URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802 TITLE: Practical Advice on Scientific Design of Freeze-Drying Process ERROR: None [Skip to main content](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#main-content) ![Image 1](https://cdn.ncbi.nlm.nih.gov/pmc/pd-medc-pmc-cloudpmc-viewer/production/a2b04810/var/data/static/img/us_flag.svg) An official website of the United States government Here's how you know Here's how you know ![Image 2](https://cdn.ncbi.nlm.nih.gov/pmc/pd-medc-pmc-cloudpmc-viewer/production/a2b04810/var/data/static/img/icon-dot-gov.svg) **Official websites use .gov** A **.gov** website belongs to an official government organization in the United States. ![Image 3](https://cdn.ncbi.nlm.nih.gov/pmc/pd-medc-pmc-cloudpmc-viewer/production/a2b04810/var/data/static/img/icon-https.svg) **Secure .gov websites use HTTPS** A **lock** ( ) or **https://** means you've safely connected to the .gov website. Share sensitive information only on official, secure websites. 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Learn more: [PMC Disclaimer](https://pmc.ncbi.nlm.nih.gov/about/disclaimer/) | [PMC Copyright Notice](https://pmc.ncbi.nlm.nih.gov/about/copyright/) ![Image 14: Pharmaceutical Research logo](https://cdn.ncbi.nlm.nih.gov/pmc/banners/logo-springeropen.png) Pharm Res . 2023 Oct 2;40(10):2433. doi: [10.1007/s11095-023-03607-9](https://doi.org/10.1007/s11095-023-03607-9) * [Search in PMC](https://pmc.ncbi.nlm.nih.gov/search/?term=%22Pharm%20Res%22[jour]) * [Search in PubMed](https://pubmed.ncbi.nlm.nih.gov/?term=%22Pharm%20Res%22[jour]) * [View in NLM Catalog](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Pharm%20Res%22[Title%20Abbreviation]) * [Add to search](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802?term=%22Pharm%20Res%22[jour]) # Practical Advice on Scientific Design of Freeze-Drying Process: 2023 Update [Serguei Tchessalov](https://pubmed.ncbi.nlm.nih.gov/?term=%22Tchessalov%20S%22[Author]) ### Serguei Tchessalov 1 grid.410513.20000 0000 8800 7493Pfizer Inc, Andover, MA USA Find articles by [Serguei Tchessalov](https://pubmed.ncbi.nlm.nih.gov/?term=%22Tchessalov%20S%22[Author]) 1, [Vito Maglio](https://pubmed.ncbi.nlm.nih.gov/?term=%22Maglio%20V%22[Author]) ### Vito Maglio 1 grid.410513.20000 0000 8800 7493Pfizer Inc, Andover, MA USA Find articles by [Vito Maglio](https://pubmed.ncbi.nlm.nih.gov/?term=%22Maglio%20V%22[Author]) 1, [Petr Kazarin](https://pubmed.ncbi.nlm.nih.gov/?term=%22Kazarin%20P%22[Author]) ### Petr Kazarin 2 https://ror.org/02dqehb95grid.169077.e0000 0004 1937 2197Birck Nanotechnology Center, Purdue University, 1205 W State St., West Lafayette, IN 47907 USA Find articles by [Petr Kazarin](https://pubmed.ncbi.nlm.nih.gov/?term=%22Kazarin%20P%22[Author]) 2, [Alina Alexeenko](https://pubmed.ncbi.nlm.nih.gov/?term=%22Alexeenko%20A%22[Author]) ### Alina Alexeenko 2 https://ror.org/02dqehb95grid.169077.e0000 0004 1937 2197Birck Nanotechnology Center, Purdue University, 1205 W State St., West Lafayette, IN 47907 USA Find articles by [Alina Alexeenko](https://pubmed.ncbi.nlm.nih.gov/?term=%22Alexeenko%20A%22[Author]) 2, [Bakul Bhatnagar](https://pubmed.ncbi.nlm.nih.gov/?term=%22Bhatnagar%20B%22[Author]) ### Bakul Bhatnagar 1 grid.410513.20000 0000 8800 7493Pfizer Inc, Andover, MA USA Find articles by [Bakul Bhatnagar](https://pubmed.ncbi.nlm.nih.gov/?term=%22Bhatnagar%20B%22[Author]) 1, [Ekneet Sahni](https://pubmed.ncbi.nlm.nih.gov/?term=%22Sahni%20E%22[Author]) ### Ekneet Sahni 3 https://ror.org/02f51rf24grid.418961.30000 0004 0472 2713Regeneron, Troy, NY USA Find articles by [Ekneet Sahni](https://pubmed.ncbi.nlm.nih.gov/?term=%22Sahni%20E%22[Author]) 3, [Evgenyi Shalaev](https://pubmed.ncbi.nlm.nih.gov/?term=%22Shalaev%20E%22[Author]) ### Evgenyi Shalaev 4 https://ror.org/02g5p4n58grid.431072.30000 0004 0572 4227Pharmaceutical Sciences, R&D, Abbvie, Irvine, CA USA Find articles by [Evgenyi Shalaev](https://pubmed.ncbi.nlm.nih.gov/?term=%22Shalaev%20E%22[Author]) 4 * Author information * Article notes * Copyright and License information 1 grid.410513.20000 0000 8800 7493Pfizer Inc, Andover, MA USA 2 https://ror.org/02dqehb95grid.169077.e0000 0004 1937 2197Birck Nanotechnology Center, Purdue University, 1205 W State St., West Lafayette, IN 47907 USA 3 https://ror.org/02f51rf24grid.418961.30000 0004 0472 