Biomedical Engineering Reference
In-Depth Information
clinical performance. A number of considerations for the target product profile are
described including dosage form, strength, release characteristics, and drug product
quality characteristics (e.g., sterility, purity). All of these are also considerations for
biotechnology products; however, there may be a difference in focus for these complex
products.
Currently, many protein products are delivered parenterally, although orally admin-
istered enzymes [14, 15] and novel dosage forms such as inhaled insulin [16] have been
developed. Even for parenteral dosage forms, there are important considerations
regarding formulation (e.g., liquid versus lyophilized) and route (e.g., intramuscular,
subcutaneous, or intravenous). The choice of delivery system, such as prefilled syringes,
is also important. For complex as well as for simple drugs, desired pharmacology,
targeted patient population(s), and disease state(s) should be carefully considered in
decisions on drug product dosage form, strength, and route of administration.
For biotechnology products, the complex processes, raw materials, and biological
substrates used in manufacturing can lead to a broad range of process-related impurities.
These impurities may impact product performance beyond direct toxicities. Impurities
may impact the attributes of the active pharmaceutical ingredient, such as protein
aggregation by tungsten moieties [17]. Contaminating proteases may also impact
stability of a protein product. Some impurities can act as adjuvants and thus may have
the potential to alter protein immunogenicity. Such impurities have been suggested as
playing a role in erythropoietin immunogenicity [18, 19] although other possible causes
have also been suggested [20, 21].
Product quality characteristics for complex products encompass a wide variety of
product variants that include product-related substances and product-related impurities
[22]. The three-dimensional structure of proteins is important for receptor interactions.
Changes in folding may alter receptor binding and/or signaling. Protein multimerization
may change receptor blockade to receptor activation. Abnormally folded proteins may
impact immunogenicity through aggregation, generation of novel epitopes, and/or
altered uptake by antigen presenting cells. Protein folding depends on low-energy
interactions such as hydrogen bonds. Thus, minor environmental changes could impact
protein structure and generate structural variants. Environmental excursions during
processing or shelf life may interact with other impurities such as trace proteases and
impact degradation.
In addition to variants in higher order structure, proteins can have many post-
translational modifications. Biotechnology products are often heterogeneous mixtures
with many variants that have different sets of modifications. Although many post-
translational modifications may not impact product performance, others may alter
pharmacokinetics, activity, or safety (e.g., immunogenicity). In Fig. 2.2a, a schematic
of a monoclonal antibody is shown with a subset of potential post-translational
modifications, such as N-terminal pyroglutamines, oxidations, deamidations, glyca-
tions, C-terminal lysines, and glycosylations. One of these modifications, an oxidation
site, is considered in a decision tree regarding a potential impact on performance
(Fig. 2.2b). Such a decision tree can be assigned for each of the modifications. Decision
trees can also be constructed regarding specific safety concerns, such as immunogenicity.
Ideally, a probability or risk ranking can be applied to the various possibilities in each of
