Serum being sent to europe for medical treatment of the wounded required refrigeration, but because of the lack of simultaneous refrigeration and transport, many serum supplies were spoiling before reaching their intended recipients. Pharmaceutical development of a parenteral lyophilized formulation. Freeze drying results in a high quality product because of the low temperature used in processing. Download pdf journal of drug delivery and therapeutics.
Presenter a quality by design approach to cycle development and optimization for freezedried parenterals steven l. Freezedrying is used to preserve food and make it very lightweight. Biopharmaceuticals in particular require an especially gentle manufacturing process due to their complex andthermosensitive molecular structure. A fundamental goal of freezedrying is to produce a welldried product with elegant cake appearance, short reconstitution time, long shelf life, and. Since freeze drying is a change in state from the solid phase to the gaseous phase, material to be freezedried must first be adequately prefrozen. Publication date 1993 title variation fda guide to inspections of lyophilization of parenterals note distributed to depository libraries in microfiche. Freezedrying involves three basic stepsfreezing solidification, primary drying ice sublimation, and secondary drying moisture desorptionwhich can take several days to complete.
Food industry food needs to be preserved by freezedrying for consumption by individuals in the fields of space exploration, hikers, military personnel, as well as the availability of dehydrated foods such as noodles, soups, etc. Lyophilization process development project pharmaceutics. Practical aspects of lyophilization using nonaqueous co. Freezedrying, or lyophilization as it is often called, has become a standard process in the. An overview of the lyophilization process as well as the.
A key concept in the quality by design paradigm is design. International biopharm baxter, biopharma solutions. Freezedrying works by freezing the material and then reducing the surrounding pressure to allow the frozen water in the material to sublimate directly from the solid phase to the gas phase. Hence, the main purpose of the present study was to enhance ibuprofen solubility as a result of formulation composition and the freeze drying process. However, newer units provide for microcomputer control of the freeze drying process. Lyophilization is the removal of water from frozen state to the gaseous state without going in the liquid state.
Lyophilization and freeze drying are terms that are used interchangeably depending on the industry and location where the drying is taking place. The presentation and nature of a specimen prior to freeze drying depends on the user and the application. Isotonic although strictness of isotonicity depends on the route of administration. The information presented is generic in nature and is the result of research and experience by labconco personnel and users of freeze drying equipment. Incorporating qbd into lyophilization manufacturing. Lyophilization or freeze drying is a process in which water is frozen, followed by its removal from the sample, initially by sublimation primary drying and then by desorption secondary drying. Irrespective of this, however, there is a prorequisite for good fast freezing, this is probably the most singularly influential factor on the final result, within the limitations previously considered of. This document is reference material for investigators and other fda personnel.
Historically, freezedrying of smallvolume parenterals was a domain of serum tubing vials. If the product exceeds the te, drying takes place from liquid instead of the solid. Parenteral preparations freeze drying sterilization. It is a drying process applicable to manufacture of certain pharmaceuticals and biologicals that are thermolabile or otherwise unstable in aqueous solutions for prolonged storage periods, but that are. Freezedrying is a process of drying in which water is sublimed from the product after it is frozen 1. Differential scanning calorimetry studies were conducted to determine the freezedrying cycle. This is in contrast to dehydration by most conventional methods that evaporate water using heat. Quality by design approach to cycle development and. Primary packaging materials for pharmaceutical freeze.
Freezedrying was selected as the manufacturing process. The freeze drying technique is most suitable process for the development of unstable drug for its betterment for use as parenteral formulation by. Freeze drying is a process of drying in which water is sublimed from the product after it is frozen. Some important aspects to be considered during the freeze drying process are as follows. Freezedrying process optimization pharmaceutical technology. Freezedrying, also known as lyophilisation, lyophilization, or cryodesiccation, is a dehydration process typically used to preserve a perishable material or make the material more convenient for transport. Process analytical technologies pat in freezedrying of. Most studies have been done for solid dosage forms, with very little attention paid to parenterals. 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. The effect of chamber pressure on heat transfer in the. Data are presented to demonstrate that the rate limiting resistance to conductive heat transfer is the gas phase resulting from lack of intimate contact between the heat source and the product.
This chapter also provides an overview of lyophilization, or freezedrying, which is a way to increase the shelf life of certain. The us food and drug administrations quality by design qbd initiative is a new regulatory philosophy based on predefined quality targets and a deep understanding of how formulations and processes interact to influence critical quality attributes of pharmaceutical products. In freeze drying process, nutrients are largely retained. Freezedrying is a process of drying in which water is sublimed from the product after it is frozen.
