Biomedical Engineering Reference
In-Depth Information
TABL E 9.1. Summary of Product Requirements and Attributes Pertinent to Develop
Formulation Design Space
Product Requirements
Product Attributes
Parenteral dosage form via subcutaneous
dosing
Sterile ready to use solution
Single use for patient self-administration
Simple disposable delivery device such
as prefilled syringe
24 months shelf life stability under refrigerated
storage conditions
Stable solution formulation
Injection considerations such as volume and
needle size
Prefilled syringe with suitable needle size
Viscosity of solution formulation is acceptable
and not a limiting factor for syringeability
compliance, and marketing requirements. Some examples of the product requirements
and attributes, and hence pertinent to formulation development, are summarized in
Table 9.1.
Based on initial evaluation of these product requirements and corresponding
attributes as per the target product profile, the type of dosage form, for example, aqueous
solution formulation, and suitable container closure system and manufacturing process
can be proposed.
9.4 MOLECULAR DEGRADATION CHARACTERIZATION
An important step to develop a stable solution formulation is to identify the “degradation
hot spots” in the molecule through a combination of stress methods to induce and
force the structural and chemical modifications. The aim of the forced degradation
studies is to understand how sensitive different degradation pathways are to external
stress and other factors. The stress methods include temperature, pH, buffer effects, and
oxidation susceptibility with respect to peroxide, trace metals, oxygen, headspace,
and light. These studies provide important information to help identify the likely
degradation pathway and intrinsic stability properties of the molecule. Different types
of degradation products can be monitored by various analytical methods to assess the
ability of the protein drug molecules to withstand these stresses. The data from these
studies are critical to understanding the stability properties, to determine which
analytical methods indicate stability, and are used to aid in the design of preformulation
studies.
In the case of a monoclonal antibody that is composed of two heavy chains and two
light chains joined to form a “Y-shaped” molecule, it is important to understand the
molecular structure and activity relationship. A schematic of antibody structure is shown
in Fig. 9.2 [3].
