With the pressure on API manufacturers mounting as efforts to develop vaccines and treatments for COVID-19 evolve, pharmaceutical companies want to partner with an API manufacturer they can trust. Dr. Benzion Dolitzky, VP R&D at Wavelength Pharmaceuticals, discusses some of the challenges of scaling up API production in the midst of the pandemic and explains how Wavelength has successfully tripled and quadrupled its output of several urgently needed APIs without compromising on quality.
Common challenges of scale up
Scaling up drug production is a notoriously challenging exercise. A multitude of factors can affect product quality and yield, meaning that transitioning from lab-scale production to a scale suitable for commercial supply necessitates an in-depth knowledge of process design.
According to Dolitzky, switching from small-scale to large-scale is by no means a 1:1 operation and instead involves comprehensive process characterization and control of critical parameters to ensure scale up is successful the first time.
“Gathering sufficient knowledge about the critical parameters in each of the manufacturing process steps puts you in a strong position to perform troubleshooting should you run into any unexpected challenges,” he said. “For instance, even something as seemingly trivial as altering the geometry of a vessel or the design of a mixing impeller can have serious adverse effects on reaction dynamics and product properties. Understanding the potential impact of such changes is key to avoiding these issues and means you can readily increase production capacity at a later stage.”
Successfully scaling up production also requires having the right equipment to do the job. Where additional instrumentation must be purchased, this not only involves identifying equipment that is fit for purpose, but also installing it and subsequently qualifying and validating its performance. “The COVID-19 pandemic has led many companies to bring in additional technologies to increase capacity,” said Dolitzky. “However, purchasing equipment can be a lengthy process involving decision-making at multiple levels. Staying ahead of the game means maintaining a current working knowledge of both new and existing technologies to streamline selection and integration of equipment when the time comes.”
Another major challenge of scale up relates to the supply chain since it is widely recognized that using multiple API suppliers does not necessarily guarantee uninterrupted drug production.
With many API manufacturers sourcing raw materials from a shared provider, continuous drug manufacturing can be jeopardized should that provider suddenly become subject to restrictions or experience unforeseen delays in acquiring raw materials. “Communicating frequently with providers and understanding the measures they are taking to secure their own supply chains and assure consistent quality of product is vital to understand rolling forecasts as well as retaining sufficient stock levels of starting material for API production,” said Dolitzky. “Having that transparency prevents any unwanted surprises that can ultimately impact on manufacturing the final drug.”
Practical measures to support increased demand
Acknowledging the many different challenges of scale up is the first important step toward implementing effective solutions to deliver on increased demand. This translates to performing rigorous process design; using equipment and methods representative of commercial processes during scale up; and meticulously qualifying suppliers of raw materials and intermediates in order to identify and address potential problems.
“When process design is done properly, it inevitably paves the way to more efficient scale up,” said Dolitzky. “For example, within our capacity as a CDMO, we’ve noticed that some of the technology packages we’ve received to support tech transfer programs have had significant gaps. It is this missing information that differentiates between a scale up that goes to plan first time and a scale up that requires considerable troubleshooting efforts.” One way of closing such gaps is to leverage an API manufacturer’s vast multidisciplinary expertise. Having encountered many similar problems before, an experienced team will be well-practiced in problem-solving within a short time frame, allowing any missing data to be generated before moving to scale.
“Having the internal capability to react quickly to an issue or support a sudden need for increased production is vital to keep projects on track,” said Dolitzky. As an example, he describes how Wavelength recently identified a potential bottleneck in one of the drying processes used to manufacture a product experiencing hugely elevated demand as a result of COVID-19. “By increasing the production capacity of one of our wet manufacturing processes, we quickly became aware that downstream lyophilization could become a major limiting factor in delivering the end product to our clients,” he said. “By improving the existing drying cycle, we were able to shorten the drying time, thereby increasing the throughput of the entire process. Then, to further enhance production, we quickly purchased and installed another lyophilizer, using our existing knowledge to rapidly validate the process on the new equipment.”
Expanding on this point, Dolitzky stresses the value of continuous investment in back integration of strategic products. “Our approach to develop additional synthetic steps for manufacturing strategic products from simpler, more readily available starting materials has once again demonstrated its worth during the COVID-19 crisis,” he said. “Having the option to apply these steps in-house if required, or to transfer the knowhow for quick implementation by an alternate supplier, is an important contingency with proven utility across many different projects.”
As for moving quickly on complex projects with challenging timelines, company size can be highly relevant when it comes to decision-making. Typically, in smaller companies with senior management more accessible and involved for rapid decision-making, an API manufacturer can respond more dynamically to changing customer needs. Dolitzky notes that transitioning to increased scale can also be expedited by having a shared commonality across equipment and processes used for small-scale and large-scale production. “During scale up, the quality and yield can be affected by many different variables,” he said. “By ensuring consistency at the equipment level as production increases, the risk of introducing additional factors that can impact key product parameters is greatly reduced.”
Irrespective of the vast amount of effort an API manufacturer has put into process design, assuring reliable delivery of the finished product hinges on having a robust supply chain in place. “At Wavelength, we carefully select our suppliers based on their quality processes and regulatory track record,” said Dolitzky. “This includes qualifying at least two suppliers from different geographies for key starting material so that we have a back-up in crisis situations such as that presented by COVID-19. By working closely with our suppliers to plan ahead, typically on a rolling 12-month basis and with supplies coming in continuously over that time, we ensure we have sufficient starting material to avoid shortages. This has been fundamental in allowing us to respond to increased demand from countries worldwide as the pandemic hit.”
Proven success in meeting COVID-19 demand
Midazolam, Cisatracurium, and Rocuronium are examples of drugs that have experienced massively increased demand as a result of the COVID-19 pandemic. Used as a first-line approach in the management of COVID-19 patients being placed on mechanical ventilation, the drugs’ availability became a major concern early on. By being closely aligned with this need, Wavelength was able to rapidly triple and quadruple API production for all three drugs, thereby meeting the needs of global customers and providing a lifeline for patients ventilated in critical care.
Approaches employed by Wavelength to assure continuity of operations and supply during the COVID-19 pandemic included changing shift patterns to allow for 24/7 manufacturing while maintaining social distancing in fixed ‘capsules’; implementing e-meetings; and introducing additional PPE measures to ensure the safety of personnel.
“The time and effort we’ve invested in supply chain assurance over more than 30 years enabled us to react extremely quickly to the current crisis,” said Dolitzky. “By rapidly expanding our manufacturing capacity in response to global demand, we were able to support pharmaceutical manufacturers, public health and government agencies, and group purchasing organizations (GPOs) for hospitals across multiple geographies through increased supply of these urgently needed drugs. Moreover, by continually improving our manufacturing processes and our expertise in scale-up, we continue to drive current efforts toward tackling the pandemic, as well as being prepared for additional waves of COVID-19 infection.”
Ilan Avni – B.Sc. Pharm, MBA, is VP Business Development, Marketing & IP at Wavelength Pharmaceuticals. Mr. Avni has over 20 years of experience in the global pharma, API and medical devices industries, serving in various business development, pipeline, portfolio and strategic account management roles.