Lyophilization process design space patel 20 journal of. Preliminary studies on design space creation different vial size. A design space can be updated over the lifecycle as additional knowledge is gained. Innovative software and consulting for scaleup and optimisation of freeze drying processes. Focus on process safety and efficiency freeze drying makes it possible to preserve highly sensitive pharmaceutical and biotechnological medicines in the long term.
Using the approach presented here, one can create a design space proven acceptable range and embrace quality by design qbd for the lyophilization process without conducting at scale experiments to gain similar knowledge and experience. Line of sight range freezedrying experts sp scientific. However, simple steps can be taken to minimize risks and costs. How design space improves lyophilization cycle success. But that process has some limitations due to crystalline nature of sodium fluoride. Freeze drying is the removal of ice or other frozen solvents from a material through the process of sublimation and the removal of bound water molecules through the process of desorption. Process modelling is an important improvement, but the model was used as an accessory tool, without giving the requested answer in a simple way, as will be discussed later. Lyophilization involves the removal of water or other solvents from a given product by a process called sublimation.
Lyophilization is a process whereby a product is dried by removing the water under low temperature and pressure. Current regulatory considerations on pharmaceutical lyophilization kumar janoria, ph. Therefore, a proper risk assessment is a precursor to proper design space studies. Qbd is a systematic approach that emphasizes process understanding and. Lyophilization process has various important advantages compared to other drying and preserving techniques. Principle and process of lyophilization authorstream. A singlestep drying approach article pdf available in journal of pharmaceutical sciences 1084 november 2018 with 529 reads how we measure reads. No freezing or secondary drying models are used to date. This course will cover the process and benefits of using an empirical. Examples of different potential approaches to presentation of a design space are presented in appendix 2.
Establishing design space for lyophilized drug products k. In addition to promoting standardized lyophilization process development. Using a design space approach, a safe zone of operation for primary drying is identified. Application of the quality by design approach to the freezing step.
Use of design of experiment and microscale down strategies in. Digital design of robust lyophilization processes innovative software and consulting for scaleup and optimisation of freeze drying processes gproms formulatedproducts lyophilization process models allow for efficient design and operational enhancements for drying heat sensitive products at low temperature. Current regulatory considerations on pharmaceutical. Effect of freezing on lyophilization process performance and.
Lyopat software calculates vial heat transfer coefficient k. The critical elements of qbd are the design space and process analytical. Apr 23, 2014 these design space studies are projects generated from the risk assessment. In the quality by design framework, there is a significant emphasis on the robust characterization of manufacturing processes and prospectively identifying manufacturing design space that ensures product quality. We present an overview of our methodology and its application to lyophilization process characterization for a monoclonal antibody formulation. Lyophilization process a freeze dryer consists of three main components. Lyophilization technology process pharmaceutical freeze. Excipients in a lyophilized formulation the design of a lyophilized formulation is dependent on the requirements of the active pharmaceutical ingredient api and intended route of administration.
Jun 05, 2014 analysis of historical data can contribute to the establishment of a design space. Quality by design lyophilization freeze drying process. Lsne is a trusted cdmo specializing in process development, aseptic fill finish and lyophilization for over 23 years. Line of sight equipment and technologies have been integrated for pharmaceutical application to provide enhanced equipment capability, increased process and product understanding bringing. Lyophilization process design space request pdf researchgate. Lyophilization or freeze drying is a process in which water is removed from a product after it is frozen and placed under a vacuum, allowing the ice to change directly from solid to vapor. We bring experts together to discuss best practices.
Investigation of the freezedrying design space would require multiple experimental runs and can be very expensive especially if the experiments involve fullscale freeze dryers, although the process is conceptually. Thus, the understanding of the lyophilization process has proceeded. Monitoring routine pharmaceutical freeze drying with tdlas. Feb 12, 2019 monitoring routine pharmaceutical freeze drying is important for many pharmaceutical and biotechnology products to ensure product stability, efficacy and long shelf life prior to distribution to.
