Liquid Measurements in Pharma Manufacturing: Refractive Index as a PAT Tool
Health is a crucially important social and economic asset, and the development of effective drugs goes hand in hand with the development of modern human and societies. We can cure, prevent and manage more diseases than ever. However, with emerging medical conditions and diseases, pharma researchers are constantly looking into new drug developments.
Drugs consists of two parts: the Active Pharmaceutical Ingredients (API), which are the disease healing components, and the appropriate chemically inactive excipients, which are the vehicle delivering the drug to the human or animal body. An important focus in pharmaceutical R&D and product engineering is exploring new API components to develop new, innovative and perhaps in the future, personalized medicines.
The Complexity of Pharmaceutical Manufacture
The development of new drugs is a high-risk, costly and long process. Just to give an idea, The Tufts Center for the Study of Drug Development estimated that bringing a drug to market costs over USD 2 billion, and according to Pharmaceutical Journal, only 1 of every 10 drugs that start the clinical phase make it to the market. Additionally, it takes around 10-15 years to develop a drug, and by the time it is available for sale there could be only 10 years to recoup the high investment cost. To balance the risks involved in making new drugs, many pharma companies manufacture generics, focusing on products from expired patents or slightly modifying a patent.
Other challenges for pharma companies are the tight regulations related to drug manufacturing and the elevated operating costs that follows. Drugs manufacturing requires a system which ensures that the final product meets predetermined specifications. The conventional approach has been to produce drugs in batch processes with separate steps, including lengthy storage times and off-line quality check after every stage. Batch production may even require that the intermediate product is transferred from one facility to another for further production steps. This approach ensures compliance and high-quality products, but it also creates major bottlenecks and inefficiencies in the process, extending the overall processing time and increasing production costs considerably.
This all affects the financial performance of the pharma companies and ultimately the costs of products to the patients and society. At the same time, there is an increasing pressure to bring drug prices down, and as a solution, pharma companies are looking into new ways of working. Many of the industry’s leaders are investing heavily in R&D in exploring technical solutions that can speed-up drug development time and make the process cost-efficient.
Implementing Continuous Manufacturing (CM)
The Food and Drug Administration (FDA) is on the mission to support pharmaceutical innovation and modernization as part of their commitment of protecting and promoting public health. Based on this, the FDA has launched the Process Analytical Technology (PAT) initiative and published a framework, which supports the use of timely measurements and analytical tools that provide means for acquiring sufficient information for process understanding. The PAT strategy also provides the right foundation to move from batch processes to continuous manufacturing (CM) in pharmaceutical and biopharmaceutical production.
To implement CM, a full understanding of the process is required to create a control strategy that minimizes the incoming material variation. The drug’s critical quality attributes must be identified, as well as the production variables that have effect on them, in order to set acceptable deviation tolerances and define the correct PAT tools for monitoring and control. Real-time measurements from the early stages of drug discovery help to collect large amount of data to obtain scientific knowledge to mitigate risks associated with new drug development, and to design robust processes capable of delivering consistently high product quality.
Refractive Index as a PAT Tool
PAT involves not only using the conventional process sensors such as pressure, temperature and pH, but also new in-line analyzer technologies. One emerging technology is refractive index (RI), a direct measurement of liquid concentration based on the refraction of light. RI measurements have been adopted by other industries for decades - for example in pulp and paper for measurement of solid content of black liquor, and sugar industry for Brix measurement in sugar manufacturing - but by the time the PAT initiative started it had still been fairly unexplored in the pharma sector.
A major advantage of RI is that it can be measured in-line by a process refractometer, supporting the current trend in pharma to move towards continuous processing. Process refractometers are mainly used for measuring, monitoring and controlling liquid concentrations. These measurements are also important in pharmaceutical processing as many processing steps are carried out in a liquid medium. But it is in the more unconventional applications where the principle behind the measurement, refractive index, offers many other opportunities for drug development and processing.
Refractive index measurements have proven to be accurate for product identification, even more than density and conductivity measurements, as every chemical has a distinctive refractive index value. This unique characteristic reveals the potential of refractive index as a PAT analytical tool in other applications such as interface detection between different solvents or between solvent and product, and reaction monitoring where the RI value of the mixture changes as reactants become products. In-line refractive index measurements provide a window to the process and information that could not be obtained by traditional laboratory off-line testing.
Refractive Index Brings Huge Potential for Fundamental Process Understanding
A study by a large pharmaceutical company in Europe few years back identified 11 potential applications for refractive index solely in API manufacture. The scientists concluded that when measuring RI in real-time, a process profile specific for the process is obtained, which can be used as a reference for LEAN development and scale-up of the process, and ultimately for reducing considerably the drug development work and time.
The benefits of the refractive index measurements are not limited to API manufacture. The RI measurements are already widely applied in biopharma processing and refractometers are nowadays used for monitoring applications such as fermentation, cell culture, vaccines, protein, blood plasma and enzymes production.
Refractive index is becoming a revolutionary method for creating fundamental process understanding. In addition, it is useful to investigate several process dynamics and chemicals interactions required for the design of cost-effective robust processes and control strategies that reduce product variability. The examples presented above are only a few, but there is no doubt the opportunities will grow, as the pharma companies start looking to the future and refractive index measurements are used to the fullest potential in pharmaceutical processing.
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