Studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal stability studies. Data from these studies, in addition to long term stability studies, can be used to assess longer term chemical effects at non accelerated conditions and to evaluate the effect of short term excursions outside the label storage conditions such as might occur during shipping. Results from accelerated testing studies are not always predictive of physical changes. (See chapter E.1.A.)
Numerical limits, ranges, or other suitable measures for acceptance of test results. [EU GMP Guide Part II, chapter C.5]
Product specifications and acceptance/rejection criteria, such as acceptable quality level and unacceptable quality level, with an associated sampling plan, that are necessary for making a decision to accept or reject a lot or batch (or any other convenient subgroups of manufactured units). [21 CFR 210.3, chapter D.1.1]
Numerical limits, ranges, or other suitable measures of test results necessary to determine acceptance of the drug substance, drug products, or materials at stages of their manufacture. [FDA Guidance for Industry cGMP for Phase 1 Investigational Drugs, chapter D.15]
Numerical limits, ranges, or other suitable measures for acceptance of the results of analytical procedures. [ICH Q6A, chapter E.6.A]
Numerical limits, ranges, or other suitable measures for acceptance of the results of analytical procedures which the drug substance or drug product or materials at other stages of their manufacture should meet. [ICH Q6B, chapter E.6.B]
Measurable terms under which a test result will be considered acceptable. [WHO GMP: Main Principles for Pharmaceutical Products, chapter G.1.1.1]
The accuracy of an analytical procedure expresses the closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value and the value found. This is sometimes termed trueness. (ICH Q2A, see chapter E.2.)
The Federal Food, Drug, and Cosmetic Act, as amended (21 U.S.C. 301 et seq.). (CFR, see chapter D.)
An established microbial or airborne particle level that, when exceeded, should trigger appropriate investigation and corrective action based on the investigation. [FDA Guidance for Industry Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice, chapter D.10]
Established criteria, e.g. microbial or particulate levels, requiring immediate follow-up and corrective action if exceeded. [PIC/S PI 007, chapter F.2]
Action level (in clean rooms)
An established microbial or airborne particle level that, when exceeded, should trigger appropriate investigation and corrective action based on the investigation.
Any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. The term includes those components that may undergo chemical change in the manufacture of the drug product and be present in the drug product in a modified form intended to furnish the specified activity or effect. (CFR
Active pharmaceutical ingredient (API)
Any substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form and that, when used in the production of a drug, becomes an active ingredient of that drug. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure and function of the body. (WHO)
Advanced electronic signature
An electronic signature, which meets the following requirements:
a) it is uniquely linked to the signatory;
b) it is capable of identifying the signatory;
c) it is created using means that the signatory can maintain under his control; and
d) it is linked to the data to which it relates in such a manner that any change of the data is detectable.
Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. (DIRECTIVE 2001/20/EC), see also Serious adverse event (SAE)
All untoward and unintended responses to an investigational medicinal product related to any dose administered. (DIRECTIVE 2001/20/EC)
The Food and Drug Administration. (CFR, see chapter D)
A system of cleaning in which the manufacturing equipment is filled with cleaning solution, and the cleaning solution is agitated, usually with the exiting agitation equipment in that equipment.
The mixing or movement of a cleaning solution in the equipment. Agitation may occur from flow of the cleaning solution, or it may be due to mixers or impellers. Agitation continually supplies fresh cleaning solution to the surfaces.
An enclosed space with two or more doors, and which is interposed between two or more rooms, e.g. of differing class of cleanliness, for the purpose of controlling the air-flow between those rooms when they need to be entered. An air lock is designed for and used by either people or goods. (EU GMP Guide)
Air separation plant
Air separation plants take atmospheric air and through processes of purification, cleaning, compression, cooling, liquefaction and distillation separate the air into the gases oxygen, nitrogen and argon (see Annex 6 Manufacture of Medicinal Gases).
An established microbial or airborne particle level giving early warning of potential drift from normal operating conditions and triggering appropriate scrutiny and follow-up to address the potential problem. Alert levels are always lower than action levels.
