Entrapment and blow-out of product with the vapor flow is termed ablation. This is most common in formulations which have not produced a cohesive cake but remain loose and friable.
The incorporation of a substance in one state into another of a different state (e.g. liquids being absorbed by a solid or gases being absorbed by a liquid).
Adhesion of the molecules of gases, liquids, or dissolved substances onto the surface of another phase, for example to the freeze dryer or container.
A solid which is not crystalline. The atoms are arranged in a random order. An amorphous solid may also be called a glass.
A small glass tubular vessel in which liquids, mainly for injections, are hermetically sealed. Freeze drying can be performed in ampoules, usually attached to a manifold as the ampoules have a round bottom and therefore will not stand up on a shelf.
A process involving controlled heating and cooling of a solution to encourage crystallization.
Containing water; a solution in which the solvent is water.
Free from any living micro-organisms.
After freeze drying the chamber can be filled with an inert gas, i.e. nitrogen, prior to stoppering. This prevents the product oxidizing while in storage and also reduces the potential loss of product on opening the vial to atmosphere.
A substance that is added to a formulation to increase solute concentration when the amount of active ingredient is very small.
Freeze dried product in a vial is sometimes called a cake or plug.
The failure of a frozen product to maintain its structure, due to an unsuitable product temperature during sublimation.Collapse temperatures are often gradual in onset and can be difficult to measure.
The part of the freeze dryer that traps the moisture that has been expelled from the product and holds it as ice. It also provides the driving force for the sublimation of the solvent.
Critical Quality Attributes (CQAs)
A term used in Quality by Design (QbD). CQAs are physical, biological or chemical characteristics, by which the quality may be quantified at various stages of development or production. CQAs are defined following evaluation of QTPPs.
The temperatures that reflect the points at which key changes occur in a solution, for example freezing point and collapse/eutectic temperature.
A substance that is added to a formulation in order to protect the active ingredients during the freezing stages. The cryoprotectant can also be used as the bulking agent.
A crystal or crystalline solid is a solid material, whose component atoms, molecules or ions are arranged in an orderly repeating structure.
A freeze drying cycle describes operationally the entire freeze drying process. The control of parameters such as shelf temperature, condenser temperature, and chamber pressure (vacuum) is described in a stepwise manner. The aim is to precisely record the process of producing a satisfactorily dried product so that it can be repeated. Freeze drying cycles are programmed directly into a freeze dryer (or freeze dryer control system) and recorded electronically for recall whenever required.
The removal of water from a solution.
To alter the structure of a molecule so that its biological activity is disrupted or entirely lost.
By taking into consideration all the product and process variables, acceptable parameters can be defined for all relevant inputs. The resulting “Design Space” will provide reliable and proven results.
DOE (Design Of Experiment)
Planning a study with specific goals in mind. Particularly relevant to QbD (Quality by Design).
The removal of solvent from a solution.
Primary Drying: The first drying stage of the freeze drying process, involving sublimation of mobile (not adsorbed) ice molecules.
Secondary Drying: The second drying stage of the freeze drying process, which aims to remove (or desorb) the water molecules that were adsorbed.
The freeze drying front describes the moving interface within a frozen product where the drying (sublimation) is occurring. Drying starts from the outer edge of the ice and progresses inwards, with the product in the bottom and center of the container drying last. The freeze drying front can be viewed in real time using the Lyostat freeze-drying microscope.
A chemical change that is accompanied by absorption of heat.
The temperature at which a crystalline solid melts. Very few solids are purely crystalline, therefore it is more relevant to talk about glass transition and collapse temperatures for the majority of formulations.
When a substance changes from a liquid phase to a gaseous phase.
An inactive substance that is added to a formulation to provide benefits to the processing of the active ingredient, i.e. increase critical temperatures or provide protection. Any component of a finished dosage form other than the active ingredient(s) e.g. to adjust the pH or tonicity of a parenteral solution.
A chemical change that is accompanied by liberation of heat.
Water in a solution that is not chemically or physically bound.
The process of drying a material by first freezing it and then encouraging the ice within it to sublimate. Also known as lyophilization.
The solidification of a liquid, usually with the removal of heat. A product must be thoroughly frozen for freeze drying to take place effectively. The freezing point is the temperature at which a solution crystallizes.
