Ruth Freitag Introduction

The modern biotechnology industry has provided the medical community with a new type of pharmaceutical, namely recombinant proteins and peptides. The number of such protein-based drugs is already impressive and expected to increase considerably in the future, as the function and gene sequence of more and more proteins is discovered, for example, as a result of the human genome project and related activities (genomics, proteomics). Soon gene therapy may bring about the next revolution in medical treatment, where for the first time it will be possible to correct the genetic causes of a disease rather than to just counteract the consequences of that genetic defect, i.e., the symptoms of the disease. Gene vaccines present another evolving medical possibility, which has been shown to have some significant advantages over the prophylactic measures taken at present against certain infectious diseases. Biopharmaceuticals, such as proteins and nucleic acids, thus extend the possibilities of medical treatment and thereby improve the quality of life. From an engineering point of view, however, the production and especially the purification of these biopharmaceuticals poses a considerable challenge. ,

Proteins, i.e., the majority of the current biopharmaceuticals, are fragile, easily denatured substances. They are generally found in a complex environment such as cell, culture media or lysates (inclusion bodies). The concentration of the target molecule in the raw feed is often low, while extremely high final purities have to be reached in order to fulfill current legal require-ments( see Table 3.1 for details). The production scale in the biopharmaceutical industry is often smaller than in the conventional pharmaceutical industry, i.e., in the kg/year rather than the t/year range. Speed (throughput) is another issue since prolonged exposure to a nonsterile environment or certain impurities (proteases) may lead to significant product degradation. Last but not least, the biotech industry, as any other, is governed by economic demands.3

Conventional pharmaceuticals, on the other hand, are usually small biochemically active molecules which inhibit or enforce a metabolic function. Such substances can be purified by a host of well-understood separation methods including extraction, precipitation, filtration, refraction and crystallization for highest purity. Most of these separation methods cannot be used for the separation of proteins due to the prevalence of harsh "nonphysiological" conditions such as elevated temperatures, extreme pH values and organic solvents. Thus, the challenge of industrial bioseparation can be summed up as: The need to perform an economically sound, high-resolution separation on a large scale, while maintaining "physiological" conditions throughout.

Synthetic Polymers for Biotechnology and Medicine, edited by Ruth Freitag. ©2003 Eurekah.com.

Table 3.1. Requirements for the final purity of a

recombinant pharmaceutical

intended for parenteral use in humans (combined from information given

in reference 1)

Contaminant/Impurity

Maximum Residual Allowed

Host cell DNA

10 pg/dose

Endotoxin

0.25 units/ml

Foreign proteins (total)

< 1 %

Host cell protein

< 10 ng/dose

Protein A

<10 ppm

Aggregates

< 1 %

The fact that product isolation contributes heavily to the overall production costs is well known in the bioindustry.4,5 Another important issue is the time-to-market, i.e., the time required for process development and scale up to production. The latter aspect, in particular, seems to argue in favor of the continued use of well-established methods such as chromatogra-phy.6 However, on close scrutiny, both the costs and the process development and adaptation time may in fact be improved by the rapid integration of evolving new separation principles into the category of "established techniques."7,8

The goal is a reduction in the number of steps and an increase in the overall efficiency of a given downstream process. New developments in the material sciences will be essential in advancing this issue. Smart or intelligent materials, such as stimulus-responsive polymers capable of sensing a certain change in their environment and reacting in a corresponding and predetermined way, offer many possibilities in this regard.

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