Can Standards Help Pharma Modernize Lyophilization?
ASTM’s E-55.05 committee aims to turn best practices into industry standards in order to eliminate variability and allow a 70-year-old process to leverage 21st century tools, technologies, and practices.
Lyophilization, or freeze-drying, carne into prominence during the 1940s after early experiments in the mid 1930s at the University of Pennsylvania, when it was used to prolong the stability of blood plasma and treatments such as penicillin, allowing them to be shipped long distances without losing efficacy. The process has been a mainstay of the pharmaceutical industry ever since and has become essential to biopharmaceutical manufacturing, as treatments such as monoclonal antibodies assume greater importance. Currently, more than half of the injectable drugs sold have been lyophilized.
Lyophilization involves removing solvent such as water from a substance by first freezing and then sublimating the ice to vapor. The three stages of the process are freezing, primary drying, and secondary drying. Despite its importance , the process itself has seen relatively little change since it was introduced decades ago, even though process understanding has improved by leaps and bounds. This has led to a disconnect between current practice and market needs. LyoHub, a consortium of pharma and biopharmaceutical manufacturers, equipment designers and suppliers, researchers, and academics with participation from regulatory bodies, headquartered at Purdue University, is trying to address this problem. The group has established a Technology Roadmap, prioritizing efforts and areas for improvement (1).
In 2017, the group published best practices for instrumentation (2). LyoHub is now working with the American Society for Testing and Materials International’s (ASTM’s) E-55 Committee to make these best practices into industry standards.
ASTM provides an open and balanced process for standards development. With stakeholders around the world, E-55 members can participate and maintain an equal voice in the development and approvai of standards, explains Travis Mur dock, manager of ASTM’s technical committee operations. “Participation within E-55 is open to any and all stakeholders with interests relateci to the standards being developed,” he says.
“There is a need for lower cost, better product quality, improved compliance, and consistent quality for each vial of product within the same batch.” Ferdinando Aspesi, ASTM
LyoHub was attracted to the transparency and inclusivity of standards setting via ASTM, says Ferdinando Aspesi, chair of the organization’s E-55 committee for pharmaceutical and biopharmaceutical manufacturing. “It’s a place where one can write standards for any industry, to ensure that the best science and technology available are used to protect patients and to standardize the ways we develop and make products and establish how to’s for consistent results backed by sound rationale.
Lyophilization was a natural fit for standardization, he explains, since it has been widely used for decades. Although the industry has automated more equipment and processes, the basic approach to lyophilization has not been modernized, and the practices are sometimes based on legacy rather than sound rationale. Moreover, the process is inefficient and costly, he says.
One of the biggest problems is the conservative design of the process due to lack of knowledge of the process and equipment limits. Even though more pharmaceutical manufacturers are moving
to smaller batches of product, lyophilization is still mainly clone on a grand scale, with 50,000 to 100,000 vials typical per batch. This leads to vari ability with scale, Aspesi says. Because all vials are not exposed to the same drying conditions, the result could lead to variable product characteristics. “This is really a physics problem, and results in process inefficiency as well as quality issues,” he notes.
The industry has realized that it doesn’t need to process so much materiai at one time, says Aspesi.
“Equipment manufacturers are responding by changing designs. Where lyophilizer shelves used to target 50 m2 in the past, some vendors are now looking at 1 m2.” There is also a need to optimize lyophilization for use in biopharmaceutical manufacturing, particularly for monoclonal antibodies, bioproteins, and cell therapies, he says.
LyoHub drove the formation of E-55.05, which currently involves over 100 representatives from bio/pharma manufacturers, equipment designers and suppliers, researchers, and acadernics. Representatives from FDA and NIST are also participating in the group. Arnab Ganguly, chair of E-55.0S’s new subcommittee on lyophilization and scientist/technology manager at IMA Life and formerly at Purdue University’s School of Aeronautics and Astro nautics, shared insights into E-55.0S’s goals with Pharmaceutical Technology.
The road to standard setting
PharmTech: Why did LyoHub establish the standard committee? A. Ganguly: Efforts began about four years ago, stem-ming from informal conversation about what we could do to promote industry and academic collaborations to advance lyophilization. One problem was the fact that there were few or no best practices documents. LyoHub identified some priority areas, focusing on process instrumentation, equipment qualification, and scale-up/tech transfer.