2713Regeneron, Troy, NY USA 4 https://ror.org/02g5p4n58grid.431072.30000 0004 0572 4227Pharmaceutical Sciences, R&D, Abbvie, Irvine, CA USA Received 2023 Mar 20; Accepted 2023 Sep 9 © The Author(s) 2023, corrected publication 2024 **Open Access** This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/). [PMC Copyright notice](https://pmc.ncbi.nlm.nih.gov/about/copyright/) PMCID: PMC10661802 PMID: [37783925](https://pubmed.ncbi.nlm.nih.gov/37783925/) ## [](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802)Abstract ### Objective The purpose of this paper is to re-visit the design of three steps in the freeze-drying process, namely freezing, primary drying, and secondary drying steps. Specifically, up-to-date recommendations for selecting freeze-drying conditions are provided based on the physical–chemical properties of formulations and engineering considerations. ### Methods and Results This paper discusses the fundamental factors to consider when selecting freezing, primary drying, and secondary drying conditions, and offers mathematical models for predicting the duration of each segment and product temperature during primary drying. Three simple heat/mass transfer primary drying (PD) models were tested, and their ability to predict product temperature and sublimation time showed good agreement. The PD models were validated based on the experimental data and utilized to tabulate the primary drying conditions for common pharmaceutical formulations, including amorphous and partially crystalline products. Examples of calculated drying cycles, including all steps, for typical amorphous and crystalline formulations are provided. ### Conclusions The authors revisited advice from a seminal paper by Tang and Pikal (Pharm Res. 21(2):191-200, 2004) on selecting freeze-drying process conditions and found that the majority of recommendations are still applicable today. There have been a number of advancements, including methods to promote ice nucleation and computer modeling for all steps of freeze-drying process. The authors created a database for primary drying and provided examples of complete freeze-drying cycles design. The paper may supplement the knowledge of scientists and formulators and serve as a user-friendly tool for quickly estimating the design space. ### Supplementary Information The online version contains supplementary material available at 10.1007/s11095-023-03607-9. **Keywords:**freeze-drying, lyophilization, mathematical modeling, process design ## [](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802)Introduction Freeze-drying (lyophilization) is a common pharmaceutical manufacturing process used to produce various drug products. Freeze-drying consists of 3 segments, i.e., freezing, primary drying (ice sublimation), and secondary drying (desorption of unfrozen water), with primary drying (ice sublimation) being the longest. Freezing is a critical stage of a freeze-drying cycle, as the structure and morphology of a frozen cake can influence product behavior during primary drying. Freezing conditions could also majorly impact freeze-dried products' critical quality attributes and shelf life. The primary drying segment typically attracts the most attention because it provides the best opportunity to significantly reduce overall cycle time, while it may also be associated with significant product defects if performed under the wrong conditions. Furthermore, product behavior during primary drying can be controlled by adjusting heat/mass transfer conditions and is far more predictable than freezing, which depends on a stochastic nucleation process. Acceleration of primary drying requires maintaining a higher product temperature, while product temperature should not exceed a critical product temperature limit to achieve a quality product. Secondary drying, during which an unfrozen fraction of water is removed from the product to achieve a target residual water content level, is usually a relatively straightforward part of freeze-drying. In a seminal publication by Tang and Pikal[[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#CR1)], guidance on the selection of freeze-drying conditions was provided, along with a brief description of scientific principles behind the practical advice. It has been 18 years since the publication of this milestone paper by two co-authors from