Annex 1 to the Good manufacturing practices guide – Manufacture of sterile drugs (GUI-0119): Glossary

On this page

• Acronyms and abbreviations
• Definitions

Acronyms and abbreviations

API

active pharmaceutical ingredient

cfu

colony forming unit

EO

ethylene oxide

GMP

good manufacturing practices

PIC/S

Pharmaceutical Inspection Cooperation/Scheme

RABS

restricted access barrier systems

SOP

standard operating procedure

WFI

water for injection

Definitions

These definitions explain how terms are used in this document. Definitions quoted from other documents are identified in brackets at the end of the definition. If there is a conflict with a definition in the Food and Drugs Act or Food and Drug Regulations, the definition in the act or regulations prevails. More applicable definitions can be found in the Good manufacturing practices guide for drug products (GUI-0001).

Airlock:

An enclosed space with interlocked doors, constructed to maintain air pressure control between adjoining rooms (generally with different air cleanliness standards). The intent of an airlock is to preclude ingress of particle matter and microorganism contamination from a lesser controlled area.

Action limit:

An established relevant measure (for example, microbial or airborne particle limits) that, when exceeded, should trigger appropriate investigation and corrective action based on the investigation.

Alert level:

An established relevant measure (for example, microbial or airborne particle levels) giving early warning of potential drift from normal operating conditions and validated state, which does not necessarily give grounds for corrective action but triggers appropriate scrutiny and follow-up to address the potential problem. Alert levels are established based on routine and qualification trend data and periodically reviewed. The alert level can be based on a number of parameters including adverse trends, individual excursions above a set limit and repeat events.

Aseptic preparation/processing:

The handling of sterile drug, containers and/or devices in a controlled environment in which the air supply, materials and personnel are regulated to prevent microbial, endotoxin/pyrogen and particle contamination.

Aseptic process simulation (APS):

A simulation of the entire aseptic manufacturing process in order to verify the capability of the process to assure product sterility. Includes all aseptic operations associated with routine manufacturing (for example, equipment assembly, formulation, filling, lyophilization and sealing processes as necessary).

Asepsis:

A state of control attained by using an aseptic work area and performing activities in a manner that precludes microbial contamination of the exposed sterile drug.

Bacterial retention testing:

This test is performed to validate that a filter can remove bacteria from a gas or liquid. The test is usually performed using a standard organism, such as Brevundimonas diminuta, at a minimum concentration of 10⁷ colony forming units/cm².

Barrier:

A physical partition that affords aseptic processing area (usually grade A) protection by separating it from the background environment. Such systems frequently use, in part or totally, the barrier technologies known as RABS or isolators.

Bioburden:

The total number of microorganisms associated with a specific item such as personnel, manufacturing environments (air and surfaces), equipment, product packaging, raw materials (including water), in-process materials or finished products.

Bio-decontamination:

A process that eliminates viable bioburden by using sporicidal chemical agents.

Biological indicators (BI):

A population of microorganisms inoculated onto a suitable medium (for example, solution, container or closure) and placed within a sterilizer, load or room locations to determine the sterilization or disinfection cycle efficacy of a physical or chemical process. The challenge microorganism is selected and validated based upon its resistance to the given process. Incoming lot D value, microbiological count and purity define the quality of the BI.

Blow-Fill-Seal (BFS):

A technology in which containers are formed from a thermoplastic granulate, filled with product and then sealed in a continuous, integrated, automatic operation. The 2 most common types of BFS machines are the shuttle type (with Parison cut) and the rotary type (Closed Parison).

Campaign manufacture:

A manufacture of a series of batches of the same product in sequence in a given period of time with strict adherence to established and validated control measures.

Classified area:

An area that contains a number of cleanrooms. (Refer to the definition for "cleanroom".)

Cleaning:

A process for removing contamination (for example, product residues and disinfectant residues).

Clean area:

An area with defined particle and microbiological cleanliness standards that usually contains a number of joined cleanrooms.

Cleanroom:

A room designed, maintained and controlled to prevent particle and microbial contamination of drug products. Such a room is assigned and reproducibly meets an appropriate air cleanliness level.

Cleanroom classification:

A method of assessing the level of air cleanliness against a specification for a cleanroom or clean air equipment by measuring the total particle concentration.

Cleanroom qualification:

A method of assessing the level of compliance of a classified cleanroom or clean air equipment with its intended use.

Closed system:

A system in which the product is not exposed to the surrounding environment. For example, this can be achieved by using bulk product holders (such as tanks or bags) that are connected to each other by pipes or tubes as a system, and where used for sterile drugs, the full system is sterilized after the connections are made. Examples of these can be large-scale reusable systems, such as those seen in active substance manufacturing, or disposable bag and manifold systems, such as those seen in the manufacture of biological products.

Closed systems are not opened until the end of an operation.

The use of the term "closed systems" in this Annex does not refer to systems such as RABS or isolator systems.

