Developing and manufacturing accurate reproducible APIs

The measurement of refractive index (RI) is employed by a wide variety of industries to determine the level of dissolved solids in liquids. This is an important but relatively new measurement in the development and manufacture of active pharmaceutical ingredients (APIs) at laboratory scale, pilot plant scale and industrial scale in pharmaceutical manufacturing and processing plants. 

Background

As manufacturers of APIs continuously implement the FDA’s Process Analytical Technology (PAT) and try to comply with GMP guidelines, the requirement for continuous process monitoring grows. Real-time data provides insights and opportunities for process design, control, troubleshooting, and optimization, as well as quality control and cost savings.

RI is a tool for PAT, capable of providing sufficient process understanding that helps in the design, analysis, and control of pharmaceutical manufacturing processes. Data collected through RI measurements can be used for example to identify and set deviation tolerances for critical process parameters (CPP) that have a direct impact on the quality and safety of the final drug. 

In order for measurement technologies to be suitable for pharmaceutical processes, there are a number of essential requirements. Firstly, documentation should be available to qualify specification and performance criteria, as well as confirmation that all materials are pharmaceutical grade, with appropriate testing and traceability. Secondly, the measurement should be accurate, reliable, and easily scalable. The technology and equipment used must be the same and capable of providing reproducible data that can ease process validation at lab, pilot, or full scale. Thirdly, data authenticity should be protected, with all measurements permanently stored electronically, and with tracking and attribution of any additions or amendments. Finally, evidence of traceable calibration should be available, in addition to regular, documented performance verification.

The Refractive Index principle

Refractometers determine the concentration of dissolved solids by making an optical measurement of a solution’s refractive index (nD) and temperature. The RI measurement is based on the refraction of light in the process medium, known as the critical angle of refraction, using a yellow LED light source with the same wavelength (580 nm) as the sodium D line (hence nD). The concentration is calculated taking pre-defined process conditions into account. So, Vaisala’s refractometers are supplied factory calibrated to meet the specific process requirements. These instruments are also able to provide measurements in different scales, such as Brix, liquid density, or concentration by weight.

Importantly, the refraction of light is not affected by particles, bubbles, crystals, or color, so RI instruments can be employed in a wide variety of solutions for liquid identification and for monitoring the concentration of chemicals, solvents, and liquid pharmaceuticals. 

Advantages of RI in pharmaceutical processes

In general terms, the monitoring of RI can improve the understanding of process conditions, reduce drug development time, increase production capacity and stability, improve product quality, and demonstrate compliance with regulations. Pharmaceutical manufacturers are required to demonstrate process validation from drug discovery to full production; this can be achieved through RI measurements which provide a unique process profile that can be used for validation at any scale.

All solutions have a specific RI value, which changes as the reaction proceeds. This means that RI monitoring can provide insight into the reaction and extraction processes as well as chemical identification. Changes in RI can therefore be used to track the progress of the reaction and to determine the end-point. For example, where products are extracted from natural materials such as plants, RI measurements can be employed to determine the optimal time for extraction to finish.

In some processes, it is necessary to conduct a solvent swap in order to facilitate subsequent processes such as distillation. The correct mixture of original and swap solvent should be maintained during the various steps of this process and RI monitoring is ideal for this application. For example, a Vaisala customer utilized an RI monitor during the scale-up of solvent swap operations from laboratory to pilot plant and discovered that one of the swap steps could be eliminated, which resulted in an increased yield of over 6%.

Many processes produce APIs through crystallization from the liquid phase. The aim of this process is to maximize the yield of high-quality pure crystals that are easy to process, whilst avoiding fines and conglomerates by ensuring good particle size distribution. This can be achieved by maintaining the concentration and temperature above the solubility curve or supersaturated level. Continuous monitoring of concentration by RI offers major benefits for crystallization control because this method is not influenced by crystals or bubbles, so selective monitoring of the mother liquor concentration is simple. By monitoring mother liquor saturation, it is also possible to determine the optimal seeding point.

It is normally necessary to wash produced crystals with solvent to remove impurities and any remaining mother liquor from the filter cake. This process must be carefully controlled to maximize yield and avoid product dissolution. By monitoring the RI of filtrate it is possible to determine the end-point of cake washing which helps maximize yield, saves time, and avoids excessive solvent usage. These measurements also enable the differentiation between clean and saturated solvents with the API and between different solvents. This means that at the end of the washing process, if the RI value is closer to the saturated value than the pure solvent value, some of the product must have been washed out, indicating that a process revision is required.

Summary

The critical quality attributes of drugs must be identified, as well as the production variables that affect them, in order to set acceptable deviation tolerances and define the correct PAT tools for monitoring and control. RI measurements represent a simple but hugely valuable tool in the development and operation of API production processes, providing valuable insights into the key processes, facilitating optimization and process control to deliver accurate, reliable, reproducible products.

The Vaisala RI instruments that were initially developed by K-Patents have been designed for application in the pharmaceutical industry, with full scalability so that drug development and process design can be undertaken seamlessly from the lab to full-scale production.