the University of Connecticut. The majority of recommendations from that paper are as relevant today as they were in 2004, and several exact citations from Tang and Pikal[[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#CR1)] paper are included in this manuscript. At the same time, there have been significant advancements in science and technology of freeze-drying, which warrant re-visiting. Freezing remains the most elusive part of freeze-drying, partly because of the fundamental unpredictability of a nucleation phenomenon. There are ongoing efforts to evaluate the feasibility of controlling ice nucleation at different scales. Studies have been performed to explore relationships between ice nucleation conditions and the quality of the finished product. As discussed in this paper, a mathematical model has also been developed to predict the freezing time. A significant part of this paper is focused (predictably) on primary drying, emphasizing building a design space for different products to provide initial guidance on process design for a laboratory freeze-dryer. For a scientist/formulator with limited freeze-drying experience, the database provides specific primary drying conditions for a range of formulations, vials, and fill volumes, while it can also be helpful for an advanced user. For example, the database provides a user-friendly way to explore design space. In a brief discussion of secondary drying, a simple computational model is introduced, which allows the estimation of secondary drying duration to achieve target residual water content for a typical amorphous product at different shelf temperatures. Suggestions on selecting conditions for all three stages of the freeze-drying process are provided, including examples of freeze-drying cycle recipes for amorphous and crystalline formulations. ## [](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802)Selection of The Freeze-Drying Conditions: Overview ### Loading and Freezing #### Overview As “the theater begins with the cloakroom” (as attributed to a famous Russian art director Konstantin Stanislavsky), any freeze-drying recipe begins with the loading temperature. Freeze-dryers are usually loaded at either room temperature (usually 20 to 25°C) or 5°C when liquid stability is a potential concern. On rare occasions, a product is loaded onto shelves cooled below 0°C (e.g., to -50°C); this could be a case when a fast cooling rate is required if there are major concerns with liquid stability or for scheduling reasons in a manufacturing environment to reduce cycle time by eliminating a long cooling step. In such cases, water from the atmosphere could condense on the shelves to form ice, which is highly undesirable. After loading a freeze-dryer, vials are typically equilibrated for at least 30 min before cooling to minimize vial-to-vial temperature variations. In selecting the shelf cooling rate, one should remember that the shelf temperature/time program is not the same as the product temperature/time response, as illustrated in Fig.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#Fig1)a. A faster cooling rate results in a larger difference between shelf and product temperature (Fig.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#Fig1)b). In this example the larger dryer (Lyomax 42 with 42 sq.m shelf area) shows a more significant difference between inlet temperature and product temperature even when it was only partially loaded (2 shelves out of 15) as opposed to a fully loaded pilot dryer (6 sq.m). As discussed below, an approach to a cooling program depends on formulation type, i.e., if the formulation is completely amorphous or partially crystalline.Fig. 1An example of product and shelf temperatures during cooling of a product in a lyophilizer (**a**). (**b**) represents an average difference between inlet (shelf) temperature and product temperature as a function of cooling rate for the pilot (green line) and commercial dryer (blue line). As illustrated in Fig.