Colony forming unit (cfu):

A microbiological term to describe a single detectable colony that originates from 1 or more microorganisms. Colony forming units are typically expressed as:

• cfu per ml for liquid samples
• cfu per m³ for air samples
• cfu per sample for samples captured on solid medium
  • such as settle or contact plates

Contamination:

The undesired introduction of impurities of a microbiological nature (quantity and type of microorganisms, pyrogen) or of foreign particle matter, into or onto a raw material, intermediate, active substance or drug product. Can occur during production, sampling, packaging or repackaging, storage or transport. Has the potential to adversely impact product quality.

Contamination control strategy (CCS):

A planned set of controls for microorganisms, endotoxin/pyrogen and particles, derived from current product and process understanding that assures process performance and product quality. Controls can include:

• parameters and attributes related to active substance
• excipient and drug product materials and components
• facility and equipment operating conditions
• in-process controls
• finished product specifications
• associated methods and frequency of monitoring and control

Corrective intervention:

An intervention that is performed to correct or adjust an aseptic process during its execution. These may not occur at a set frequency in the routine aseptic process.

Examples include clearing component jams, stopping leaks, adjusting sensors and replacing equipment components.

Critical surfaces:

Surfaces that may come directly into contact with, or directly affect, a sterile drug or its containers or closures. Critical surfaces are rendered sterile prior to the start of the manufacturing operation and sterility is maintained throughout processing.

Critical zone:

A location within the aseptic processing area in which product and critical surfaces are exposed to the environment.

Critical intervention:

An intervention (corrective or inherent) into the critical zone.

D-value:

The value of a parameter of sterilization (duration or absorbed dose) required to reduce the number of viable organisms to 10% of the original number.

Dead leg:

Length of non-circulating pipe (where fluid may remain static) that is greater than 3 internal pipe diameters.

Decommission:

When a process, equipment or cleanroom are closed and will not be used again.

Decontamination:

The overall process of removing or reducing any contaminants (chemical, waste, residue or microorganisms) from an area, object or person. The method of decontamination used (for example, cleaning, disinfection, sterilization) should be chosen and validated to achieve a level of cleanliness appropriate to the intended use of the item decontaminated. (Refer to the definition for "bio-decontamination".)

Depyrogenation:

A process designed to remove or inactivate pyrogenic material (for example, endotoxin) to a specified minimum quantity.

Disinfection:

The process by which the reduction of the number of microorganisms is achieved by the irreversible action of a product on their structure or metabolism, to a level deemed to be appropriate for a defined purpose.

Endotoxin:

A pyrogenic product (for example, lipopolysaccharide) present in the gram negative bacterial cell wall. Endotoxin can lead to reactions in patients receiving injections ranging from fever to death.

Equilibration time:

Period that elapses between the attainment of the sterilization temperature at the reference measurement point and the attainment of the sterilization temperature at all points within the load.

Extractables:

Chemical entities that migrate from the surface of the process equipment, exposed to an appropriate solvent at extreme conditions, into the product or material being processed.

First air:

Filtered air that has not been interrupted prior to contacting exposed product and product contact surfaces with the potential to add contamination to the air before reaching the critical zone.

Filter integrity test:

A test to confirm that a filter (product, gas or HVAC filter) retains its retentive properties and has not been damaged during handling, installation or processing.

Form-Fill-Seal (FFS):

An automated filling process, typically used for terminally sterilized products. The process constructs the primary container out of a continuous flat roll of packaging film, while simultaneously filling the formed container with product and sealing the filled containers in a continuous process. FFS processes may use:

• single web system
  • where a single flat roll of film is wrapped around itself to form a cavity or
• dual web system
  • where 2 flat rolls of film are brought together to form a cavity, often with the aid of vacuum moulds or pressurized gases

The formed cavity is filled, sealed and cut into sections. Films typically consist of a polymeric material, polymeric coated foil or other suitable material.

Gowning qualification:

A program that establishes, both initially and on a periodic basis, the capability of an individual to don the complete gown.

Grade A air supply:

Air that is passed through a filter qualified as capable of producing grade A total particle quality air, but where there is no requirement to perform continuous total particle monitoring or meet grade A viable monitoring limits. Specifically used to protect fully stoppered vials where the cap has not yet been crimped.

HEPA filter:

High efficiency particulate air filter specified in accordance with a relevant international standard.

Inherent interventions:

An intervention that is an integral part of the aseptic process and is required for either set-up, routine operation and/or monitoring (for example, aseptic assembly, container replenishment, environmental sampling). Inherent interventions are required by procedure or work instruction for the execution of the aseptic process.

Intrinsic sterile connection device:

A device that reduces the risk of contamination during the connection process. These can be mechanical or fusion sealing.

Isokinetic sampling head:

A sampling head designed to disturb the air as little as possible so that the same particles go into the nozzle as would have passed the area if the nozzle had not been there. For example: the sampling condition in which the mean velocity of the air entering the sample probe inlet is nearly the same (± 20%) as the mean velocity of the airflow at that location.

