Improving scalability and efficiency of production in process chromatography

Healthcare industries specifically the pharmaceutical, health supplement and nutraceuticals industry and researchers make use of adsorptive and chromatographic separation and purification processes for various products such as fermentation-based products, proteins, peptides, enzymes, antibiotics, vaccines, natural products, sugar, antioxidants, many synthetic API and ingredients.

Many challenges are encountered while using these chromatographic systems during process development. These include less or no pulsation in flow, ability of pump system to pump the liquid at a required pressure/backpressure without compromising on flow rate, low shear (specifically in case of proteins, enzymes, peptides etc.), accuracy of flow, dead volumes, and scalability from small to large scale distinguishing industry practices.

We often process fragile and, in many cases, expensive products that require gentle and sensitive handling. To produce medicines, drugs and new generation health supplements, natural products within Good Manufacturing Practice (GMP), we must be sure that that we create them precisely with what we expect to deliver and that we can do so with reliability and accuracy in the quantities the world requires.

GMP consists of a strict set of rules and procedures for laboratories and scale up sites for production of pharmaceuticals for clinical investigation, validation, and market-purpose manufacturing.

We must be sure that that we create [products] precisely with what we expect to deliver and that we can do so with reliability and accuracy in the quantities the world requires

These broad-reaching ordinances encompass all facets of the process, from the analytical specifications required for chromatographic analysis acceptance to how pilot and production scale processes are done with adsorptive and chromatography and other unit operations, extending to how chemicals in the lab are labelled and handled.

Pharmaceutical, health ingredients and nutraceuticals manufacturing specifications can and do vary by country and region. However, there are some standard requirements in case of preparative and process chromatography, including limit to leachables/extractables, a steady baseline with quantitative limits for this, reduced or no carry over, pressure and flow stability, constant flow delivery, maintaining materials’ molecular integrity and peak shape.

During the last decade, the Indian pharmaceutical industry has been making strides in many of these areas. Sanovaskale is overcoming obstacles through research and development, scale up to pilot scale for validation and then scale up to production levels through technical design, engineering, system integration and intensification, manufacturing efficiency, and economic viability.

Pharmaceutical, health ingredients and nutraceuticals manufacturing specifications can and do vary by country and region. However, there are some standard requirements in case of preparative and process chromatography

A smooth liquid flow with minimal pulsation is critical in increasing efficiency, accuracy and manufacturing consistency within a preparative and process chromatography, preparative high-performance liquid chromatography (HPLC) etc. for pharmaceutical and other healthcare manufacturing processes.

Pulsating liquid flow is proven to cause numerous problems, including reduced separation efficiencies, peak shape, peak profile disturbance leading to extra volume in effect during elution, pressure variations, and detection inaccuracies.

The need for extremely low pulsation pumps for process chromatography and pre-HPLC systems has become crucial for pharmaceutical and even for allied industry applications, where legislation on chemical composition, reproducibility and precision is highly stringent.

For example, in one case we were metering a solution with 50%v/v and 80%v/v isopropanol in water as the solvent, a flammable material, dosing aqueous hydrochloric acid (5%w/v) and sodium hydroxide (6%w/v) at flow rates from 30 LPH to 7.5 m³/h flow at a pressure in the range of 4 to 30 bar.

We required a smooth-flowing, high-accuracy, low-maintenance pumping solution with a minimal footprint that did not require pulsation dampeners. Secondly, most detectors used in liquid chromatography systems are sensitive to the system's flow and pressure. As a result, a pulsating flow will result in an inconsistent detector/sensor signal and thus the baseline, significantly impacting elution profile, volumes and quantitation.

This can be particularly problematic when looking for small peaks, such as known impurities, chromatographic concentration and separation steps. A stable baseline/signal from sensors and detectors with no peaks is routinely part of the specifications required for a process and prep-HPLC chromatogram to be in accordance with GMP.

In column chromatography, sudden changes in flow can adversely affect column peak broadening and resolution between two closely migrating products, reduced separation efficiency shown by HETP and number of plates under such conditions, column health wherein column packing quality or chromatographic bed is affected.

This is particularly important in HPLC (both small and large scale), where columns and resins or adsorbents are often re-used and have significant replacement costs. Furthermore, changing columns mid-project can affect results, as a new column may change retention times and quantitation.

Having the right selection of pump for preparative and process chromatography systems, in continuous chromatography and in continuous synthesis/conversion using microreactors, is crucial

Inconsistent liquid flow caused by pulsation can compromise the integrity of chromatography system tubing or piping. Repeated compression and relaxation reduce the lifespan of the tubing material and will require more frequent replacement.

Further, in few cases, preparative and process chromatography requires constant flow delivery at a certain backpressure, without which operation is not possible and under such cases, the pumps have given excellent results and reproducibility at our site with small and large scale critical chromatographic separations.

Generally, columns are packed at site in case of pilot and large scale preparative and process chromatography, and therefore, any issues occurring with the column due to flow pattern, calls for long downtimes due to the need for unpacking and repacking, qualifications and thus significant delays in operation and production.

Wherever, pre-packed columns are used, it may be just replacement of column is required, but column replacement with new column in case of process systems is a very costly affair and impacts product operating cost. Therefore, constant and non-pulsating flow is important.

Adding a pulsation dampener can alleviate many of these issues; however, it adds additional costs to the set-up and system maintenance and adds an extra component susceptible to problems or leaks, and moreover residuals or tailing effect for phase change during the operation in process chromatography.

Dampener also leads to carryover effects. For instance, due to the harsh nature of the chemicals used in process, a Hastelloy pulsation dampener will be needed—it can cost $4,000 or more and require periodic, if not continuous, monitoring.

It's clear why handling pulsation is so vital to the industry. After conducting trials with several pump technologies, we found the solution to deliver all these benefits in the Wanner Hydra-Cell seal-less diaphragm pump which achieved a virtually pulse-less flow with extremely low shear, essential in keeping the process solutions intact and undamaged.

The pump gives accurate meter readings without the use of dampeners, and reduces the maintenance required and footprint of the system. This efficiency and accuracy are also achieved over a large turndown ratio due to the patented technology. The consistency achievable for flow allows for a consistent signal from sensors and detectors used, stable baseline so that consistency and quantitation is highly accurate.

In another case, the company switched to continuous production and implemented the Wanner pump, which reliably handles corrosive liquids, with low pulse, and requires minimal service and maintenance. It is now accurately dosing chlorinated mass in ethanol within a flow range of 30-80 LPH at a pressure of 10 bar.

Further, we also work on continuous processes of microreactor based synthesis, catalysis and biocatalysis from development to scale up. In these applications also a consistent flow at a particular constant pressure is important to achieve quality results.

In conclusion, having the right selection of pump for preparative and process chromatography systems, in continuous chromatography and in continuous synthesis/conversion using microreactors, is crucial. Moreover, it has significant impact on cost of the product and affordability.

Low or no pulse, inertness, pressure stability and flow delivery, compatibility of material and available selection for various chemicals, qualification, ATEX certification in case of solvents usage, low maintenance, low power consumption etc. are the key features which has helped us to build efficient chromatography systems for research, pilot scale and large-scale chromatography and synthesis using microreactors.

Dr Smita Sandeep Kale is managing director of Sanovaskale Technologies in Pune, India