Line of sight equipment and technologies have been integrated for pharmaceutical application to provide enhanced equipment capability, increased process and product understanding bringing together the tools to expand your design space and enable more successful scaleup of a lyophilization process, from formulation to full commercial production. Within the safe zone, conditions resulting in a minimum time cycle are identified which can significantly reduce manufacturing. Using the approach presented here, one can create a design spaceproven acceptable range and embrace quality by design qbd for the lyophilization process without conducting at scale. Pharmacy industrial pharmacy 170211889011 introduction. These tools models, procedures and sensors are targeted for application by research and development scientists and will enable application of rapid and standardized procedures for quality by design qbdbased process development and process. Pr106 how design space improves lyophilization cycle.
Use of design of experiment and microscale down strategies. Stable lyophilization formulation for your drug product. Sundaram j, max shay yh, hsu cc, sane su 2010 design space development for lyophilization using design of experiment and process modelling. As the singlestep drying approach with a 1day cycle time is becoming a reality, the lyophilizer and not the formulation is now becoming the limiting factor for the lyophilization process design space. Lyophilization process design for a given formulation. Freezedrying is widely used in the pharmaceutical industry to stabilize active. Develop a relevant design space without full factorial doe. Mar 16, 2017 in addition to the above examples the model can also be used to proactively describe the design space of a lyophilization process, nail et al. Jul 15, 2011 process modelling is an important improvement, but the model was used as an accessory tool, without giving the requested answer in a simple way, as will be discussed later. Lyophilization process freeze drying simulation of. Ich q8 r2 lyophilization process of removing water from liquid formulations in order to increase stability of the dosage form. The reason our process takes so long and costs so much. An industry perspective on the application of modeling to. Digital design of robust lyophilization processes innovative software and consulting for scaleup and optimisation of freeze drying processes gproms formulatedproducts lyophilization.
Establishing design space for lyophilized drug products. This course will cover the process and benefits of using an empirical approach to design an optimized lyophilization cycle, which will improve the quality and consistency of the product while also reducing the cycle time and. Beyond the design space, real time data is important proof of a process well. Process understanding is a major goal of a qbd program. Modification of the drying recipe shelf temperature passing from equipment 1 to equipment 2 for uniform batches. Through the thoughtful integration of 6 cgmp facilities, qualified staffing. Lyophilization cycle design a practical guide to process. In the present work, the design space is defined as the. Additionally, a welldesigned process can greatly reduce risks, and increase product robustness and quality. Depending on what should be dried, the sample chamber that is directly connected to the condenser and vacuum pump is designed with an appropriate number of shelves which can be moved up and down if closing the vials is. Patel sm,jameel f,pikal mj 2010 the effect of dryer load on freeze drying process design. Design space development for lyophilization using doe and.
We bring experts together to discuss best practices for developing a lyophilization process, including quality by design and design space. Innovative approaches for lyophilization process, equipment. Risk assessments, as part of the risk management process, help steer the focus of. The design space for a lyophilization process is also referred to as the safe zone for operation 27, or the operational space 28. Lyophilization or freeze drying is a process in which water is removed from a product after it is frozen and placed under a vacuum, allowing the ice to change directly from solid to vapor without. This occurs when the ice of a frozen product converts directly to the. Software and hardware tools for pharmaceutical lyophilization.
The application of key elements of quality by design qbd, such as risk assessment, process analytical technology, and design space. Apr 11, 2019 dr ward discusses how operating a lyophilization cycle within the design space will result in a product meeting a predefined quality. Overview introduction design space lyophilization scientific. Excipients in a lyophilized formulation the design of a lyophilized. Recent development of optimization of lyophilization process. Regardless of how a design space is developed, it is expected that operation within the design space will result in a product meeting the defined quality.
Design space development for lyophilization using doe and process modeling. In this article, we discuss an approach that leverages risk assessments, design of experiments, and mechanistic modeling of unit operations to establish a design space that is. Having a larger design space, or parameters in which to work, increases the probability of executing a successful cycle, even in the face of potential problems, such as process excursion due to unplanned power loss. Overview introduction design space lyophilization scientific basis for process design process development defining design space conclusion quality by design a systematic approach to development that. Process refinement, troubleshooting, and technical transfer are additional services we provide. This document describes the approach to process development for lyophilized products. As few as 3 and as many as 810 measurement points per shelf can be employed. Optimized lyophilization cycle design can be an extremely difficult and daunting task for the scientist that is unskilled or under skilled in the process. On the use of mathematical models to build the design space for.
