Biomedical Engineering Reference
In-Depth Information
material control also contributes to product safety because of impurities in the
material. Manufacturers must be able to test and verify the identity of raw mate-
rials. Vendor-supplied information, in the form of a certificate of analysis, may
not be sufficient to adequately control raw material. Vendors should be certified
to ensure a continuous supply of safe, consistent material.
The origin of materials may be an important factor in the supply chain.
Historically, raw materials used in biopharmaceutical manufacturing have been
naturally derived and have included animal serum, albumin, enzymes, etc. These
materials are used to prepare both active substances and excipients, (e.g., polysor-
bates, collagen, and gelatin), and may contain microbial contamination and/or
support microbial growth. Contamination by microorganisms including bacte-
ria, fungi, mycoplasma, viruses, and transmissible spongiform encephalopathies
(TSEs) and/or proteolytic enzymes is not unusual. Bacteria and fungi can express
extracellular proteins and directly influence the material itself and/or the cell cul-
tures from which the biopharmaceutical is derived. Mycoplasma, viruses, and
TSEs can interact with and influence the cell cultures, potentially impacting
yields, purity, and the efficacy of downstream processes. Perhaps the greatest
challenge provided by TSEs is the inherent difficulty that they present to removal
from manufacturing processes. Not only is their removal difficult but the ability
to validate the removal process is itself difficult to demonstrate.
Contamination is controlled and/or minimized by a series of actions that span
the entire process from collection through processing and testing. The collection
process is controlled through strict requirements regarding geographic sourcing
of materials, definition and documentation of donor animal herds, the collection
of serum according to protocols and by trained personnel.
Current regulatory requirements include provisions to test animal-derived raw
materials for adventitious contaminants before use [7-9]. The tests include assays
to determine bacterial and fungal levels, mycoplasma assays, and a series of tests
to detect both viral antibodies and viral particles. These tests are to be performed
before the implementation of any inactivation steps to assess total contaminant
load as the total load may impact the efficacy of removal/inactivation steps.
Gamma irradiation is currently the preferred means of microorganism control.
The irradiation process sterilizes the raw materials and renders them safe for
use. After gamma irradiation, manufacturing processes that physically remove
contaminants, for example, filtration or precipitation, are the preferred means
of microorganism control; however, chemical inactivation of contaminating
microorganisms may be acceptable in some situations. In instances where
physical removal or inactivation of TSE forms the basis of a regulatory claim
concerning product safety relative to TSE, all removal and inactivation process
must be adequately validated to demonstrate efficacy for their intended purpose.
In addition, many companies impart a degree of control over their raw materi-
als by maintaining an active supplier quality program through which they verify
the continued compliance of raw material suppliers to applicable health authority
and company standards. Suppliers in such programs are included on the basis of
the criticality of the individual raw material and its associated product. A relative
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