Biomedical Engineering Reference
In-Depth Information
Mammalian cell cultures are challenging to scale-up and
comparatively expensive to run. FP or biologic product
designs that allow for more straightforward manufacturing
can therefore be advantageous. All of the FPs involving an
Fc domain use mammalian expression except for two prod-
ucts, which are both peptibodies (Fc-peptide). The most
advanced of these, Nplate (romiplostim), is produced using
bacterial fermentation and as a result, unlike mammalian
cell-expressed Fc fusions, has a nonglycoslated Fc domain.
The glycan structure has a key bearing on the ability of an Fc
domain to bind to Fc receptors, but more importantly for
most mAbs, is critical for effector function [43,44]. Simi-
larly to peptibodies, a number of Ab scFv fragment struc-
tures offer scope for bacterial production, although such FPs
are currently in earlier stages of development. Approxi-
mately 28% of identified FPs in Phase II or above use
bacterial fermentation. Escherichia coli is used in all cases
except for one, Protox's PRX302, which uses Aeromonas
salmonicida. The applicable manufacturing processes will
depend on both components of an FP and certain classes
offer more scope for bacterial production than others, such
as those based on the short peptides of microbial toxins,
antigen fragments, or endogenous ligands (that are fre-
quently peptides rather than larger proteins). Short peptides
can also be synthesized by combinatorial chemistry, facili-
tating conjugation approaches.
Regulators require products to be produced in a suffi-
ciently consistent manner to ensure patient safety. For
example, a key challenge of conjugated Abs has been to
achieve homogenous product with the same number of
partner components attached per molecule. Furthermore,
the attached moiety should ideally be bound at the same
site in each case, such that its stability or release will be
consistent. Severe adverse events could, for example,
occur if a patient was to receive an immunotoxin dose
with a greater toxin ratio, or where toxin more readily
detached and distributed to unintended areas of the body. A
key advantage of FPs is that the partner moiety is inher-
ently built in to the sequence of the expressed protein,
giving a more consistent position in the final structure. FPs
also offer advantages in terms of number of process steps.
Formed as a fused molecule, they require only a single
fermentation and can be purified in a single stream. In
contrast, the two (or more) components of a conjugated
protein will usually be produced in separate fermentations
(or chemical synthesis stages) and individually purified
before being joined. However, having two (or more)
components can make purification of FPs more challenging.
A single protein may have specific characteristics that can be
exploited for it to be preferentially selected over impurities,
but these can be altered by addition of a partner compo-
nent. As such, conjugated products based on a common
platformmay offer a more regularized process compared to
FP alternatives.
These manufacturing differences will alter the cost of
producing a product. Although a more complex process is
not necessarily a more expensive process to run, having a
greater number of processing steps increases variability,
potentially raising the risk of product inconsistency.
Similarly, in the development stages, a more straightfor-
ward manufacturing process facilitates optimization of
yield and purity. The manufacturing options available
and respective costs for different FP and non-FP structures
will vary on a case-by-case basis, but should be assessed in
the wider context of other factors for commercial success.
That is, in addition to cost considerations, an FP should be
administrated in a competitive formulation and offer an
adequate efficacy and safety profile. For novel brands,
particularly those addressing areas of high unmet need, the
in-market price of a product may have less bearing on
its ability to capture market share. In contrast, the use
of products that are positioned against next-generation
or biosimilar versions
can be more
sensitive
to
differential pricing.
We were able to identify manufacturers for 37 of the 43
FPs in Phase II development or beyond. These included 30
different companies, of which the vast majority was the
innovator or partner, rather than an external contract manu-
facturer. We consider this an indication of the broad capa-
bilities of both small and large biopharmaceutical
companies in terms of development-stage FP manufactur-
ing. It should though be noted that with over half of the FPs
currently in Phase II development, we would anticipate that
a number will subsequently be transferred to alternative
manufacturers, for production of Phase III trial material or
commercial supply.
3.2.4.2 Intellectual Property: Freedom to Operate and
Protection from Copies Aside from manufacturing costs,
the choice of product design against a particular target will
be somewhat directed by the indirect costs of any intel-
lectual property (IP) licensing requirements. Development
and commercialization costs will be lower where there is
freedom to operate and the structure, therapeutic use or
manufacturing processes do not infringe others' IP. In
keeping with this, a number of FPs and their underlying
technology platforms are designed to avoid the patents
held by others. This freedom can be exploited either by the
inventor for in-house product candidates, or out-licensed
to others.
The IP landscape for heavily researched areas such as
mAbs can though be a challenge to navigate, particularly
where patents are in earlier stages and the full breadth of
allowable and granted claims has not yet be issued. Licen-
sure of certain aspects may be unavoidable. We note that
while novel, noninfringing approaches can yield greater
profit margins, having the right product is critical. It may
be better to pay a license fee and/or royalties on a strong
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