Effect of freezing on lyophilization process performance. Request pdf lyophilization process design space the application of key elements of quality by. Investigation of the freezedrying design space would require. Understanding lyophilization formulation development. Point at which all of the free ice has been removed from all the vials and there are no concerns of collapse or melt back when the temperature is ramped up for secondary drying desorption. Nail, rapid freezedrying cycle optimization using computer programs.
As the singlestep drying approach with a 1day cycle time is. Lyophilization process freeze drying process passage freezedrying software is a finiteelement modeling software aimed at assisting the user and designer of freezedrying processes in improving the quality of freeze dried products in pharmaceutical, chemical and food processes. In addition to the above examples the model can also be used to proactively describe the design space of a lyophilization process, nail et al. Applying quality by design to lyophilization biopharm. The design of the cycle at each stage of the freezedrying process freezing, primary drying and secondary drying is influenced by product temperature to equipment. The lyophilization process is based on the fundamental principles of heat and mass transfer and hence fits really well to the application of qbd principles. Lyophilization cycle optimizationptimization following a decision to use a lyophilized presentation, the cycle may be optimized. The application of key elements of quality by design qbd, such as risk assessment, process analytical technology, and design space, is discussed widely as it. The application of key elements of quality by design qbd, such as risk assessment, process analytical technology, and design space, is discussed widely as it relates to freeze. Principles of process scale up and transfer, introduction to the design space.
An industry perspective on the application of modeling to lyophilization process scale up and transfer. The number of data points required to validate a lyophilization process is dependent on the size of the lyophilizer load and the type of product being freezedried. A singlestep drying approach article pdf available in journal of pharmaceutical sciences 1084 november 2018 with 529 reads how. However, the process can present difficulties, particularly when scaling up from the laboratory to commercial production.
This can create a demand for a large number of data loggers for lyophilization chamber validation. Monitoring routine pharmaceutical freeze drying is important for many pharmaceutical and biotechnology products to ensure product stability, efficacy and long shelf. This document describes the approach to process development for lyophilized products conducted at baxter. Sp scientifics line of sight range offers a suite of freezedrying equipment, enabling. Lyophilization process development requires good understanding of the following parameters. In order to design optimum lyophilization process, process development scientific need to the critical properties of the formulation and how to apply to this information to process design. Unit operation design space the applicant can choose to establish independent design spaces for one or more unit operations, or to establish a single design that spans multiple operations.
Apr 10, 2019 dr ward discusses how operating a lyophilization cycle within the design space will result in a product meeting a predefined quality. Lyophilization lyophilization freezedrying is the process of removing water from temperature sensitive products by the sublimation of ice. Lyophilization is a difficult and expensive process. Sheraton boston hotel 25th october 2019 boston, usa.
Lyophilization process freeze drying process passage freezedrying software is a finiteelement modeling software aimed at assisting the user and designer of freezedrying. Five companies routinely use primary drying model for process design, optimization and scale up. What is a primary drying end point in a lyophilization cycle. Process parameters design space control strategy product lifecycle management and continual. Design space for primary drying was described in another article although design space term was not used in that paper. Design space in qbd definitions quality by design for. Lyostm control software, providing a seamless transition between systems.
In this article, we discuss an approach that leverages risk assessments, design of experiments, and mechanistic modeling of unit operations to establish a design space that is relevant for manufacturing. Detailed software for analysis and optimization of the lyocycle. Statistical modelling for optimized lyophilization of. Contributing authors david latshaw, janssen suresh nulu, biogen. The aim of this article is to show a procedure to build the design space for the primary drying of a pharmaceuticals lyophilization process. Until then, singlestep drying may be a costeffective and highthroughput approach for the manufacturing of biologics.