Biomedical Engineering Reference
In-Depth Information
which may lead to loss of biological activity. Due to the complex physicochemical
characteristics of proteins, the only technically viable dosage forms are in most cases
parenterals. These dosage forms are usually aqueous solution and suspension formula-
tions or lyophilized powders that are reconstituted in a well-defined diluent system
immediately before injection. The manufacturing process for parenteral solutions
employs typical unit operations whereas the suspension may require more complex
unit operations. The formulations are filled in a container/closure system (e.g., vials,
prefilled syringes, and cartridges) and dosed using a delivery device (e.g., syringes and
injectors).
To have quality built into the product by design, the development scientists need to
understand and fully characterize the inherent stability properties of these complex and
reactive protein molecules during the design and development of the dosage form,
formulation composition, container closure system, and manufacturing process. Among
these aspects, the formulation composition needs to be established first, where the
relationship between the critical stability properties and the formulation variables has
been identified according to risk assessment [2], optimized and evaluated for shelf life
requirements, defined and summarized in the context of formulation design space [1].
The design of the formulation composition should also, to some extent, take into
consideration the selection, justification, and control strategies of other drug product
components such as the properties of the active pharmaceutical ingredient (API),
excipients, container closure system, and manufacturing process. This chapter aims at
providing an overview of QbD principles and risk assessment approaches with emphasis
on the development of formulation design space using the example of a monoclonal
antibody. The development of manufacturing process design space and application of
process analytical technology (PAT) will not be discussed here.
9.2 QUALITY BY DESIGN (QbD) APPROACH
TheQbD approach for formulation development starts with a clear definition of the target
product profile (TPP) in accordance with patient needs related to dosing, convenience,
and compliance, as well as marketing requirements for the intended therapeutic
indication. Specific formulation requirements and attributes pertinent to the TPP, for
example, the need to have a single use sterile stable solution formulation, need to be
determined prior to the start of commercial development. For biotechnology-derived
products, a significant hurdle to successfully develop a stable solution formulation is
mostly derived from the multiple degradation pathways and modifications located in the
different regions of the molecule. Extensive preformulation and characterization studies
with proper analytical and bioassay support are conducted to first understand the types
and location of the various chemical modifications, physical instability challenges, and
the impact on the biological activity relevant to the target therapeutic indication.
In particular, the effect of the various formulation-related factors such as pH, tempera-
ture, headspace, trace metals, excipients, and so on needs to be fully characterized.
A preliminary stability risk assessment, based on the molecular degradation knowledge,
is used to establish those degradations that are likely to have the greatest risk of impacting