Freeze-drying has existed for a while, and while process instruments have improved, quite often the technology is decades old. The question was: Can we provide a set of best practice guidance documents to use with process instrumentation for monitoring lyophilization processes?
The first effort was led by Steve Nail at Baxter, and the resulting paper coauthored by eight others and published in February 2017. It has generated aver 3900 downloads since and a great deal of discussion within the industry (2) that has also involved regulator participation.
While we realized that it was important to publish this work, the real success would come from seeing these practices implemented across industry.
We realized that we needed to find a path and to provide guidelines needed to bring into place some form of standardized practice.
Discussions began at the ISLFD conference in Cuba. Ali Afnan, a member of the original FDA Process Analytical Technology (PAT) team and previous
chair of ASTM’s E-55 committee, suggested that standardization would be the best way to go about this. Within a few months, we put together plans for a committee and its scope. The goal was to move from guidance to standard with the different best practice initiatives starting with the document on process instrumentation applied to freeze-drying.
Two other best practice papers are now in progress: one on equipment qualification for freeze dryers, which I am leading, and another on scale up and tech transfer which is being led by Serguei Tchessalov and Bakul Bhatnagar at Pfizer. We expect to publish the equipment qualification standard by June 2018 and the tech transfer paper by Spring 2019.
Process instrumentation focus
PharmTech: What did you focus on, in process instrumentation? Ganguly: Accurate process monitoring and control for critica! process parameters such as pressure and temperature is crucial in the freeze drying process. Yet, we find that there are situations where the choice of instrumentation, its placement, or even the usefulness of the same, leads to lengthy debate. Here we focused broadly on monitoring/controlling pressure in the freeze dryer during the process and best practices in monitoring the product temperature. A brief discussion on developing technologies is also presented. PharmTech: What will tomorrow’s PAT tools for lyophilization be? Ganguly: Upcoming technologies that are proving to be important in this area include wireless sensors, tunable diade laser absorption spectroscopy (TDLAS) for real-time vapor flow rate monitoring, and heat-flux sensors. In addition, mass spectroscopy can provide gas composition and contaminant detection down to few ppm. The best practices papers are meant to be living guidance documents. The year is incorporateci into each paper’s title so that best practices can evolve as knowledge evolves. Today’s best practice may not be tomorrow’s. PharmTech: What are some of the themes that are driving new research? Ganguly: Lyo is a batch process, and, as FDA pushes the industry to consider continuous processing, we are seeing greater interest in looking into continuous lyophilization processes. Another industry trend is the move to smaller batches. In the future, we will need equipment that can deal with custom batches of varying sizes.
Yet another major trend for the future is the move to patient self-administered devices, which will require different vials and container systems, cartridges, syringes, and specialized devices/ equipment. And then there is the move to personalized medicine. Each of these areas poses more challenges, and today, most processing equipment is still largely based on legacy designs. PharmTech: Where is work going on to develop continuous lyophilization processes? Ganguly: A number of academic groups are looking into developing continuous lyophilization, including the University of Ghent, MIT, and the University of Torino. PharmTech: What will be needed to facilitate use of dual chamber syringes and cartridges and smaller batches? Ganguly: Work began in this area over 10 years ago. One of the first papers was from the University of Lyons, and there have been several contributions from the late Prof Mike Pikal’s research group at Purdue, as well as from the University of Munich, Vetter, and Pfizer to name just a few. As far as the move to smaller batches are concerned, we surely will see a move towards smaller, more efficient systems with better reliability and control enabled by PAT from today. PharmTech: What are your goals for the committee, in the short and mid-term? Ganguly: Short term, we are inviting members to contribute to E-55.05. We want the group to reflect the different voices involved in different points of view , including members from industry, academia, tech equipment vendors, vial manufacturers, excipient manufacturers, and regulatory professionals. Mid-term goals will be to convert best practices paper issues into fundamental standards and standard practice within the industry. We’ve had good conversations so far within the industry on the first best practices paper. PharmTech: Your PhD work involved modeling for pressure and vapor flow. Is the industry becoming more accepting of advanced modeling and control for lyophilization? Ganguly: As I see it, the lyo community is showing increasing levels of confidence in using modeling to understand processes, equipment, and product (3). Specific examples include use of the Lyo Calculator or alike physics based models, computational fluid dynamics to better understand processes, and qualify equipment and address any gaps in understanding of its characteristics.