Automated in-line dilution is an increasingly popular technology in the biopharmaceutical industry. In-line dilution is a process that can help solve capacity, financial, and quality concerns that biopharmaceutical manufacturing plants may be facing regarding process solution preparation and delivery. This technology has several applications in biopharmaceutical manufacturing, such as purification processes, chromatography systems, solvent adjustment, pH adjustment, and cleaning systems. The fundamental aspects of automated in-process dilution systems are discussed, including engineering considerations, equipment components, process materials, operation, maintenance, and quality considerations.
ADVANTAGES OF AUTOMATED IN-LINE DILUTION SYSTEMS
The use of automated in-line dilution systems provides very significant advantages to biopharmaceutical manufacturing. One of the many concerns in biopharmaceutical facilities is capacity; biopharmaceutical companies are now obtaining much higher fermentation and cell culture yields than in the past, leading to capacity shortages in downstream processing equipment. Another challenge is manufacturing at large scale. Manufacturing 10,000-L batches of process solutions in large tanks is inherently difficult. Making a 1-L solution in a laboratory can be done very precisely using analytical instruments that are calibrated at milligram sensitivity. In contrast, making a 10,000-L solution requires load cells or level probe technology with much less precision. Mixing at large scale necessitates mixing studies and process validation to ensure that the mixing process is reliable and repeatable.
In-line dilution technology provides significant advantages compared to traditional large-scale processes because the mixing and preparation was actually being done at a small scale; compare the holdup volume of the in-line dilution skid versus a 10,000-L buffer prep tank. In addition, in-line dilution processes can incorporate feedback control with mixing to achieve highly accurate solution concentrations.
It is not uncommon for organizations to hesitate or be uncertain about implementing new technologies. There is comfort with traditional processes where there are known failures and a general knowledge of how they are addressed. In addition to addressing new process methods, biopharmaceutical manufacturers must consider recent US Food and Drug Administration and International Conference on Harmonization (ICH) guidelines.1–3 These guidances urge companies to use process analytical technologies (PAT) in support of quality by design (QbD) and continuous improvement initiatives. The thought of incorporating PAT adds another level of complexity to adopting new process methodologies.