QUALITY CONSIDERATIONS
Validation/Qualification
In-line dilution process equipment and associated components should be validated or qualified to comply with FDA regulations.
Qualification of an in-line dilution skid may include factory acceptance testing (FAT), site acceptance testing (SAT), installation
qualification, and operational qualification. Failure mode and effects analyses (FMEAs) have shown that the traditional manual
preparation methods cannot result in a more robust method than in-line dilution equipment, even with risk mitigation implemented.
Incoming Quality Assurance of Process Materials
The quality requirements of the product concentrates must be evaluated and appropriate for the design of the in-line dilution
equipment. The acceptance specifications for processes with PAT control may not be as stringent as for processes without PAT
control. In-line dilution systems designed with parametric feedback and dynamic blending are able to compensate for variations
in the concentrate solution, whereas systems controlled by pressure, mass-flow, and volume cannot.
Change Management and Risk Analysis
The importance of the dilution process and its influence on subsequent manufacturing processes makes any change to materials,
equipment, or process an important consideration because the dilution process is often one of the first significant steps
in the manufacturing process. The effects on subsequent downstream processes and cleaning must be evaluated.
Quality Control Sampling
In-line dilution equipment with mechanical controls (mass, volume, or pressure) do not reduce quality control (QC) sampling
requirements because the system does not directly control the CPPs. However, systems designed with PAT controls can significantly
reduce QC sampling because CPP data are measured and recorded in real time. This helps reduce the number of deviations typically
seen in the traditional process, which are mainly the result of human error. In equipment designed with PAT controls, the
QC sampling is more of a confirmation that the product is acceptable, unlike the traditional manual process, where QC sampling
plays a much bigger role.
CONCLUSIONS
Automated in-line dilution can help the biopharmaceutical industry overcome some capacity, financial, and quality challenges.
This technology is compact, generates significant savings compared to traditional processes, and adds increased control to
solution manufacturing processes. In-line dilution is a simple and very basic concept with relatively few equipment design
options. Incorporate process analytical technology into this equipment enables superior performance that is consistent with
the principles of Quality by Design and can achieve significant improvements to biopharmaceutical manufacturing and associated
processes. Automated in-line dilution should be considered for new installations and for improvement to existing manufacturing
processes.
ACKNOWLEDGEMENTS
The author thanks Lou Bellafiore, president of Asahi Kasei TechniKrom, for helpful discussions.
This article is based on the article "Automated In-line Dilution—A QbD Manufacturing Method" originally printed in the Journal
of GXP Compliance.
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Brandon J. Patterson is a senior process engineer at Kymanox, Highland Park, IL, 847.433.2200, brandon.patterson@kymanox.com
REFERENCES
1. US Food and Drug Administration. Pharmaceutical cGMPs for the 21st Century—A risk-based approach, Final Report. Rockville,
MD; 2004 Sept.
2. US FDA. PAT—A framework for innovative pharmaceutical development, manufacturing, and quality assurance. Rockville, MD;
2004 Sept.
3. International Coference on Harmonization. Q10, Pharmaceutical quality systems. Geneva, Switzerland; 2007 May.
4. Walker J. Kick-starting PAT to achieve Quality by Design in cGMP bioprocessing. Available from: http://www.technikrom.com/.
5. Patterson BJ. Automated in-line dilution—A QbD manufacturing method." J GXP Compliance. Fall 2008;12(5)20–34.
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