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17.70 Agents, brokers, traders, distributors, repackers, or relabellers should maintain records of
complaints and recalls, as specified in Section 15, for all complaints and recalls that come
to their attention.
17.71 If the situation warrants, the agents, brokers, traders, distributors, repackers, or relabellers
should review the complaint with the original API or intermediate manufacturer in order
to determine whether any further action, either with other customers who may have
received this API or intermediate or with the regulatory authority, or both, should be
initiated. The investigation into the cause for the complaint or recall should be conducted
and documented by the appropriate party.
17.72 Where a complaint is referred to the original API or intermediate manufacturer, the record
maintained by the agents, brokers, traders, distributors, repackers, or relabellers should
include any response received from the original API or intermediate manufacturer
(including date and information provided).
17.8 Handling of Returns
17.80 Returns should be handled as specified in Section 14.52. The agents, brokers, traders,
distributors, repackers, or relabellers should maintain documentation of returned APIs and
intermediates.
18. Specific Guidance for APIs Manufactured by Cell Culture/Fermentation
18.1 General
18.10 Section 18 is intended to address specific controls for APIs or intermediates manufactured
by cell culture or fermentation using natural or recombinant organisms and that have not
been covered adequately in the previous sections. It is not intended to be a stand-alone
Section. In general, the GMP principles in the other sections of this document apply.
Note that the principles of fermentation for “classical” processes for production of small
molecules and for processes using recombinant and non-recombinant organisms for
production of proteins and/or polypeptides are the same, although the degree of control
will differ. Where practical, this section will address these differences. In general, the
degree of control for biotechnological processes used to produce proteins and
polypeptides is greater than that for classical fermentation processes.
18.11 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.
18.12 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.
18.13 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