58
8.0 Berinert
®
Production
Chapter 8 Highlights
•
Berinert has a high purity profile
compared with other plasma-derived
C1-INH concentrates.
•
The manufacturing process for Berinert
®
includes multiple steps to purify and to reduce
the risk of virus transmission by the finished
product.
•
Virus reduction steps include pasteurization,
HIC, and virus filtration (also called
nanofiltration).
•
When manufacturing Berinert
®
, CSL Behring
employs a 4-step Integrated Safety System to
help ensure that the product meets and/or
exceeds industry standards for quality in
plasma protein production.
The 4-step Integrated Safety System
includes:
1) Careful donor selection and
rigorous screening of donations and
plasma pools for fractionation
2) Manufacturing processes for virus
inactivation and removal
3) Strict adherence to Good Manufacturing
Practices and Quality Assurance; and
4) Postmarketing surveillance.
•
The virus inactivation/removal steps
for Berinert
®
have been validated in an
in vitro
study, which demonstrated
overall mean virus reduction factors
of
≥
14.5 to
≥
19.9 log
10
.
8.1 The Berinert
®
Manufacturing Process
112
Berinert
®
is a plasma-derived C1-INH concentrate, pro-
duced as a sterile, pyrogen-free, lyophilized white pow-
der for intravenous injection after reconstitution. The
potency of C1-esterase inhibitor is expressed in Interna-
tional Units (IU), which are related to the current WHO
Standard for C1-esterase inhibitor products. The starting
material for the manufacture of Berinert
®
is human
plasma. C1-INH is isolated from cryo-depleted plasma by
adsorption steps.
Three virus reduction steps are performed during the
manufacturing process:
•
Virus inactivation by heating the mixture for 10 hours in
aqueous solution at 60°C (pasteurization)
•
Hydrophobic interaction chromatography (HIC)
•
Virus filtration using a 20N and a 15N filter in series
(also called nanofiltration).
The solution is then dialyzed, filtered, and lyophilized
(Figure 29).
This purification process ensures the reduction of impuri-
ties to a very low level that is generally of no toxicological
concern.