes driven by public health outbreaks because many doses could
be given in a crowded setting, allowing simple administration with limited manipulation. This provides for less probability
of handling errors in a prefilled syringe presentation, which is preferred. Lastly, there is a different economic factor than
for example biologics and is driven by key stakeholders in the public health sector. The minimal overfill in a prefilled syringe
as opposed to vial can also provide an economic advantage, because costs per unit must be low. In summary, there are clear
scientific, practical, and economical drivers for developing vaccines products in prefilled syringes.
Vaccine product development is complex in many aspects. First, vaccine products are prophylactic as opposed to therapeutic,
and more often than not, the target population is children and pregnant women, so the regulatory standard is high. Second,
the product types are diverse such as recombinant proteins, glycoconjugates, virus-like particles, attenuated viruses, and
live viruses. The dosing requirement is also challenging, in that doses are typically very small. Multiple antigens are often
combined to reduce the number of injections, and adjuvants are added in some cases to boost the immune response. Lastly, the
complex properties and interaction with prefilled syringe results in an acute challenge to vaccine manufacturers.