Annex 2 to the Good manufacturing practices guide - Manufacture of biologics (GUI-0027): Glossary and definitions

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• Glossary
• Definitions

Glossary

ATMP

advanced therapy medicinal product

CCAC

Canadian Council on Animal Care

CFIA

Canadian Food Inspection Agency

CTA

clinical trial authorization

GLP

good laboratory practices

GMP

good manufacturing practices

HVAC

heating, ventilation and air conditioning

ICH

International Conference on Harmonisation

MA

marketing authorization

MAb

monoclonal antibody

MCB

master cell bank

MSL

master seed lot

MVS

master virus seed

OIE

Office International des Epizooties, World Organization for Animal Health

OSE

on-site evaluation

PHAC

Public Health Agency of Canada

PIC/S

Pharmaceutical Inspection Cooperation/Scheme

QC

quality control

QRM

quality risk management

ROEB

Regulatory Operations and Enforcement Branch

WCB

working cell bank

WHO

World Health Organization

WSL

working seed lot

WVS

working virus seed

Definitions

The following definitions explain how terms are used in this document. If there is a conflict with a definition in the Food and Drugs Act (act) or associated regulations such as the Food and Drug Regulations (FDR), the definition in the act or regulations prevails.

For other applicable definitions, consult:

• Good manufacturing practices guide for drug products (GUI-0001)

Active ingredient

A drug that, when used as a raw material in the fabrication of a drug in dosage form, provides its intended effect. (FDR, C.01A.001 (1))

Adjuvant

A chemical or biological substance that enhances the immune response against an antigen.

Adventitious virus

Unintentionally introduced contaminant virus.

Allergoids

Allergens that are chemically modified to reduce IgE reactivity.

Antibody

Proteins produced by the B-lymphocytes that bind to specific antigens. Antibodies may be divided into 2 main types based on key differences in their method of manufacture:

• monoclonal antibody (MAb): homogenous antibody population obtained from a single clone of lymphocytes or by recombinant technology and which bind to a single epitope
• polyclonal antibody: from a range of lymphocyte clones, produced in human and animals in response to the epitopes on most 'non-self' molecules

Antigens

Substances (such as toxins, foreign proteins, bacteria, tissue cells) capable of inducing specific immune responses.

Area

A specific set of rooms within a building associated with manufacturing a product or multiple products that has a common air handling unit.

ATMP

Any of the following medicinal products for human use:

• gene therapy medicinal products
• tissue engineered medicinal products
• somatic cell therapy medicinal products

ATMPs may incorporate, as an integral part of the product, 1 or more medical devices (referred to as "combined ATMPs").

Batch (or lot)

A specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous within specified limits. In the case of continuous production, a batch may correspond to a defined fraction of the production. The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval.

Bioburden

The level and type (for instance, objectionable or not) of microorganism present in raw materials, media, intermediates or drugs in dosage form. Regarded as contamination when the level and/or type exceed specifications.

Biological starting material

Raw material from a biological source that is intended to be used to fabricate a drug and from which the active ingredient is derived:

• directly
  • for example, plasma derivatives, ascitic fluid, bovine lung
• indirectly
  • for example, cell substrates, host/vector production cells, eggs, viral strains

Biologics

A drug that is listed in Schedule D to the act.

Blood

Human blood that is collected either for transfusion or for use in manufacturing a drug for human use. For greater certainty, includes whole blood and blood components (for example, red blood cells, platelets, plasma, granulocytes).

Blood component

A therapeutic agent produced by physical or mechanical separation of the constituents of whole blood. Components include red blood cells, platelets, plasma and cryoprecipitated anti-hemophiliac factor (AHF).

Blood establishment

A person who conducts any of the following activities related to blood:

• importation
• processing
• distribution
• transformation
• transfusion

(Section 1, Blood Regulations)

Blood products

Any therapeutic product from human blood or plasma.

Bulk process intermediate

An active ingredient used to fabricate either a drug of biological origin that is listed in Schedule C to the Act or a drug that is listed in Schedule D to the act (FDR, C.01A.001).

Note: Other Health Canada guidance documents refer to the bulk process intermediate as a "drug substance".

Campaigned manufacture

The manufacture of a series of batches of the same product in sequence in a given period of time followed by strict adherence to accepted control measures before transfer to another product. The products are not run at the same time but may be run on the same equipment.

Closed system

Process equipment (such as fermenter, transfer lines, harvest apparatus) or process step in which the product is not exposed to the external environment. A closed system requires that the quality of materials entering or leaving the system and the manner in which these materials are added /removed from the system is carefully controlled.

Concurrent production

Simultaneous processing of more than:

• 1 product in the same room/suite of a multi-product facility or
• simultaneous processing of more than 1 lot of a product in a dedicated facility

Contained use

An operation:

• where genetically modified organisms are cultured, stored, used, transported, destroyed or disposed of and
• for which barriers (physical, chemical, biological) are used to limit their contact with the general population and the environment

Containment level (CL)

Minimum physical containment and operational practice requirements for handling infectious material or toxins safely in laboratory, large-scale production and animal work environments. There are 4 containment levels ranging from a basic laboratory (containment level 1 (CL1) to the highest level of containment (containment level 4, or CL4).

