Contains Nonbinding Recommendations
The term biotechnological process (biotech) refers to the use of cells or organisms that have been
generated or modified by recombinant DNA, hybridoma, or other technology to produce APIs.
The APIs produced by biotechnological processes normally consist of high molecular weight
substances, such as proteins and polypeptides, for which specific guidance is given in this
Section. Certain APIs of low molecular weight, such as antibiotics, amino acids, vitamins, and
carbohydrates, can also be produced by recombinant DNA technology. The level of control for
these types of APIs is similar to that employed for classical fermentation. (18.11)
The term classical fermentation refers to processes that use microorganisms existing in nature
and/or modified by conventional methods (e.g., irradiation or chemical mutagenesis) to produce
APIs. APIs produced by classical fermentation are normally low molecular weight products
such as antibiotics, amino acids, vitamins, and carbohydrates. (18.12)
Production of APIs or intermediates from cell culture or fermentation involves biological
processes such as cultivation of cells or extraction and purification of material from living
organisms. Note that there may be additional process steps, such as physicochemical
modification, that are part of the manufacturing process. The raw materials used (media, buffer
components) may provide the potential for growth of microbiological contaminants. Depending
on the source, method of preparation, and the intended use of the API or intermediate, control of
bioburden, viral contamination, and/or endotoxins during manufacturing and monitoring of the
process at appropriate stages may be necessary. (18.13)
Appropriate controls should be established at all stages of manufacturing to ensure intermediate
and/or API quality. While this guidance starts at the cell culture/fermentation step, prior steps
(e.g., cell banking) should be performed under appropriate process controls. This guidance
covers cell culture/fermentation from the point at which a vial of the cell bank is retrieved for use
in manufacturing. (18.14)
Appropriate equipment and environmental controls should be used to minimize the risk of
contamination. The acceptance criteria for determining environmental quality and the frequency
closed, or contained systems). (18.15)
In general, process controls should take into account the following: (18.16)
• Maintenance of the working cell bank (where appropriate)
• Proper inoculation and expansion of the culture
• Control of the critical operating parameters during fermentation/cell culture
• Monitoring of the process for cell growth, viability (for most cell culture processes) and
productivity, where appropriate
• Harvest and purification procedures that remove cells, cellular debris and media
components while protecting the intermediate or API from contamination (particularly of
a microbiological nature) and from loss of quality
• Monitoring of bioburden and, where needed, endotoxin levels at appropriate stages of
production