and economic pressures are creating profound changes in the biopharmaceutical
industry, as rising healthcare costs put increased scrutiny and regulation on
the industry, particularly in the United States. Companies are facing intense competition from
low-cost manufacturers in other regions of the world. Generics and biosimilars add to this competition,
diminishing market share for branded medications. These market and
environmental conditions are increasing the need and focus on sustainable
processes, with lower operating costs and minimal environmental impact.
Process Economics Drivers
These aforementioned factors require a re-imagining of
biopharmaceutical processes. Processes
can be improved in several different ways:
the cost of raw materials
Fewer blockbuster drugs generally mean fewer continuous
production processes. With shorter
production campaigns, flexibility in unit operations is critical. Single-use products allow production
facilities to accommodate multiple products, as well as reduce validation costs. Emphasis has been placed on upstream fermentation, however, downstream
purification processes can not be ignored.
Economical, large particle size polymeric resins make excellent
single-use guard columns. These guard
columns, used in a negative adsorption mode, can remove contaminants such as
color bodies and host cell proteins thereby reducing the contaminant load on
more expensive chromatographic media.
Process economics can also be improved by carefully controlling
materials costs. Process costs include
initial raw materials, regeneration and disposal costs. Downstream purification costs are reduced by protecting
or substituting expensive chromatographic media with polymeric resin. Additionally, effective process development
results in lower process cost from decreased solvent usage through higher mass
concentration in product effluent, and efficient solvent recycling. This article will focus on these two
applications, Dimer Removal and Solvent Recovery.
Low molecular weight (<1000 kDa) active pharmaceutical
ingredients (APIs) are sometimes prone to dimerization. Product dimers are undesirable from the
standpoint that they decrease product purity and potency. Typical approaches for dimer removal include:
crystallization, solvent extraction or adsorption with diatomaceous earth. These methods are not very efficient, expensive,
and can generate hazardous wastes. Adsorptive
chromatography is an alternative which not only provides high-capacity dimer
removal, but can also eliminate other contaminants as well.
In this example, the API is poorly soluble under aqueous
conditions (<2g/L), unstable at both high pH and high temperature. Additionally, the process requires that the
API be recovered at high mass concentration (>100g/L) or low liquid volume,
and the process step needs to be conducted within the constraints of one work
shift (<8 hours).
Process development is performed using a reversed-phase polystyrenic
resin with an average pore size of 150 angstroms, high surface area (900m2/g)
and an average particle size of 75 microns.
Complicating the development is the poor aqueous solubility of the API.
The solvent concentration in the loading mobile phase requires a balance
between reasonable API solubility and sufficient retention of the API on the reversed
The key to the process development is dissolving the API at
high concentration. While the water
solubility of the API is poor, the API is very soluble in acetone
(>100g/L). Therefore, initial
dissolution of the API is performed in acetone and the feed is then mixed with
40 percent acetone so that the loaded feed concentration is 10g/L in 40 percent
acetone. The schematic for the
purification process is shown in Figure 1.
This solvent concentration, combined with the relatively high feed concentration,
provides high operational capacity of the API on the reversed phase column
(>80g/L). The solvent conditions also
allow high linear velocity during loading, thus decreasing the total operation
time for this step to <6 hours. High
mass loading and optimized elution conditions provide high mass concentration
of the API in the column effluent, reducing overall solvent volume and the
requirements for further filtration or evaporation. Most importantly, the API is recovered at
high purity with high yield. A summary
of the optimized process conditions and results is shown in Table 1.
1 – API Loading Process with Solvent Recycle
of Dimer Removal Process
Some synthetic APIs required synthesis under totally
anhydrous conditions so that the chemical reactions are most efficient. While anhydrous solvents are readily
available, solvents may contain water after synthesis is complete. Rather than dispose of these solvents, they
can be recovered, thereby reducing raw materials and disposal costs. To recover
and re-use solvents, desiccation may be required.
Strong cation exchange resins, with a low moisture level,
can be used as desiccants for organic solvents, similar to the use of silica
gels and molecular sieves. However,
these strong cation exchange resins have the advantage of being very easily
regenerated at low temperatures. The
resins are particularly useful for the removal of trace amounts of water from
non-polar solvents, such as chlorinated hydrocarbons. Most non-polar materials are not imbibed into
the resin structure, and therefore, many of the inhibitor systems used in these
solvent systems are not taken from the solvent upon drying.
Solvents which are relatively non-ionic in character can be
dried by the strong cation to moisture levels of less than 10ppm. Capacities of 20 pounds of water adsorbed per
10 pounds of dried resin desiccant are obtainable. Reversibility can be accomplished using
temperatures as low as 300°F, a decided improvement over the 365 – 650°F required by
molecular sieves, thereby decreasing energy costs and providing a safer
Water content in the organic liquid fed to the desiccant
affects the capacity obtained, with higher water content yielding higher
capacity as shown in Figure 2. This is
typical isotherm behavior with small molecule adsorption. Similarly, flow rate through the desiccant
affects the capacity, with lower flow rates yielding higher capacity as shown
in Figure 3.
Figure 2: Effect
of Water Content in Feed on Dessicant Capacity
Figure 3: Effect
of Flow Rate on Dessicant Capacity
Ion exchange resins used for desiccant applications are
strong acid exchange resins based on polymers of styrene crosslinked with
divinylbenzene, and functionalized by sulfonation. This yields a resin containing a sulfonate
group to which an exchangeable counter-ion is attached. For desiccation, the sodium counter-ion is
the most common. It is sometimes advantageous
to use the resin in the potassium form to improve the kinetics of drying a
specific solvent system.
The use of ion exchange resins as desiccants are most
effective when using column operations.
In this operation, the fluid to be dried is passed through the dry resin
bed under controlled temperature and flow rate.
Resin bed depths are typically between three and six feet, with column
depths sufficient to contain the volume change which the ion exchange resin
undergoes when water is imbibed during the drying process. The resin swells about 1 percent on a dry
volume basis for each 1 percent of water imbibed on a weight basis. This expansion requires that the column
dimensions are such that the volume change can occur vertically. Tall, narrow columns might restrain expansion
and cause strong lateral pressure resulting in crushed resin or column
rupture. Typical flow rates for
non-polar solvents are in the range of 5 -10 gpm/ft2
based on the empty column cross-section. For polar liquids, the flow rates are
generally lower (~1gpm/ft2)
since the kinetics of drying decrease as the polarity of the liquid increases.
As shown in
the two process examples, biopharmaceutical production economics are improved
through the effective use of polymeric resins.
These resins are not only employed in the purification of APIs, but in
the recovery of valuable raw materials as well.
- API purification processes
using polymeric resins can reduce solvent consumption while still
delivering high purities, and high product yields. Reduced solvent consumption decreases
overall production costs.
- Ion exchange resins are
effective, high-capacity desiccants for solvent recovery and water
removal. They have lower
reactivation temperatures than molecular sieves resulting in lower energy
- B.A. Perlmutter, Env. Progress
16 (2007) 132-136.
- M. Rios, Bioprocess Intl. (May