Containment system

Dedicated equipment that functions to provide and maintain containment. This includes primary containment devices (for example, biological safety cabinets), heating, ventilation and air conditioning (HVAC) and control systems, and decontamination systems (for example, autoclaves).

Containment zone

A physical area that meets the requirements for a specified containment level. A containment zone can be:

• a single room
  • for example, containment level 2 (CL2) laboratory
• a series of co-located rooms
  • for example, several non-adjoining but lockable CL2 laboratory work areas or
• several adjoining rooms
  • for example, containment level 3 (CL3) suite with dedicated laboratory areas and separate animal rooms, or animal cubicles

Dedicated support areas, including anterooms (with showers and "clean" and "dirty" change areas, where required), are part of the containment zone.

Contamination

The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or onto a raw material or intermediate during production, sampling, packaging or repackaging, storage or transport. (ICH Q7)

Continuous culture

Process by which growth of cells is maintained by periodically replacing a portion of the cells and medium such that there is no lag or saturation phase.

Contract fractionation program

A contract fractionation in a local plant of a fractionator/manufacturer, using starting material from other countries and manufacturing products not intended for the local market.

Cross-contamination

Contamination of a product or biological starting material or in-process intermediate with another product or biological starting material or in-process intermediate. In multi-product facilities, cross-contamination can occur throughout the manufacturing process, from generation of the master cell bank and working cell bank through finishing.

Dedicated

Facility or piece of equipment used only to fabricate a particular product or a closely related group of products.

Deviation

Departure from an approved instruction or established standard. (ICH Q7)

Drug

A drug that is listed in Schedule D to the Act that is in dosage form or a drug that is an active ingredient that can be used to prepare a drug listed in that Schedule.

Note: Other Health Canada guidance documents refer to the bulk process intermediate, which is an active ingredient, as a "drug substance" and to the drug in dosage form as a "drug product" or "finished product".

Drug establishment licence

A licence issued to a person in Canada to conduct licensable activities in a building that has been inspected and assessed as being in compliance with the applicable requirements of Divisions 2 to 4 of the FDR.

Fabricate

To prepare and preserve a drug for the purpose of sale. (FDR, C.01A.001)

Feeder cells

Used in co-culture to maintain pluripotent stem cells. For human embryonic stem cell culture, typical feeder layers include mouse embryonic fibroblasts (MEFs) or human embryonic fibroblasts that have been treated to prevent them from dividing.

Fermentation

A process in which cells or microorganisms are cultured in a container (bioreactor or fermenter), in liquid or solid medium, for experimental or commercial processes.

Fermenter

In case of (mammalian) cell lines, should be understood as bioreactor.

Finishing operations

Formulation, filling and packaging.

Fractionation, fractionation plant

Fractionation is the manufacturing process in a plant (fractionation plant) during which plasma components are separated/purified by various physical and chemical methods (for example, precipitation, chromatography).

Gene

A sequence of DNA that codes for 1 or more proteins.

Hapten

A low molecular weight molecule that is not in itself antigenic unless conjugated to a 'carrier' molecule.

Harvesting

Procedure by which the cells, inclusion bodies or crude supernatants containing the unpurified active ingredient are recovered.

Hybridoma

An immortalized cell line that secretes desired (monoclonal) antibodies and is typically derived by fusing B-lymphocytes with tumour cells.

Import

To import into Canada a drug for the purpose of sale. (FDR, C.01A.001)

Inactivation

Removal of infectivity of microorganisms by chemical or physical modification.

Individual responsible for the quality management system

Person who ensures that every unit of blood or blood components has been collected and tested, processed, stored and distributed in compliance with the laws in force. This term is equivalent to the EU term "responsible person" and the PIC/S term "responsible person for blood establishment".

Label

Includes any legend, word or mark attached to, included in, belonging to or accompanying any food, drug, cosmetic, device or package. (Section 2, FDA)

To put a drug in its immediate container or to affix the inner or outer label to the drug. (FDR, C.01A.001)

Look back

Documented procedure to trace biologics that may be adversely affected by the use or incorporation of animal or human materials when either:

• such materials fail release tests due to the presence of contaminating agent(s) or
• conditions of concern become apparent in the source animal or human

Look-back information

Information that appears if a subsequent donation from a donor previously found negative (for example, viral markers) is found positive for any of the viral markers or any other risk factors that may induce a viral infection.

Look-back units

Plasma units donated by donors during a defined period before it is found that a donation from a high-risk donor should have been excluded from processing (for example, due to a positive test result).

