(2002; 166 pages)
Regulation of products derived from recombinant DNA technology in China
Professor Haijun Zhou, China
The major difference between recombinant DNA products and other pharmaceutical products is that biotechnology makes use of genetically modified living organism to produce proteins and peptides, whereas other pharmaceutical products are derived from naturally occurring substances, or by chemical synthesis. However, biotechnology products are no different from other biological products after the process of protein purification. For this reason, the requirements for process validation, environmental control, aseptic manufacturing and quality assurance are fundamentally similar. However, the complexity of the system is greater for biotechnology products because their production requires highly developed cell propagation processes and complicated purification methods.
The following principles underlie the regulation of r-DNA products in China:
• Specific concerns about particular products should be raised with the appropriate specialists on a case-by-case basis.
• A new licence application is required even if the active ingredient is identical in molecular structure to a naturally occurring or previously approved product.
• Differences can arise at different production stages. Because ability to characterize the identity and structure and to measure the activity of the clinically active components is limited, emphasis has to be put on the control of the manufacturing process.
The following need to be considered during the evaluation process:
• the different vector and host cells used in constructing the engineered cell;
• the specificity of different kinds of r-DNA products in different animals;
• the different usage and frequency of administration of specific products and their implications for the acceptable levels of impurities;
• the need for special attention to modified moieties;
• possible contamination with potentially hazardous impurities if the purification process is not capable of eliminating them;
• unintended variability in the culture, which may lead to differences in impurities and inconsistencies in the product itself.
In ensuring the quality of r-DNA products, controls must cover:
• Source materials: expression of vector and host cells, sequence of the cloned gene, and the measures used to promote and control the expression of the cloned gene.
• Manufacturing process: master cell bank, consistency of yield product from full-scale culture, criteria for rejection of the culture lots, etc.
• Final product: physicochemical characterization, biological tests for identity and potency, tests for contaminants.
• Preclinical toxicity evaluation.
• Clinical trials.