Biomedical Engineering Reference
In-Depth Information
While for drugs such as insulin and other bacterial-expression drugs, the
size of production will remain high, drugs made using cell cultures are most
likely to be made in smaller-size bioreactors as the lines enter a productivity
of 10 g/L.
Still, there remains a large market for smaller-volume drugs, clinical sup-
plies, and more recently cell therapy that holds great promise for the dis-
posable manufacturing industry to begin to show its promise in terms of
approval marketing authorizations.
The requirements for regulatory submission using a disposable system are
exactly the same as those for hard-walled manufacturing systems. The usual
validation, calibration, and operational qualification of the equipment are
required. However, this does create a challenge especially when it comes to
managing characterization, robustness, and scalability. The fact is that the
manufacturer must submit robust studies to prove that all leachables are
identified and that they do not affect the quality of the product if present.
Leachables apply to every component from the mixing bags to transfer tubes
to filters, connectors, and storage devices. The manufacturer is also required
to demonstrate the scalability of membrane chromatography, flow distribu-
tion, and device variability.
There is a belief that membranes are more variable than chromatogra-
phy resins and that it is the manufacturer's responsibility to prove through
extensive process analytic technology (PAT) practice that the variation does
not affect the quality.
Finally, the manufacturer must demonstrate comparability of the prod-
uct with the innovator product if it is a biogeneric product. This includes
lot-to-lot variations as well, and this is where some problems can arise.
There will never be two batches of a biological drug that are always the
same; variability is inherent in biological systems and it is for this reason
alone that regulatory agencies require strict environmental and compli-
ance control.
To demonstrate how the FDA views the single-use or disposable tech-
nology, a review of the
Manual for Biologicals Compliance Program Guidance
Manual
, Chapter 45—Biological Drug Products; Inspection of Biological Drug
Products (CBER) 7345.848, implementation date of October 1, 2010, (
www.
fda.gov/cber/cpg/7345848.htm
)
, has one entry for “single-use,” and none for
“disposable” or “plastic.” The entry on “single-use” states as follows:
8c) Filtration
There are various types of filtration methods, such as
diafiltration, ultrafiltration, and microfiltration that may be used in the
purification of vaccine products. Some of the filters used may be single-
use and some may be multiuse. The filters are usually placed within a
filter housing apparatus. The criteria used for the evaluation of the col-
umn purification should also be applied to the filter housings and the
multi-use filters.