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#Fig1), product behavior during cooling can be described by two factors, i.e., ice nucleation temperature and freezing time. Ice nucleation can be measured directly by detecting an abrupt increase in the product temperature due to an exothermic process of ice formation. An exact definition of freezing time would require monitoring water-to-ice conversion in real-time, which would be a difficult task in practice. As a conceptual (and approximate) definition, freezing time can be defined as the period between ice nucleation and the time when the product temperature trend resumes following the shelf temperature trend. At this point, most “freezable” (in a kinetic sense) water is converted to ice, although water-to-ice transformation could probably continue below this point, depending on formulation composition and specifics of heat/mass transfer in a particular container. Operationally, the freezing time is commonly defined as the hold time at the final freezing temperature, sometimes including freezing ramp duration. Lower supercooling (i.e., higher ice nucleation temperature) is considered beneficial, as it is expected to result in larger ice crystals with lower surface area [[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#CR2), [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#CR3)]. Frozen mass with larger and inter-connected ice crystals would have a lower resistance to water vapor transfer and a lower risk for protein destabilization because of a lower ice/solution interface and, therefore, a lower fraction of protein molecules exposure to the interface. A temperature equilibration step prior to the initiation of cooling is recommended [[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#CR1)] to reduce the vial-to-vial difference in ice nucleation. There is no definite agreement on the relationships between cooling rate and ice nucleation temperature. While it has been suggested that slow cooling causes larger supercooling [[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#CR4)], and it also reported that the cooling rate (range 0.6–40 K/min) did have some impact on the homogeneous ice nucleation temperature in solutions of LiCl with a concentration above 6.8 mol % [[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#CR5)], there are also reports to the contrary. Indeed, no impact of the cooling rate on the homogeneous ice nucleation temperature was observed for LiCl solutions at 5 mol % [[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#CR5)]. Furthermore, it was reported that an increase in the cooling rate from 0.1 to 1000 K/min resulted in only a 2°​C difference in the heterogeneous ice nucleation temperature and 4°​C in homogeneous ice nucleation [[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#CR6)]. No difference in the ice nucleation temperature was observed with cooling rates of 0.5 to 3.2°​C/min [[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#CR7)], 0.07-​7°​/min [[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#CR8)], and 0.05 to 1°​C/min [[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#CR2)] Also, nucleation rate coefficients (nucleation events per unit time per unit area) of ice on kaolinite did not demonstrate any significant difference in cooling rates between 0.8 and 10 K/min [[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#CR9)]. As noted in [[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#CR1)], “_it is not practical to manipulate the supercooling by changing the cooling rate in a freeze dryer because the cooling rates are usually limited to less than 2°C/min, and the degree of supercooling is unlikely to change within such a small range_.” It remains a true statement based on almost two decades since the publication of that paper. One approach to eliminating the differences in freezing due to varying degrees of supercooling across a shelf of vials is by employing controlled ice nucleation. The product temperature is reduced below the equilibrium freezing point (or melting temperature). After a brief equilibration, ice nucleation is initiated by a variety of approaches: (i) pressurization and depressurization of the drying chamber [[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#CR10)]; (ii) introduction of an ice-fog [[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#CR3)]; (iii) reduction of chamber pressure [[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#CR11)]; and (iv) utilization of ultrasound [[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#CR12), [13](https://pmc.ncbi.nlm.nih.gov/articles/PMC10661802#CR13)]. 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