Terminology

A

Ablation

Entrapment and blow-out of product with the vapour flow is termed ablation. This is most common in formulations which have not produced a cohesive cake but remain loose and friable.

Amorphous

A solid which is not crystalline. An amorphous solid may also be called a glass.

ALUS

Automatic Loading and Unloading Systems. Product, typically in vials, placed in a freeze dryer for freeze drying and removed after completion of the cycle entirely by machine, reducing the cost, contamination and safety implications of loading / unloading by hand.

Ampoule

A small glass 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.

Annealing

A process involving controlled heating and cooling of a solution to encourage crystallisation.

Aqueous

Containing water; a solution in which the solvent is water.

ANSI

American National Standards Institute. Visit their website here.

Aseptic

Free from any living organisms. Aseptic processing is used to sterilize a product and package the product in a way that maintains sterility.

ASME

American Society of Mechanical Engineers. Visit their website here.

B

Backfilling

After freeze drying the chamber can be filled with an inert gas, i.e. nitrogen, prior to stoppering. This prevents the product oxidising while in storage and also reduces the potential loss of product on opening the vial to atmosphere.

Backstreaming

When oil and diffusion pumps are used in low-pressure systems, vapours from the pump can sometimes migrate back into the chamber and into the product. This is known as backstreaming.

Blank-Off

The lowest pressure or temperature that a system can attain.

Bulk

Product can be freeze dried in a variety of formats, including ampoules, vials and in bulk. For liquid product this generally means poured into stainless steel or plastic trays.

C

Cake

Freeze dried product in a vial is sometimes called a cake or plug.

Calibration

The process of adjusting an instrument to ensure its accuracy and reliability.

Capacitance Gauge / Manometer

A gauge for measuring vacuum. They can be very accurate and also offer excellent zero stability and high signal to noise ration. They are suited to clean vacuum environments.

Chamber

The product or drying chamber is the section of the freeze dryer in which the shelves are situated and the product is placed during freeze drying. The condenser chamber is a separate vessel, linked by means of a valve, in which the process condenser is situated. In some freeze dryers the condenser is situated in the same chamber as the shelves.

CIP

Clean-In-Place. A method of cleaning the interior surfaces of equipment, such as pipework, chamber surfaces and fittings, without disassembly. See also SIP.

Cleanroom

A room designated for sterile research or production, in which the amount of airborne particulates, moisture, etc is precisely controlled.

Collapse

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.

Condenser

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 Temperatures

The temperatures that reflect the points at which key changes occur in a solution, for example freezing point and collapse/eutectic temperature.

Cryoprotectant

A substance that is added to a formulation in order to protect the active ingredients during the freezing stages.

CSQ

Control System Qualification. Documented verification that the control system functions as specified.

Cycle

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 direct into a freeze dryer (or freeze dryer control system) and recorded electronically there for recall whenever required.

D

Defrosting

The process of removing the ice from the condenser by melting or mechanical means. Many freeze dryers offer hot air or water systems to speed up defrosting, especially in systems with large condensers which will hold a lot of ice.

Denature

To alter the structure of a molecule so that its biological activity is disrupted or entirely lost.

DIN

Deutsche Industrial Norms. A German standard for engineering units, that has become widely recognised and used across the world.

DQ

Design Qualification. Documented verification that the proposed design of the equipment or systems is suitable for the intended purpose.

Drying

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.

Dry Weight

The weight of the product after it has been completely dried.

E

Eutectic Point The temperature at which a crystallise 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.

End Point

In freeze drying there are two main end points to determine – the end of primary drying and the end of the overall process.

Excipient

A 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 ingredients.

F

Freeze Drying

The process of drying a material by first freezing it and then encouraging the ice within it to sublimate. Also known as lyophilisation.

FAT

Factory Acceptance Testing. The manufacturer demonstrates that the system manufactured meets the agreed specifications.

FDA

Food and Drugs Administration. A US governmental agency that regulates the development and manufacture of drugs and medical devices. Visit their site here.

Flask

Freeze drying can be carried out in specially designed flasks. They are typically round-bottomed and fitted with a rubber lid which attaches to the manifold of a freeze dryer. The freezing stage is often carried out with a separate piece of equipment such as a shell freezer. They are most commonly used in the research stage of drug development.

Functional Analysis

After a URS has been submitted, the Functional Analysis is written, normally by the manufacturer. It explains the URS in technical detail and becomes the controlled design document for the project.

G

GAMP

Good Automated Manufacturing Practice.

Gas Ballast

On a vacuum pump, the gas ballast valve is used to admit air in the compression stage of pumping. This
reduces the condensation of vapour and is useful in removing air and water trapped in the vacuum oil.

Glass

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.

GMP

Good Manufacturing Practice. The FDA’s guidelines on production for various industries, including Biotech and Pharmaceutical. cGMP stands for Current Good Manufacturing Practice.

H

I

IQ

Installation Qualification. Documented verification that all key aspects of the installation adhere to any applicable codes, the customer’s requirements and the manufacturer’s design requirements.

