ABSTRACT
Lifetime studies for membrane reuse remains a critical issue for biotech companies producing therapeutic and diagnostic products.
Two approaches commonly used for establishing membrane lifespan are prospective validation and concurrent validation. Creation
and qualification of the scale-down model, and performance of small-scale reuse studies to support prospective validation,
is time-consuming and costly. However, if a high likelihood of cleaning failure exists, performing these studies may be essential
and may prevent loss of manufacturing lots at scale. For certain cases, concurrent validation may be more appropriate and
performing an identical testing regimen in the form of routine in-process testing may provide the same, if not higher, levels
of assurance for lifetime membrane performance. A production schedule may be significantly influenced when additional sampling
and testing are required between lots. Therefore, a cost–benefit analysis should be performed to determine which validation
approach, prospective or concurrent, is more appropriate and also how many reuses should be targeted.
INTRODUCTION
Membrane filtration steps such as ultrafiltration or diafiltration (UF/DF) and microfiltration are extensively used in biotech
processes. The objective of these steps may be clarification, concentration, or diafiltration. The popularity of filtration
steps stems from their robustness, ease of process development, and scale up. Membrane filters, however, can be expensive.
For example, UF/DF membranes required to process a single batch corresponding to a 10-kiloliter cell-culture process cost
between $100,000 and $1 million.1 Therefore, from a process economics point of view, it is important to reuse membrane filters for multiple cycles before replacing
them. The benefits of reuse include cost savings for the filters themselves, reduced changeover times and the resulting operational
flexibility, and reduced labor and materials costs.
Cleaning procedures, and possibly steam sanitization procedures, are routinely performed before membrane use. Depending on
the specific application and process involved, membrane performance and functionality may be adversely affected over time.
Anurag S. Rathore, PhD
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Potential negative effects of long-term reuse include physical deterioration of the membranes or associated hardware due to
repeated exposure to cleaning agents at elevated temperatures and pressures. These effects may influence the filtration performance
of the membranes, which, in turn, may affect product quality. Moreover, microbial contamination may occur in membrane systems
that cannot be cleaned by routine operations. Such buildup may result in carryover of impurities or product from one lot to
subsequent lots. Thus, lifetime studies for membrane reuse are necessary to ensure that membrane functionality does not deteriorate
over time to the point where it affects the process and the product.
The topic of reuse of membrane media, unlike the topic of reuse of chromatographic media, has not received much attention
in the literature. The present article is the ninth in
BioPharm International's
"Elements of Biopharmaceutical Production" series, and it presents approaches toward establishing and demonstrating lifetimes
for membrane media.
KEY PROCESS PARAMETERS TO ASSESS MEMBRANE PERFORMANCE
An appropriate subset of parameters should be chosen when planning a reuse study. These parameters should be based on the
purpose of the intended application. This section briefly discusses some important process parameters commonly used to assess
the performance of a membrane step.
Normalized water permeability (NWP) is perhaps the most commonly used performance parameter for monitoring the cleanliness
of a UF/DF membrane. NWP uses water to measure the permeability of a membrane , and it allows for a comparison of pre- and
post-use membrane cleanliness. Ideally, NWP measurement should be performed after every reuse in a lifespan study.