A solid which has a non-crystalline (amorphous) structure. The temperature at which the glass first exhibits a change in viscosity is termed the glass transition temperature.
Good Manufacturing Practice or GMP
A quality system covering the manufacture and testing of active pharmaceutical ingredients, pharmaceutical products, diagnostics, foods and medical devices. GMPs are guidelines that outline the aspects of production and testing that can impact the quality of a product. cGMP stands for current Good Manufacturing Practice.
A function of capacitance, resistance and inductance that allows detection of changes in the molecular mobility of a product in its frozen state.
The process of drying a material by first freezing it and then encouraging the ice within it to sublimate. Also known as freeze drying.
A substance that is added to a formulation in order to protect the active ingredients. Note that lyoprotectants protect during the drying stages whereas cryoprotectants protect during the freezing stages. A lyoprotectant can also be used as the bulking agent.
The system of crystals in a frozen product is called the ice matrix or frozen matrix. The structure created and retained by the product after freeze-drying is called the freeze-dried matrix.
A less common name for collapse and eutectic melting.
The change from a solid to a liquid. The Melting Point is the temperature at which this occurs. Note that the melting point and the freezing point are not necessarily the same (freezing is a random process).
A solution that does not contain water.
The process by which (ice) crystals form. When a product first starts to freeze, crystals initially form on particles in the formulation or cluster around existing crystals, and the ice matrix expands outwards from these nuclei.
Refers to a route of administration other than by the alimentary tract e.g. administered by injection.
A graph which shows how the phase (solid, liquid, gas) of a substance is related to temperature and pressure.
Researching the relevant properties of a product and the processes by which it is obtained, and attempting to refine and streamline production to increase efficiency and improve effectiveness.
A generic term referring to whatever is to be freeze dried. In pharmaceuticals or biotechnology, “product” can refer to either the complete formulation or just the active ingredient.
QbD (Quality by Design)
The principle that through definition, planning, analysis and testing, the quality of a final product can be designed into its production.
QTPP (Quality Target Product Profile)
QTPPs form the basis of the product design and QbD process. Where CQAs are specific product-based characteristics, QTPPs are property-based. For example a QTPP might be a certain shelf life, where the resulting CQA would be a defined moisture content range.
Adding a solvent such as water to a freeze-dried product to return it to its original liquid state.
The growth of large crystals at the expense of smaller crystals.
The ability of a material to resist the flow of an electric current through itself. Changes in the structure of a substance as its temperature is raised or lowered will affect its resistivity. In freeze drying analysis generally resistance is measured in ohms and resistivity is derived by calculation.
The length of time a product can be stored before the active ingredient degrades to a level where it is ineffective or other changes such as appearance are unacceptable.
A layer found on the surface of some freeze dried products caused by a concentration of solute. This can be a result of a high concentration of solute excluded by the ice matrix during freezing. Often relatively impermeable, the formation of a skin impedes the drying of the product below it. Also known as a crust.
The taking up of and retention of one substance by another, either absorption or adsorption.
Stoppers are ventilated rubber caps for vials. A stopper is partially seated into the vial neck to allow water vapor to escape during drying, and fully inserted at the end of the process to fully seal the vial. “Stoppering” is usually a function carried out by the freeze dryer while a vacuum or partial vacuum is still present, to help preserve the product.
The process of cooling a liquid below its freezing point, without it becoming a solid. Without a nucleation point for a frozen structure to form around, the liquid phase can be maintained at a much lower temperature.
Another name for annealing.
A measure of the osmotic pressure of two solutions separated by a semi-permeable membrane. In the case of injectable formulations this membrane refers to the red blood cell membrane. Ideally an injectable formulation should be isotonic with blood i.e. equal concentrations of impermeable solutes are on either side of the semi-permeable membrane
A theoretical point at which, due to a precise balance of temperature and pressure, a substance can exist in all three phases (solid, liquid and gas) in thermodynamic equilibrium.
Small, flat-bottomed tubular glass container with a short neck. They are usually fitted with a stopper. Vials are perhaps the most convenient and certainly the most common container used for parenteral products. Vials are available in a wide range of sizes and dimensions.
Water For Injection/Irrigation. Purified water that has been aseptically filtered to remove micro-organisms and particulates and is therefore sterile. It is used to formulate active pharmaceutical ingredients for administration by injection.