Biomedical Engineering Reference
In-Depth Information
11
Regulatory
Compliance
The logic of validation allows us to move between the two limits of dogma-
tism and skepticism.
Paul Ricoeur
The medical device industry has matured into hundreds of regulatory
approvals worldwide, and with that has come a keen understanding of bio-
compatibility, leachability, and the safety of the plastic materials used. The
disposable systems gaining wide appeal in bioprocessing have to revert to
regulatory opinions on medical devices since there are no current guidelines
available from the FDA or EMEA on the evaluation of disposable manufac-
turing factories for biological drugs.
There is sufficient guidance available on the testing and validation of any
measurement device used in cGMP conditions, ranging from calibration to
IQ/OQ/PQ to CFR 21 Part 11 compliance when there is a central processing
unit (CPU) involved.
To date, no major regulatory authority has approved any product manufac-
tured using a disposable bioreactor. It is not because of any risk factors in the
use of disposable systems but in the inability of the manufacturers to file these
applications. Generally, a manufacturer will file a regulatory marketing autho-
rization application using manufacturing systems that are capable of producing
at least 10% of the final batch size that the manufacturer plans to make when
the drug is approved. The manufacturer also wants to make sure that the larger
batches would be easily scaled-up. When using hard-walled systems, this is
relatively easy as the fermenters and bioreactors supplied by a large equipment
manufacturer offer several sizes and most of these are readily scalable. When
it comes to disposable bioreactor systems, the largest-size bioreactor that has
become available is 2,000 L in size and even that is an expensive offering as
most manufacturers have simply emulated the hard-walled systems by placing
a liner within them. All of the other hardware and software remains the same,
making it a much more expensive undertaking. Even if Big Pharma is willing
to accept those costs, the maximum size of 2,000 L is too low to convince betting
on this system. Recently, a Korean company installed a hard-walled animal cell
bioreactor greater than 80,000 L; however, this type of sizing is most likely to
become obsolete as cell lines become more productive. As an example, a com-
pany using a cell line qualified 20 years go would have to use at least 20 times a
larger scale than if they were able to replace them with a newer line.
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