Isolator:

An enclosure capable of being subject to reproducible interior bio-decontamination, with an internal work zone meeting grade A conditions that provides uncompromised, continuous isolation of its interior from the external environment (for example, surrounding cleanroom air and personnel). There are 2 major types of isolators:

• Closed isolator systems exclude external contamination of the isolator's interior by accomplishing material transfer by aseptic connection to auxiliary equipment, rather than use of openings to the surrounding environment. Closed systems remain sealed throughout operations.
• Open isolator systems are designed to allow for the continuous or semi-continuous ingress and/or egress of materials during operations through one or more openings. Openings are engineered (using continuous overpressure, for example) to exclude the entry of external contaminant into the isolator.

Leachables:

Chemical entities that migrate into products from the product contact surface of the process equipment or containers under normal condition of use and/or storage.

Local isolates:

Suitably representative microorganisms of the site that are frequently recovered through environmental monitoring within the classified zone/areas (especially grade A and B areas), personnel monitoring or positive sterility test results.

Lyophilization:

A physical-chemical drying process designed to remove solvents, by way of sublimation, from both aqueous and non-aqueous systems, primarily to achieve product or material stability. Lyophilization is synonymous with the term freeze-drying.

Manual aseptic processing:

An aseptic process where the operator manually compounds, fills, places and /or seals an open container with the sterile drug.

Operator:

Any individual participating in the processing operation, including line set-up, filling, maintenance or other personnel associated with manufacturing activities.

Overkill sterilization:

A process that is sufficient to provide at least a 12 log₁₀ reduction of microorganisms having a minimum D-value of 1 minute.

Parison:

The "tube" of polymer extruded by the BFS machine from which containers are formed.

Pass-through hatch:

Synonymous with "airlock" but typically smaller in size. (Refer to the definition for "airlock".)

Patient:

Human or animal, including participants in a clinical trial.

Post-aseptic processing terminal heat treatment:

A terminal moist heat process employed after aseptic processing which has been demonstrated to provide a sterility assurance level (SAL) ≤10^-6 but where the requirements of steam sterilization (for example, F₀≥8 min) are not fulfilled. This may also be beneficial in destroying viruses that may not have been removed through filtration.

Pyrogen:

A substance that induces a febrile reaction in patients receiving injections.

Rapid transfer system/port (RTP):

A system used to transfer items into RABS or isolators that minimizes the risk to the critical zone. An example would be a rapid transfer container with an alpha/beta port.

Radiopharmaceutical:

"A drug that exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons." (C.03.201)

Raw material:

Any ingredient intended for use in the manufacture of a sterile drug, including those that may not appear in the final drug product.

Restricted access barrier system (RABS):

System that provides an enclosed, but not fully sealed, environment meeting defined air quality conditions (for aseptic processing grade A) and using a rigid-wall enclosure and integrated gloves to separate its interior from the surrounding cleanroom environment. The inner surfaces of the RABS are disinfected and decontaminated with a sporicidal agent. Operators use gloves, half suits, RTPs and other integrated transfer ports to perform manipulations or convey materials to the interior of the RABS. Depending on the design, doors are rarely opened, and only under strictly predefined conditions.

Single-use systems (SUS):

Systems in which product contact components are used only once to replace reusable equipment, such as stainless steel transfer lines or bulk containers. SUS covered in this document are those that are used in manufacturing processes of sterile products. Are typically made up of disposable components such as bags, filters, tubing, connectors, storage bottles and sensors.

Sporicidal agent:

An agent that destroys bacterial and fungal spores when used in sufficient concentration for specified contact time. It is expected to kill all vegetative microorganisms.

Sterile drug:

In this guidance, sterile drug refers to 1 or more of the sterilized elements exposed to aseptic conditions and ultimately making up the sterile active substance or finished sterile drug. These elements include the containers, closures and components of the finished drug product or a product that is rendered sterile by a terminal sterilization process.

Sterilizing grade filter:

A filter that, when appropriately validated, will remove a defined microbial challenge from a fluid or gas producing a sterile effluent. Usually such filters have a pore size equal to or less than 0.22 µm.

Terminal sterilization:

The application of a lethal sterilizing agent or conditions to a product in its final container to achieve a predetermined sterility assurance level (SAL) of 10⁻⁶ or better. For example: the theoretical probability of there being a single viable microorganism present on or in a sterilized unit is equal to or less than 1 x 10-6 (1 in a million).

Turbulent airflow:

Air that is not unidirectional. Turbulent air in cleanrooms should flush the cleanroom via mixed flow dilution and ensure acceptable air quality is maintained.

Unidirectional airflow:

An airflow moving in a single direction, in a robust and uniform manner, and at sufficient speed, to reproducibly sweep particles away from the critical processing or testing area.

Unidirectional airflow (UDAF) unit:

A cabinet supplied with filtered unidirectional airflow (previously referred to as a laminar airflow unit, or LAF).

Worst case:

A set of conditions encompassing processing limits and circumstances, including those within standard operating procedures, that pose the greatest chance of process or product failure (when compared with ideal conditions). Such conditions have the highest potential to, but do not necessarily always result in product or process failure.

Water system:

A system for producing, storing and distributing water, usually compliant to a specific pharmacopeia grade (for example, purified water and water for injection, or WFI).

Z-value:

The temperature difference that leads to a 10-fold change in the D-value of the biological indicators.