Purdue efforts drive first consensus standard for freeze-dried pharmaceuticals

Most people are familiar with freeze-drying (lyophilization) of foodstuffs, like coffee, fruit and vegetables, but it's a big deal in the pharmaceutical industry too, to increase the shelf life of pharmaceutics and biologics prior to their reconstitution and administration as vaccines and antibiotics.
Man working in lab

Lyophilization has been particularly covered in the news lately, as pharmaceutical companies working on COVID-19 vaccines are seeking to freeze-dry their ingredients, to eliminate the complex cold chain required to maintain temperature during transport and storage at vaccination jab sites. This is especially crucial in rural areas and underdeveloped countries, which may not have the expensive equipment needed to store the vaccines at the requisite temperature settings prior to inoculation.

But lyophilization has its own demanding requirements and specifications too, and “it’s crucial that lyophilization best practices be codified into recognized consensus standards,” said Alina Alexeenko, professor of Aeronautics and Astronautics & Chemical Engineering and Associate Dean for Undergraduate Education at Purdue’s College of Engineering. “This helps to consistently develop and evaluate new products as well as manufacturing and measurement methodologies and maintain consistent quality through repeatable transparent processes. This ultimately helps medicines to be developed faster and manufactured ensuring safety and quality.”

In 2021, the American Society for Testing and Materials (ASTM) issued a new standard, ASTM E3250-21, Standard Practice for Product Temperature and Equipment Pressure Instrumentation in Pharmaceutical Freeze Drying. Much of the standard incorporated findings are laid out in a paper Alexeenko co-authored, a collaborative effort among members of Purdue University’s Advanced Lyophilization Technology Hub (LyoHUB), which was aided in its consortium development with support from the National Institute of Standards and Technology (NIST).

The paper, Recommended Best Practices for Pharmaceutical Freeze-Drying Process Instrumentation, while recognizing the need to protect intellectual property, emphasizes that there are areas where industry can benefit from information sharing and standards — in this case, for pharmaceutical freeze-drying. The paper sets out recommendations for measuring and monitoring product temperature and pressure within the freeze dryer, along with equipment capability testing. Temperature and pressure are vital variables that affect things like heat transfer, process efficiency and product quality.

The ASTM standard, taking the paper’s lead, focuses on best practices for freeze dryer instrumentation, with emphasis on monitoring the status of product for temperature and pressure. It examines and clarifies sources of uncertainty around measurement probes, and the differences between temperature-measuring instruments like thermocouples and resistance temperature detectors. On the pressure side, it considers and issues recommendations for pressure transducers — specifically, thermal conductivity type gauges and capacitance manometers for the dryer’s product chamber and condenser.

LyoHUB led the multi-year effort to deliberate the details of this first recognized consensus standard for pharmaceutical lyophilization. The technology hub, headed by Alexeenko, is a university-industry center whose goal is to advance the science and technology of freeze-drying/lyophilization as used by pharmaceutical, food, biotechnology, and nanotechnology manufacturers.

LyoHUB members include companies in the pharmaceutical and food processing sectors, equipment manufacturers, and university researchers. Its members engage in “pre-competitive” collaboration to develop technology roadmaps; identify and disseminate best practices for equipment performance, testing and validation; and conduct applied research to advance lyophilization processes and products.

The participants’ collegial, cooperative approach was vital to forging agreement on the best practices that would constitute key elements of the standard. “The consensus-building process took time, to carefully review and consider all aspects of the process across the extended value chain of stakeholders, through a series of workshops and collaborative events with ASTM at Purdue,” said Arnab Ganguly, principal engineer for pivotal drug product technologies at Amgen, chair of ASTM subcommittee E55.05.

LyoHUB also worked to establish an ongoing ASTM subcommittee on lyophilization. This subcommittee’s mission is to develop, disseminate and educate standard practices and guidance relevant to lyophilization of parenterals and other pharmaceutics and biologics for the manufacture of pharmaceutical and biopharmaceutical products. ASTM E55.05 is currently working on establishing best-practice guidance on equipment performance validation and commercial scale-up, and will be looking to convert these best practices into standards very soon as well.

“ASTM E3250-21 is a significant accomplishment,” Alexeenko said. “In 1996, U.S. Congress enacted the National Technology Transfer and Advancement Act, which requires the federal agencies and departments to utilize technical standards developed by voluntary consensus standards organizations whenever possible. Purdue is proud of its faculty involvement in such an important pharmaceutical standard, which may help to combat the pandemic.”