Manufacturer or distributor

A person, including an association or partnership, who under their own name, or under a trade, design or word mark, trade name or other name, word or mark controlled by them, sells a food or drug. (FDR, A.01.010)

Master cell bank (MCB)

An aliquot of a single pool of cells that generally has been prepared from the selected cell clone under defined conditions, dispensed into multiple containers and stored under defined conditions. The MCB is used to derive all working cell banks. The testing performed on a new MCB (from a previous initial clone, MCB or working cell bank) should be the same as for the MCB unless justified.

Master virus seed (MVS)

As above, but in relation to viruses.

Master transgenic bank

As above, but for transgenic plants or animals.

Microorganism

A cellular or non-cellular microbiological entity, capable of replication or transferring genetic material and that cannot be reasonably detected by the naked human eye. Microorganisms include bacteria, fungi, viruses and parasites, and may be pathogenic or non-pathogenic in nature.

Monosepsis (axenic)

A single organism in culture that is not contaminated with any other organism.

Multi-product facility

A facility that manufactures, either concurrently or in campaign mode, a range of different biologics and within which equipment train(s) may or may not be dedicated to specific biologics.

Package

To put a drug in its immediate container or to affix the inner or outer label to the drug. (FDR, C.01A.001)

Person in charge of the quality control (QC) department

A person responsible for ensuring that each batch of (biologics) bulk process intermediate or drug in dosage form has been manufactured and checked in compliance with the laws in force and in accordance with the specifications and/or requirements of the marketing authorization. Is equivalent to the EU term "qualified person" and the PIC/S term "responsible person".

Plasma for fractionation

The liquid part of human blood remaining after:

• separation of the cellular elements from blood collected in a container containing an anticoagulant or
• separated by continuous filtration or centrifugation of anti-coagulated blood in an apheresis procedure

Intended for the manufacture of plasma-derived products, in particular albumin, coagulation factors and immunoglobulins of human origin, and specified in the European (or other relevant) Pharmacopoeia (Ph. Eur.) monograph "Human plasma for fractionation" (0853).

Plasmid

A piece of DNA usually present in a bacterial cell as a circular entity separated from the cell chromosome. Can be modified by molecular biology techniques, purified out of the bacterial cell and used to transfer its DNA to another cell.

Processing

Any of the following activities:

• assessing donor suitability
• collection and testing or preparing blood components

Products from human blood or human plasma

Products based on blood constituents that are prepared industrially by public or private establishments. (Refer to the definition for blood products.)

Quality control (QC)

Checking or testing that specifications are met. (ICH Q7)

Quality risk management (QRM)

A systematic process for assessing, controlling, communicating and reviewing risks to the quality of the product. Can be applied both proactively and retrospectively. (ICH Q9)

Raw material

A general term used to denote starting materials, reagents and solvents intended for use in the production of intermediates. (ICH Q7)

Seed lot

Collection of appropriate containers, whose contents are of uniform composition, stored under defined conditions. In contrast to cell bank, may describe collections of plasmids, viruses and so forth.

For master and working seed lots, refer to the definitions provided for master cell bank and working cell bank.

Specification

A detailed description of a drug, the raw material used in a drug or the packaging material for a drug. Includes a:

• statement of all properties and qualities of the drug, raw material or packaging material that are relevant to the manufacture, packaging and use of the drug, including the identity, potency and purity of the drug, raw material or packaging material
• detailed description of the methods used for testing and examining the drug, raw material or packaging material
• statement of tolerances for the properties and qualities of the drug, raw material or packaging material

(FDR, C.02.002)

"Conformance to specification" means that the material, when tested according to the listed analytical procedures, will meet the listed acceptance criteria.

Specified pathogen free (SPF)

Animal materials (for example, chickens, embryos or cell cultures) used to produce or quality control biologics from groups (flocks or herds) of animals free from specified pathogens. Such flocks or herds are defined as animals sharing a common environment and having their own caretakers who have no contact with non-SPF groups.

Test

To perform the tests, including any examinations, evaluations and assessments, as specified in Division 2 of the FDR.

Consult the Good manufacturing practices guide for drug products (GUI-0001)

Transgenic

An organism that contains a foreign gene in its normal genetic component for the expression of biological pharmaceutical materials.

Validation

A documented program that provides a high degree of assurance that a specific process, method or system will consistently produce a result that meets pre-determined acceptance criteria.

Vector

An agent of transmission that transmits genetic information from a cell or organism to another (for example, plasmids, liposomes, viruses).

Viral vector

A vector derived from a virus and modified by means of molecular biology techniques in a way as to retain some, but not all, the parental virus genes. If the genes responsible for virus replication capacity are deleted, the vector is made replication-incompetent.

Working cell bank (WCB)

A homogeneous pool of micro-organisms or cells that are distributed uniformly into a number of containers derived from a master cell bank, which are stored in such a way to ensure stability and for use in production.

Working virus seed (WVS)

As above, but in relation to viruses.

Working transgenic bank

As above, but for transgenic plants or animals.