MM: How was the project managed? What type of team did you put in place?
Figure 1. Getinge La Calhene DPTE aseptic transfer system with disposable beta port for transfer of pre-assembled manifold
bags assembled with Bosch needles
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NB: The new product introduction department set up the URS, working in collaboration with the quality and engineering departments.
Nigel Wood, our engineering project manager, played an important part, particularly looking at the integration of the Bosch
system, as did our quality assurance (QA) department which took a pragmatic approach to making sound, risk-based decisions.
We also worked in close collaboration with the Millipore Mobius experts.
We carried out a full critical review of all aspects of the filling systems and identified many areas of over complication.
We challenged each of these aspects with local QA, then Millipore Mobius expert advisors, and then with the MHRA regulators.
We took the approach that every item, regardless of its excellence or complexity, has a failure rate. Thus any reduction in
items will have a beneficial effect, and many component parts were removed or at least reduced in complexity.
Other principles were that the product passage from point 1 to 2 should be as simple as possible with as few manipulations
as possible (to reduce training and error rates) and wherever practical, as few grade A manipulations as possible. No aseptic
connections (including needle assembly) means no SIP to point-of-fill, and minimal grade A intrusions. Our other main motto
is, "where there are connections, use the best available."
EJ: Our approach on such a project is to work hand-in-hand with the end-user, a collaborative approach aimed at finding the best
overall solution.
DISPOSABLES SELECTION AND IMPLEMENTATION
MM: How did you evaluate the operational aspects of the technology and the cost of the options? How did you go about risk
mitigation?
NB: If it hadn't been for the pandemic, the selection and implementation of disposables would no doubt have taken twice as long.
In this situation, convincing the sponsors was somewhat quicker than in a normal situation. QA pragmatism through risk assessment
also helped immensely.
Figure 2. Bosch single-use filling needles. GSK's use of Bosch needles began early in the development of the Bosch systems.
The Bosch manufacturing process has been improved to control all aspects of quality control, including chemical and microbial
levels.
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One of the key technologies we selected was the Millipore Mobius magnetic drive mixer for bulk drug formulation. We had already
done previous testing with this system and found it to work efficiently. The Millipore STS connector was used to secure the
sterile connection of the irradiated filter in the grade C environment. In both cases, we went through a series of trials
and training, using 10 assemblies for each connection for each process step. It is important that the operators are trained
to make the connection, because if you don't make the final click properly it can leak. We chose 50-L bags from Sartorius
Stedim Biotech for the bulk drug hold. We selected the Sartorius Stedim bags because we preferred the integrity testing methodology
that they have developed. We also carried out a full risk assessment using failure mode effect analysis (FMEA).Other key technologies
included the Getinge La Calhene aseptic transfer system, which was premounted with the disposable beta transfer port to allow
aseptic transfer of the seven pre-assembled manifold bags mounted with the Bosch needles into the RABs.
The Millipore team worked to rapidly qualify the assembly of the Bosch needles on the manifold—not a simple task when ensuring
the safety of the disposable assembly prepacked with stainless steel needles. The peristaltic pump filling systems from Groninger
and Bosch were selected for their high level of accuracy and simplicity. We also work with ready-to-use presterilized stoppers
from Helvoet & West Pharma, again eliminating washing requirements.
EJ: Cost was not the primary concern for pandemic flu. Time to get a solution and flow path security and sterility were the primary
drivers. For other applications, GSK had a cost target, but was flexible with this as they learned of the operational efficiencies
they would gain in using a single-use solution.
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