Guide to validation of terminal sterilization process of drugs (GUI-0074): Glossary 

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• Acronyms
• Definitions

Acronyms

BI

biological indicator

CAPA

corrective and preventative action

CEPA

Canadian Environmental Protection Act, 1999

CI

chemical indicator

DUR

dose uniformity ratio

ECH

ethylene chlorohydrin

EG

ethylene glycol

EO

ethylene oxide

GMP

good manufacturing practices

ISO

International Organization for Standardization

MPQ

microbiological performance qualification

PCD

process challenge device

PIC/S

Pharmaceutical Inspection Co-operation Scheme

PQ

performance qualification

SAL

sterility assurance level

SDR

standard distribution of resistances

Definitions

The following definitions explain how terms are used in this document. If there's a conflict with a definition in the Food and Drugs Act (FDA) or Food and Drug Regulations (FDR), the definition in the act or regulations prevails. These definitions supplement those provided in the glossary in the Good manufacturing practices guide for drug products (GUI-0001).

Note: The source of a definition is provided in parentheses at the end of a definition.

Aeration
Part of the sterilization process during which ethylene oxide and/or its reaction products desorb from the product/material until predetermined levels are reached. (ISO 11135:2014)

Bioburden
The total number of viable microorganisms:

• on or in a packaging material, raw materials, starting materials, intermediates or finish product or
• in the manufacturing environment before sterilization

Biological 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 in the preparation of a drug listed in that Schedule. (C.04.001, FDR)

Biological indicator (BI)
A characterized preparation consisting of a number of microorganisms (bacterial spores) of known resistance to the sterilization method to monitor adequacy of sterilization.

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 shuttle type (with Parison cut) and rotary type (Closed Parison). (PIC/S Annex 1)

Bracketing strategy/approach
The design of a stability schedule where only samples on the extremes of certain design factors (such as strength, package size) are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested. For a range of strengths to be tested, bracketing applies if the strengths are identical or closely related in composition.

Examples:

• a tablet range made with different compression weights of a similar basic granulation
• a capsule range made by filling different plug fill weights of the same basic composition into different sized capsule shells

Bracketing can be applied to different container sizes or to different fills in the same container closure system. (ICH Q1A)

Bulk drug
A drug in dosage form that's not in its final packaging, usually in quantities larger than the largest commercially available package size.

Calibration
Set of operations that establish, under specified conditions, the relationship between:

• values of a quantity indicated by a measuring instrument or measuring system or values represented by a material measure or a reference material
• corresponding values realized by standards

(ISO 11135:2014)

Chemical indicator (non-biological indicator)
Test system that reveals change in 1 or more pre-defined process variables based on a chemical or physical change resulting from exposure to a process. (ISO 11135:2014)

Change control
A written procedure that describes the action to be taken if a change is proposed:

• to facilities, materials, equipment and/or processes used to fabricate, package and test drugs or
• that may affect the operation of the quality or support system

Change management
A systematic approach to proposing, evaluating, approving, implementing and reviewing changes. (ICH Q10)

Conditioning
Treatment of product within the sterilization cycle, but before ethylene oxide admission to attain a predetermined temperature and relative humidity throughout the load.

Corrective action
Action to eliminate the cause of non-conformity and to prevent recurrence. Note 1: There can be more than 1 cause for a non-conformity. Note 2: Corrective action is taken to prevent recurrence whereas preventive action is taken to prevent occurrence. (ISO 9000:2015)

D–value
The decimal reduction time/dose or time required to reduce a microbial population by 90% (1 log value) under specified test conditions.

D₁₂₁
D-value of a microorganism at an exposure temperature of 121˚C. (Sterilization by Moist Heat)

D_maxP
The maximum process dose allowed. This dose depends on the product or is determined on a case-by-case basis. It is set below the DmaxT, to prevent damage to the product, but is high enough to achieve a processing dose range (Dmax/Dmin ratio). (Sterilization by Irradiation)

D_maxT
The maximum dose tolerated by the product before product degradents increase to significant levels. (Sterilization by Irradiation)

D_minP
The minimum process dose required to achieve the required sterility assurance level (SAL). This dose is determined by the dose-setting validation. (Sterilization by Irradiation)

Dose uniformity ratio
The ratio of the maximum dose divided by the minimum dose. (Sterilization by Irradiation)