ISA

Instrumentation, Systems and Automation Society. One of the foremost professional organisations for setting standards in automation. Visit their site here.

L

Lyophilisation

An alternative name for freeze drying.

M

Manifold

On a freeze dryer the manifold is a pipe leading up from the condenser and typically branching into four, eight or twelve branches. Flasks or ampoules with pre-frozen material are attached to the manifold for drying. Manifolds can be “drum”, wide enough to accommodate small shelves or trays, or “vertical”, which can hold only flasks.

Mapping

In freeze dryer qualification procedures, mapping can be carried out on the shelves and or cleaning/sterilisation systems. The objective of mapping trials is to prove the design and confirm the manufacture by checking conformity to acceptable standards across the system in question.

Microbar

A unit of pressure. One microbar is one millionth of a bar and equal to 0.75 millitorr. Microbars are the more commonly used unit throughout Europe, whereas millitorr are preferred in America.

Millitorr

A unit of pressure, commonly used throughout America. One millitorr is roughly equal to 1.3 microbar.

N

Non-Aqueous

A solution that does not contain water.

O

OME

Oil Mist Eliminator. Oil mist escapes from the exhaust port of rotary vane pumps when in operation. An OME retains this oil in the exhausted gases.

OQ

Operational Qualification. Documented verification that the system performs as specified.

P

P&ID

Piping and Instrumentation Diagram. A diagram showing the interconnection of process equipment, the instrumentation used to control it and services required. The symbols used as usually based on ANSI / ISA standards.

Pizza Door

A thin slot-like door on a freeze dryer. Trays of product are passed through to be loaded onto the freeze dryer shelves, usually by an automatic or semi-automatic loading system.

PQ

Process Qualification. Documented verification that the process in question functions to the required standard, whether that be the freeze drying cycle or sterilisation or some other process.

Process Development

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.

Q

Qualification

The performance of tests to determine if a component or system or process performs as required.

R

Reconstitution

Adding a solvent to a freeze-dried product to return it to its original wet or liquid condition.

Refrigerant

The refrigeration system in a freeze dryer cools both the shelves and the condenser. The most common refrigeration systems in freeze drying are cooling by liquid nitrogen – an open system, where the refrigerant is used once and lost to the atmosphere; and mechanical refrigeration, utilising a compressor. Different refrigerants have different thermodynamic properties and may be better or worse suited to different applications. Common refrigerants used in freeze dryer compressors include R408b (“Suva 95″), and R404a (“Suva HP62″).

S

Shelf Life

The length of time a product can be stored before it degrades beyond usefulness.

Shell Freezing

Shell Freezing is a method of pre-freezing product in flasks, prior to freeze drying. Flasks are placed in a chilled bath and rotated, forming a shell of frozen material around the inside of the flask in either a conical or cylindrical shape, depending on the type of equipment. Shell freezing provides a high surface area for sublimation, meaning that a larger volume of product can be processed than if it were simply poured into the bottom of the flask.

Shelves

In most freeze dryers the shelves function as heat exchangers, removing heat from the product during freezing and supplying heat back to the product during drying. They are chilled or heated by means of controlled fluid circulating through them. Stoppering systems, where fitted, require the shelf stack to be collapsible under hydraulic or some other power. Shelves can be manufactured up to 4 square metres.

Silicone Fluid

Silicone Oil is the most commonly used thermal medium for cooling / heating freeze dryer shelves.

SIP

Sterilise-In-Place. A method of sterilisng the interior of equipment, such as pipework, chamber surfaces and fittings, without dissassembly. SIP tends to use superheated steam, whereas CIP uses chemicals.

Sublimation

The change from a solid into a gas without passing through the liquid phase. In freeze drying, the majority of sublimation takes place during the Primary Drying phase.

Sterile

Free from living organisms.

Stopper

Stoppers are ventilated rubber lids for vials. A stopper is partially seated into the vial neck to allow water vapour 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.

T

Trays

Trays are used to hold product that is to be loaded onto freeze dryer shelves. Trays can be manufactured in a variety of materials including stainless steel, aluminium, plastic or glass. Trays are ideal for product that is to be freeze dried in bulk, either as a liquid or other format (for example drying of food products). For product in vials the trays can be made in two parts, an outer ring that keeps the vials in place, and a removable bottom. Once the vials are on the shelf the bottom half is removed, allowing the vials to sit directly onto the shelf and thereby granting better heat conduction. The tray is slid back underneath when the vials need to be removed.

U

URS

User Requirement Specification. A document issued by the customer detailing their requirements.

V

Vacuum Pump

All freeze dryers require at least one vacuum pump to function. The most commonly used vacuum pumps in freeze drying are rotary vane pumps or dry pumps.

Validation

The determination of the critical variables in a process, and an acceptable range of these variables.

Vial

Small, flat-bottomed glass bottle 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.

W

WFI

Water For Injection. Water that has been purified to a high degree, for use particularly in drugs that are to be injected.