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Agnes Shanley is senior editor of Pharmaceutical Technology.
Chemical engineers and chemists each bring unique skills to API process development and optimization. Success depends on their close collaboration, at both sponsor and CDMO facilities.
In API development, a clear strategy is crucial to ensure that a new compound doesn’t end up with the 90% of new molecules that fail during clinical testing. Process development and scaleup are extremely challenging, drawing upon the complementary skills of chemists and chemical engineers, and employing methods advanced by pharmaceutical quality by design (QbD).
The end goal is a safe and scaleable process that is rugged (i.e., reproducible on scale, while ensuring quality and the right level of process control), says San Kiang, research professor at Rutgers University’s chemical engineering department. The process must be able to provide enough material for clinical trials, even though it has not been finalized or commercialized.
Mr. Kiang shared best practices with Pharmaceutical Technology, along with Shyam Vispute, general manager, technology transfer, at Neuland Labs, which opened a new process development and optimization center in India in March 2017. Here is some of what they had to say.
PharmTech: What are the different goals at each phase of process development?
Kiang (Rutgers University): At the earliest stages, you’re in a hurry. You want the process to be expedient and to produce the material quickly. You really do not have time to look at efficiency and cost. You just want to make the product to get to the end of Phase I. In Phase II, you want to emphasize practicality so that the process will scale up reasonably well. At this point, efficiency and cost start to enter the picture, but process optimization isn’t really needed until Phase III.
PharmTech: How do you measure the efficiency of pharmaceutical process development?
Kiang (Rutgers University): The chemical route is very important, and engineers seek to reduce the number of chemical steps required. ‘Process intensity’ indicates how many resources are used to product a given quantity of product.
Other key questions are whether the product can be made using existing equipment and whether it will require exotic starting materials that might be difficult to source. Minimizing waste is also crucial to reducing the environmental impact, and the cost of that impact, and, thus, to minimizing overall manufacturing costs. The key disciplines required are reaction engineering; pharmaceutical engineering, which operates at the point where engineering, pharmacy, and chemistry connect; and safety engineering. In a reaction lab, you look at reaction kinetics and try to derive the reaction mechanism, or diagnose and troubleshoot problems with a reaction that you’re working on. Catalyst screening is also important, as are separation and purification, notably through process chromatography, which is used to make materials in early-stage development.
PharmTech: How do chemists and engineers collaborate on process development?
Vispute (Neuland Labs): Chemical engineers are involved in process development right from the beginning, with route selection and finalization. More interactions with chemists occur, however, once the process’ feasibility has been confirmed. Once the process has been shown to be able to manufacture compound that meets quality specifications, engineers must evaluate the process from the safety, health, and environmental standpoint. Their contribution is crucial, since they have studied the unit and process operations involved and have a clear understanding of critical utility and hardware requirements.
They also generate process safety data, using software to screen relevant examples from the literature, and performing thermal and hazard studies in order to develop an inherently safer process.
In addition, they generate data on material balances, perform energy balances to evaluate the utility requirements for plant scale, and select equipment for commercial-scale production, whether for retrofits or new facilities.
They also scout for new technology and see its potential to improve results, given the specifics of the process (i.e., the volume of products, safety threats, troubleshooting activities related to the commercial products, and the need for capacity enhancement).
Chemical engineers also lead quality and safety risk assessment efforts, including hazard and operability studies (HAZOPs), hazard identification and risk analysis (HIRA), and powder safety characterization studies.
They are also involved in particle engineering, which requires the evaluation of particle size, bulk density, surface area, and any polymorphs and their effects. This area is extremely important, and is typically done before scaling up in order to ensure that the product achieves the desired physicochemical properties.
Chemists, meanwhile, select the best synthesis route, and determine the feasibility of that route. They are also involved in optimizing and validating the process to meet the predefined quality and yield levels.
Both chemical engineers and chemists work collaboratively and must understand the critical process parameters (CPPs) and critical quality attributes (CQAs) of the process during development phases.
Chemists are experts in various types of synthetic reactions, based on the literature search and experience. They identify and characterize process impurities that could have an impact on product quality.
In addition, chemists are involved in ensuring that the process achieves the desired quality and performance specifications. They generate and qualify reference and working standards, and must interact continuously with the business and legal departments to guard against any potential patent infringements.
Engineers and chemists work closely together to plan the scale up campaign and to hand the process over to manufacturing via the technology transfer campaign report. This documented evidence of knowledge and experience connects both chemical engineers and chemists, including process and analytical chemists, ensuring that the process and product meet quality and regulatory requirements.
PharmTech: Broadly speaking, what are the key requirements for getting QbD to work for drug substance process development? How might those goals differ from those for QbD of drug product?
Vispute (Neuland Labs): Successful implementation of a QbD approach for drug products requires three fundamental elements: a clear understanding of the target product profile, which is drawn from the knowledge base around the product; determination of the product’s CQAs, within an appropriate range limit or distribution, to ensure the desired product quality; and the design, implementation, and optimization of a process to manufacture the product.
This last step is very important and includes risk assessment to evaluate the impact of raw material attributes and process parameters on the CQAs; development of an experimental method and design space (using design of experiment [DoE]); and creation of a process-control strategy that makes efficient use of multivariate analysis and feedback systems.
The main goal is to assess various parameters and what-if scenarios before taking a process to the manufacturing plant to increase the likelihood of ‘right first time’ technology transfer.
A QbD approach to manufacturing process development should include the following elements:
QbD for drug substance involves understanding the chemical conversions that will have an impact on the drug product. Some of the parameters are controlled, while others may be peripheral noise. In order to address variation in process parameters, it is necessary to develop a design space and to identify the CQAs that have the most significant impact on the drug product.
Supplement: Partnerships in Outsourcing2018
When referring to this article, please cite it as A. Shanley, “QbD and API Process Development: A Marriage of Chemistry and Engineering," Pharmaceutical TechnologyPartnerships in Outsourcing2018 Supplement (February 2018).