Dosimeter
Device with a reproducible, measurable response to radiation, which can be used to measure the absorbed dose in a given system. (ISO 11137-1:2006)

Drug
Includes any substance or mixture of substances manufactured, sold or represented for use in:

• diagnosing, treating, mitigating or preventing a disease, disorder or abnormal physical state, or its symptoms, in human beings or animals
• restoring, correcting or modifying organic functions in human beings or animals or
• disinfecting premises in which food is manufactured, prepared or kept

(Section 2, FDA)

In Division 1A and Division 2 of the FDR, "drug" does not include:

• a dilute drug premix
• a medicated feed as defined in subsection 2(1) of the Feeds Regulations, 1983
• an active ingredient that is for veterinary use and that is not an active pharmaceutical ingredient
• an active pharmaceutical ingredient that is for veterinary use and that isn't required to be sold pursuant to a prescription and that is also a natural health product as defined in subsection 1(1) of the Natural Health Products Regulations
• a drug that is used only in an experimental study in accordance with a certificate issued under section C.08.015

(C.01A.001(2), FDR)

Dwell time
The period that items are subjected to a given processing condition.

Fabricate
To prepare and preserve a drug for the purpose of sale.

(C.01A.001, FDR)

F₀
The amount of time in minutes, equivalent to time at 121.1˚C, to which a unit has been exposed during a sterilization cycle. The calculation of F₀ is based on a microorganism's D-value and the corresponding z-value (Sterilization by Moist Heat).

Gamma rays
Electromagnetic radiation (photons) originating in atomic nuclei and accompanying many nuclear reactions (such as fission, radioactive decay, neutron capture). Gamma rays are physically identical to X-rays of high energy. The only essential difference is that X-rays do not originate in the nucleus.

In-process drug
Any material or mixture of materials that must undergo further processing to become a drug in dosage form.

Ionizing radiation
Electromagnetic radiation (consisting of photons) or particulate radiation (consisting of electrons, neutrons, protons) capable of producing charged particles through interactions with matter.

Irradiation container
Holder in which product is transported through the irradiator. Note 1 to entry: The holder can be a carrier, cart, tray, product carton, pallet or other container. (ISO 11139:2018)

kGy
Gray (Gy) is the international unit for measuring the radiation dose delivered. 1 kGy=100,000 rads or 0.1 MRad (old terminology).

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)

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

Lifecycle
All phases in the life of a product from the initial development through marketing until the product is discontinued. (ICH Q8)

Material
A general term for raw materials (starting materials, reagents, solvents), process aids, intermediates, finished products and packaging and labelling materials.

Maximum acceptable dose
Dose given in the process specification as the highest dose that can be applied to a specified product without compromising safety, quality or performance. (ISO 11139:2018)

Maximum load
The maximum quantity or mass of items permitted in a sterilizer load.

Microbiological performance qualification (MPQ)
Method used to assess the rate of microbiological inactivation for a given process.

Microorganism
A cellular or non-cellular microbiological entity that can replicate or transfer genetic material and cannot be detected by the naked human eye. Microorganisms include bacteria, fungi, viruses and parasites, and may be pathogenic or non-pathogenic in nature. (Canadian Biosafety Standard, second edition)

Minimum load
The minimum quantity or mass of items permitted in a validated sterilization load.

Moist heat
Steam, steam-air mixtures and superheated water used for sterilization.

Non-condensable gases
Air and other gases that will not condense to liquid state, thereby not releasing latent heat under the conditions of sterilization.

Overkill
Sterilization process that demonstrated as delivering at least a 12 spore log reduction to a biological indicator that has a resistance equal to or greater than the product bioburden. (ISO 11135:2014)

Packaging material
Includes a label. (C.02.002, FDR)

Parametric release
A sterility release system based on effective control, monitoring, documentation and batch records review of validated sterilization process. This is in lieu of release procedures based on end-product sterility testing.

Performance qualification (PQ)
Documented verification that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on the approved process method and specifications. (ICH Q7)

Pharmaceutical
A drug other than a drug listed in Schedule C or D to the act. (C.01A.001, FDA)

Preconditioning
Treating the product before the sterilization cycle to attain a predetermined temperature and relative humidity throughout the load.

