Harvest and Recovery of Monoclonal Antibodies from Large-Scale Mammalian Cell Culture - Comparing primary harvest techniques adopted in commercial-scale operations for monoclonal antibody products. -


Harvest and Recovery of Monoclonal Antibodies from Large-Scale Mammalian Cell Culture
Comparing primary harvest techniques adopted in commercial-scale operations for monoclonal antibody products.

BioPharm International
Volume 21, Issue 5

Figure 2. Typical flux-versus-trans-membrane pressure profile for cross-flow microfiltration
Optimal operation of tangential flow MF has been investigated by several researchers.6,7 A typical flux-versus-trans-membrane pressure (TMP) relationship is shown in Figure 2. In general, this can be typified by two regimes: i) a pressure-dependent regime in which an increase in TMP results in an increase in flux, and ii) a pressure-independent regime in which increases in TMP do not further increase flux. As a general rule, it is recommended to operate at the transition between these regimes to maximize flux while not permitting the TMP to rise to a level that would cause increased pore plugging and fouling of the membrane. A similar relationship exists for the cross-flow velocity at a given TMP, the effect of which also levels off at a certain point. Because TMP and cross-flow velocity are interdependent, one can maintain constant TMP operation only by manipulating back-pressure on the membrane to vary the cross-flow velocity as the operation proceeds and concentration increases.6

Microfiltration membranes used for cell culture harvest are often plagued with the problem of membrane fouling (i.e., irrecoverable declines in membrane flux). The operating conditions for the MF operation and the cleaning regimen for the membranes after use are both significant ways to address this issue. Another important variable is the membrane chemistry, with more hydrophilic membranes generally being less susceptible to significant fouling.

Optimizing MF Harvest Operations

The development of an MF harvest process has been outlined as a step-by-step process.7 Two important determinants for using MF systems for mammalian cell culture harvest are the flux and the product yield. The flux determines the surface area of membrane needed to process the cell culture broth, which has significant economic implications, because too high a flux can foul the membrane and shorten membrane lifetime.

The measurements of flux versus TMP and cross-flow rate curves at various concentrations at laboratory scale typically are the first series of experiments that are conducted. An easy way to carry out these experiments is to operate under total recycle mode in which the permeate is fed back into the load tank to maintain a constant concentration level. Steady state flux can then be measured over a few different cross-flow velocities to produce the flux versus TMP plot shown earlier in Figure 2. In these initial experiments, the broth should be concentrated to a degree which will be representative of the final desired concentration. Various membranes can be screened to identify ones that are optimal for the application because both the chemistry and the pore size play an important role in determining flux and flux decay characteristics. It is usual to operate at the transition point between the zones of increasing flux versus TMP and the zone of TMP-independent flux to maximize flux and minimize detrimental effects of fouling and pore plugging.

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