June 17, 2014

The Importance of pH Control Throughout Drug Manufacturing

By Jill Jermaine, Sr. Product Manager, pH Measurement

Reducing the risk of product failure during drug manufacturing requires biopharmaceutical companies to implement robust risk mitigation strategies throughout their supply chain. Improving process control parameters will allow for greater lot-to-lot consistency thus decreasing the amount of scrapped batches and product reworks, which ultimately result in lost time and money. Below I will briefly discuss the significance of accurate in-process electrochemical measurements, specifically pH, that take place throughout bioproduction.

A common challenge experienced in upstream manufacturing is to accurately monitor and control pH during the fermentation process. A natural shift in pH occurs due to the metabolic activity of the cells as they grow and consume nutrients in the surrounding medium. This pH change threatens to deliver a reduced product yield since growth conditions are greatly dependent on pH. It’s crucial for process engineers to use precise & reliable pH sensors to ensure process optimization in order to achieve high levels of product yield. A poor in-process pH sensor may report erroneous information and jeopardize the health of the batch which can lead to batch loss.

After the fermentation process has concluded, the protein of interest needs to be recovered and purified. The goal of the purification process is to isolate the therapeutic protein from other impurities, by-products, and potential viruses that were produced during the fermentation phase. Liquid chromatography is a widely utilized method for purification due to its high resolution. Chromatography separation technologies include gel filtration, ion exchange, hydrophobic interaction, and affinity. High resolution during chromatography is contingent upon buffer accuracy since buffers maintain the pH and ionic strength for reproducible purification. For example, faulty pH sensor readings during buffer prep may consequently lead to protein denaturation during ion exchange chromatography. The protein may become unstable at the incorrect pH reading and begin to unfold, therefore resulting in reduced product yield or disposal of the batch.

Lastly, stringent sterilization practices are implemented to safeguard against cross-contamination between product batches. The Steam-in-Place (SIP) method applies pressurized steam in areas where product contact occurs in bioreactors, vessels, ports, etc. during the production run. In-process 338pH sensors experience a reduction in sensitivity and lifespan due to the multiple rounds of thermal shock during the SIP process. The Clean-in-Place (CIP) method typically uses vast amounts of WFI (Water-for-Injection) to rinse and re-rinse between an alkaline-based detergent wash, such as NaOH. Overtime the NaOH tends to leach the pH glass electrode causing a reduced reading response time and inaccurate measurement. Therefore, it’s critical to select pH probes that can withstand high temperatures and chemical attack.

For superior pH measurement and control during bioprocessing, the Rosemount Analytical Hx Series sensors are ideal. Our Hx Series pH sensors feature the latest innovations in reference and electrolyte technology by providing bioprocesses with the unique Tri-Triple reference technology. Tri-Triple reference is comprised of three overall reference junctions working together to help maintain a drift-free pH signal with the use of a special electrolyte solution to withstand high protein and salt concentrations, even after numerous sterilization cycles. The specialized design of the Hx Series sensors meet the critical needs of the life science industry. For more information on pH measurement in biopharmaceutical manufacturing, click HERE.