Preventive action
Action to eliminate the cause of a potential nonconformity or other potential undesirable situation. Note 1 to entry: There can be more than 1 cause for a potential nonconformity. Note 2 to entry: Preventive action is taken to prevent occurrence, while corrective action is taken to prevent recurrence. (ISO 9000:2015)

Process challenge device (PCD)
Item designed to constitute a defined resistance to a sterilization process and used to assess performance of the process. (ISO 11135:2014)

Process parameter
Specific value for a process variable. (ISO 11135:2014)

Process validation
The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a product that meets its predetermined specifications and quality attributes. (adapted from ICH Q7)

Product
A term used to refer to either raw materials, packaging components or the final pharmaceutical. The context will clarify which material is being referred to.

Qualification
Action of proving and documenting that equipment or ancillary systems are properly installed, work correctly and lead to the expected results. Qualification is part of validation, but the individual qualification steps do not constitute process validation. (ICH Q7)

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

Raw material
Any substance other than packaging material or an in-process drug that is used in drug manufacture. Includes substances that appear in the master formula but not in the drug, such as solvents and processing aids.

Requalification
Repetition of part of validation to confirm a specified process continues to be acceptable. (ISO 11135:2014)

Revalidation
Required when there's a change in any of the critical process parameters, formulation, primary packaging components, raw material fabricators, major equipment or premises. Failure to meet product and process specifications in sequential batches would also require process revalidation.

Risk
The combination of the probability of occurrence of harm and the severity of that harm. (ICH Q9)

Risk assessment
A systematic process for organizing information to support a risk decision to be made within a risk management process. Consists of identifying the hazards and analyzing and evaluating risks associated with exposure to those hazards. (ICH Q9)

Saturated steam (also referred to as dry saturated steam)
Steam that is:

• at a temperature and pressure that corresponds to the vaporization curve of water
• in a state of equilibrium between being a liquid and a gas, with no entrained liquid water

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 manufacturing, packaging and using the drug, including the identity, potency and purity of the drug, raw material or packaging material
• detailed description of the methods used to test and examine the drug, raw material or packaging material
• statement of tolerances for the properties and qualities of the drug, raw material or packaging material

(C.02.002, FDR)

State of control
A condition in which the set of controls consistently provides assurance of acceptable process performance and product quality. (ICH Q10)

Sterile
Free from viable microorganisms. (ISO 11135:2014)

Sterility assurance level (SAL)
Expected probability of a surviving microorganism on each individual product after being exposed to a valid sterilization process.

Sterilization
A suitably designed, validated and controlled process that inactivates or removes viable microorganisms in a product until sterility is obtained. (EMA guideline on sterilizing the medicinal product, active substance, excipient and primary container)

Sterilization cycle
A sequence of defined operating parameters (such as time, temperature and pressure) and conditions for rendering an item sterile. (Does not apply to Sterilization by Irradiation).

Sterilizing agent
Physical or chemical entity, or combination of entities, that have sufficient microbicidal activity to achieve sterility under defined conditions. (ISO 11135:2014)

Sterilization indicators
Devices used to monitor the presence or attainment of 1 or more of the parameters required for a satisfactory sterilization process or used in a specific test of sterilization equipment.

Survivor curve
Graphical representation of the inactivation of a population of microorganisms with increasing exposure to a microbicidal agent under stated conditions. (ISO 11135:2014)

Temperature distribution
Temperature measurement of the heating medium across the chamber load zone.

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)). (PIC/S, Annex 1)

Validation
A documented program that provides a high degree of assurance that a specific process, method or system will consistently produce a result meeting pre-determined acceptance criteria. (ICH Q7)

Validation protocol
A written plan of actions stating how process validation will be conducted. It will:

• specify who will conduct the various tasks
• define testing parameters, sampling plans, testing methods and specifications
• specify product characteristics and equipment to be used

The validation protocol must specify the:

• minimum number of batches to be used for validation studies
• acceptance criteria
• who will sign, approve or disapprove the conclusions derived from such a scientific study

Worst-case
A set of conditions encompassing upper and lower processing limits and circumstances, including those within standard operating procedures that pose the greatest chance of process or product failure (compared to ideal conditions). Such conditions do not necessarily induce product or process failure.

Z-value
The temperature change required to effect a 1 log reduction in the D-value.

X-ray
Ionizing electromagnetic radiation of extranuclear origin.