In lyophilization of parenterals, the drug is dissolved in an appropriate solvent and converted to ice form at. It has been used in the pharmaceutical industry for many years to improve the stability of medications. Freezing the solution by placing the partially stoppered containers on cooled shelves in a freezedrying chamber or prefreezing in another. Freezedrying was first actively developed during wwii. Besides optimisation of the formulation and the freezedrying cycle, the container can also greatly impact the success of the process. Pilot scale lyophilization cycle development adapted to gmp manufacturing of all kinds of freezedried drug products.
When considering the lyophilisation of moisturesensitive biopharmaceuticals, companies must not only consider the moisture transfer via the container but also the stopper, as dr heike kofler, west pharmaceutical services, explains. Freeze drying, also known as lyophilisation or cryodesiccation, is a low temperature dehydration process that involves freezing the product, lowering pressure, then removing the ice by sublimation. V diluents, delivery systems, and other drug products coadministered. Experimental drying curves at constant shelf temperature and various constant. Such vials can be processed in small sizes with high precision and thin bottom and walls. Freezedrying works by freezing the liquid material and then reducing the surrounding pressure to allow the frozen water in the material to sublimate directly from the solid phase to the gas phase. Stable chemically, physically, and microbiologically. In freeze drying, minimal structural changes or shrinkage. Selecting stoppers for use in the lyophilisation of. The advantages of using these nonaqueous solvent systems include. Solubilization of ibuprofen for freeze dried parenteral. The method of prefreezing and the final temperature of the frozen product can affect the ability to successfully freeze dry the material.
Applications of freezedrying the process of freezedrying can be employed in the following fields 9 1. Conclusion a freeze dried product with the best attributes and quality. It is a drying process applicable to manufacture of certain pharmaceuticals and biologicals that are thermo labile or otherwise unstable in aqueous solutions for prolonged storage periods, but that are stable in the dry state. During this training course, you will learn about cycles and equipment, vacuum technology use for freeze drying, sublimation in primary drying, desorption during secondary drying, application of principles to product and process development, analysis of product. Fundamentals and applications of freezedrying to biological materials, drugs and foodstuffs. Optimization of the freeze drying process ta instruments. A robust formulation must account for the freezedrying conditions to ensure that the product can withstand an aggressive lyophilization cycle. Freeze drying in practice parenteral drug association. Freezedried parenterals quality by design sp scientific. Nonaqueous cosolvent systems have been evaluated for their potential use in the freezedrying of pharmaceutical products.
Collapse may occur when the product temperature exceeds the glass transition temperature of the maximally freezeconcentrated solution t g. However, eutectic behavior is only observed when the solute crystallizes. Mechanisms of heat transfer in lyophilization of parenteral solutions are discussed, with emphasis on conduction. Guide to inspections of lyophilization of parenterals note. With freezedrying, heatsensitive drugs and biologicals can be dried at low temperatures. Guide to inspections of lyophilization of parenterals. Chapter 14 sterile filtration, filling, and lyophilization. Guide to inspections of lyophilization of parenterals microform. The process has been popularized in the forms of freeze dried ice cream. Elements of quality by design in development and scaleup. Likewise, a robust lyophilization process can only be developed based on the.
Therefore, the excipients which provide higher critical temperature are preferred for lyophilization. The conditions under which the process takes place will determine the quality of the freeze dried product. The advantages of freeze drying freeze drying, also known as lyophilisation is a method of processing a liquid product into a dry solid product. Freeze drying, also termed lyophilization or sublimation drying, is a gentle drying technique. International institute of refrigeration, science et technique du froid, refrigeration science and. Sp scientific, a world leader in freeze drying technology, has announced a new lyolearn webinar view invitation that will discuss the essential elements of quality by design in formulation and process development of freezedried parenterals. This training course will help you gain an understanding of the basic principles and practical aspects of lyophilization technology. Depending on the type of product and quantity, it can take 1272 hours to go through all of these stages. Moreover, the purpose was to prepare a freeze dried dosage form with improved ibuprofen solubility that could, after simple reconstitution with water for injection, result in an isotonic parenteral solution.
Elementsof qualityby designindevelopment andscaleupof freeze. Excipient selection in parenteral formulation development. The avoidance of high temperatures helps to reduce the extent of. Lyophilization of parenteral pharmaceutical products. Corsodi laureain chimicae tecnologia farmaceutiche.