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Pharmaceutical Manufacturing and Packing Sourcer
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Protein-based drugs are notoriously
difficult to formulate, but if their properties are assessed correctly,
an effective formulation screening can be performed to render a
successful drug substance and final product
Recombinant biologics represent a large and important class of modern
therapeutics.The development of a successful biologic medicinal product
is the result of optimised process and formulation development
activities.The goal is to obtain a stable product during manufacture,
storage and use. As biologics have a high molecular weight with almost
no permeation through biological membranes, combined with their
susceptibility to digestive fluids, the parenteral route is still the
preferred route of application. Due to their size and specific
structures, physical stability is just as important as chemical
stability, and content does not equate to potency as with small
molecules.
Taking all this into consideration, biologics are complex molecules and
successful formulation requires special strategies.These strategies
have to address both, limited availability in the early phases of drug
development as well as less time for carrying out experiments due to
short development timelines. The goal of early stage drug development
is to develop a physically and chemically stable product, addressing
not only shelf life, but also manufacturability and compatibility with
the processes later in the project. All efforts at this stage result in
the first application form (liquid or a lyophilisate) and allow moving
an investigational new drug into clinics quicker to test its
therapeutic value.
Since ‘the process makes the product’, the impact of process parameters
in the quality of the final product has to be assessed early in the
development process. Although it is possible to use a service
formulation up to proof-ofconcept, early identification of the final
robust formulation has the advantage of avoiding changes in the
formulation, or requiring repeated studies to prove comparability,
safety and efficacy. The typical timepoint for the initiation of a
formulation screening is when the project enters the preclinical
development phase (see Figure 1).
In around 12 to 14 months, the drug substance manufacturing process has
to be developed and a formulation identified. Apart from this, a
manufacturing process for the drug product also has to be developed and
GLP material for toxicity and stability studies has to be
manufactured.Taking this into consideration, the time for a formulation
development is limited to six to nine months. Subtracting the time
required for performing stability studies, the time left to decide on a
formulation for clinical studies is limited to three to six months (see
Figure 2).
In developing the same, or at least very similar, protein drugs, a
formulation platform might be useful in reducing development time and
the risk of failure. Typically, development portfolios show some
heterogeneity either in the substructure of protein drugs or more
significant differences due to different protein formats; for example
with antibodies, where IgGs are accompanied by fragments and engineered
with more artificial species like BITEs. A few examples of different
antibody formats currently in clinics can be seen in Table 1.
Performing the Formulation
Taking all the factors described into consideration (complexity,
different formats, short development timelines and limitations with the
availability of the API), an effective and reliable screening procedure
for the identification of an optimal formulation is desirable. One
approach to master this challenge is to separate physical and chemical
stability optimisation, as they are both prerequisite for a successful
product. Following this approach, the protein will be screened in a
first step for formulation conditions (pH, ionic strength, surfactants,
carbohydrates) leading to a physically stable product.This first
screening can be done using Thermofluor technology, where the impact of
external factors on the stability of a protein in solution can be
determined by measuring its unfolding temperature (1).This technology,
based on the interaction of a hydrophobic fluorescent dye with
hydrophobic domains upon heating, requires only very small amounts of
protein and can be done in a short time and using microtitreplates,
allowing highthroughput screening experiments. Figure 3 (page 38) shows
how this approach allows the screening of several formulation options
with small amounts of API at the start of the development, when often
research process are available only having non-optimised protein
titres.
The Thermofluor technology allows the selection of external factors for
the proteins for optimised protein stability in terms of a physical
constant. Consequently, when promising formulation candidates have been
preselected, they can be tested for physical stability in typical
temperature/shear stress experiments. Since continous improvements are
made on the API side in parallel, sufficient amounts of API are
available to make these experiments in original container closure
materials; either at the original scale or downsized. These experiments
add real physical stability information, since the protein is stressed
under worst-case conditions and stability can be assessed, for example
in terms of aggregation (SEC or larger aggregates). Even at this stage,
subvisible particles (1-10μm) can be assessed and taken into
consideration for further narrowing the list of formulation candidates
(3).These experiments allow the identification of ideal formulation
parameters, as well as setting the base for a selection of candidate
formulations for an orienting stability study to assess chemical
stability as well. Figure 4 illustrates the process of the formulation
selection process.
Following this approach will require specific amounts of API (as
illustrated in Table 2) and can be used for compatibility experiments
as well.Adding NaCl to the test solutions provides early information
about the stability after a saline dilution or adding solvents; the
compatibility in manufacturing processes requiring these solvents (drug
delivery systems) may also become predictable.
Besides the low amounts of API to start with, another advantage of this
procedure is the high-throughput testing capability, since the
Thermofluor test can be carried out in 96 microtitre plates. Throughput
can be increased by using liquid handling equipment or a fraction
sampler for the preparative SEC for the preparation of the protein in
different buffer solutions.
Conclusion
The approach described in this article allows us to address the main
challenges in the formulation of protein drugs. Both physical and
chemical stability optimisations of formulations are dealt with, and
each allows the effective use of resources and time to obtain a stable
protein formulation. In several development projects, this approach has
been shown to be very effective and efficient, leading to reliable
selection decisions in the development process.The concept can be
followed with limited resources, and allows scientific support of
formulation decisions,backing early proofof- concept. Another advantage
of this concept is that the selected formulation will have the
potential to be the final formulation, and no formulation related
comparability exercises will be required.
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