Alert limits (environmental monitoring)
Established microbial or particulate levels giving early warning of potential drift from normal operating conditions which are not necessarily grounds for definitive corrective action but which require follow-up investigation. (PIC/S PI 007-5: Recommendation on the Validation of Aseptic Processes)
Alert limits (media fill)
1. Established levels or numbers of positive media filled units, the cause of which should be investigated, but which are not necessarily grounds for definitive corrective action. (PIC/S PI 007-5: Recommendation on the Validation of Aseptic Processes)
2. established levels or numbers of positive media filled units, the cause of which should be investigated, but which are not necessarily grounds for definitive corrective action.
Deviation of an analytical result from the true value due to mistakes made when carrying out the testing e.g. as a consequence of technical problems. A differentiation is made between apparent (reproducible) and non-apparent (unreproductible) analysis errors. The former can be attributed to incorrectly performing the analysis (e.g. errors in documentation, incorrect calculation/evaluation, non-compliance with the conditions, incorrect standard, incorrect initial weight of sample/standard, incorrect dilution, uncalibrated analytical apparatus). The latter can be attributed to previously undetected latent errors (e.g. imprecise formulation of analytical method, unsound method).
The analytical procedure refers to the way of performing the analysis. It should describe in detail the steps necessary to perform each analytical test. This may include but is not limited to: the sample, the reference standard and the reagents preparations, use of the apparatus, generation of the calibration curve, use of the formulae for the calculation, etc. (ICH Q2A, see chapter E.2.)
Annual product review
A yearly evaluation of the production and quality control data of a preparation. The analysis of this data (e.g. from correlations, trends, deviations, unexpected variability, etc.) results in valuable indications regarding the validation status of the manufacturing process. (CFR, see chapter D.)
API starting material
A raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API Starting Materials are normally of defined chemical properties and structure. (Part II Basic Requirements for Active Substances used as Starting Materials)
A software program developed or adapted to the specific requirements of the application.
Applications (for computer systems)
Term used to describe software written to perform tasks on a computer.
Part of premises that is specific to the manufacture of medicinal gases.
A state of control attained by using an aseptic work area and per forming activities in a manner that precludes microbiological contamination of the exposed sterile product.
Operation whereby the product is sterilised separately, then filled and packaged using sterilised containers and closures in critical processing zones. (PIC/S PI 007, see chapter F.2.)
Aseptic manufacturing area
The classified part of a facility that includes the aseptic processing room and ancillary cleanrooms.
Aseptic processing facility
A building, or segregated segment of it, containing cleanrooms in which air supply, materials, and equipment are regulated to control microbial and particle contamination.
Aseptic processing room
A room in which one or more aseptic activities or processes is performed.
The condition where the installation is installed and operating, complete with production equipment but with no operating personnel present. See also In operation.
Chronological record of system activities to enable the reconstruction and examination of the sequence of events and/or changes in an event.
Term used to cover a broad range of systems, including automated manufacturing equipment, control systems, automated laboratory systems, manufacturing execution systems and computers running laboratory or manufacturing database systems. The automated system consists of the hardware, software and network components, together with the controlled functions and associated documentation. Automated systems are sometimes referred to as computerised systems.
The formation of averages from several individual values.
A physical partition that affords aseptic processing area (ISO 5) protection by partially separating it from the surrounding area.
A specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture. (ICH Q7A) (EU GMP Guide, Part II, see chapter C.5). See also Lot.
Batch (or Lot)
A defined quantity of starting material, packaging material or product processed in one process or series of processes so that it could be expected to be homogeneous. Note: To complete certain stages of manufacture, it may be necessary to divide a batch into a number of sub batches, which are later brought together to form a final homogeneous batch. In the case of continuous manufacture, the batch must correspond to a defined fraction of the production, characterised by its intended homogeneity. For control of the finished product, the following definition has been given in Annex 1 of Directive 2001/83/EC as amended by Directive 2003/63/EC: For the control of the finished product, a batch of a proprietary medicinal product comprises all the units of a pharmaceutical form which are made from the same initial mass of material and have undergone a single series of manufacturing operations or a single sterilisation operation or, in the case of a continuous production process, all the units manufactured in a given period of time. (EU GMP Guide)
Batch number (or lot number)
A unique combination of numbers, letters, and/or symbols that identifies a batch (or lot) and from which the production and distribution history can be determined. (EU GMP Guide)
Each batch of finished product must be certified by a Qualified Person within the EU before being released for sale or supply in the EU or for export.
Batch systems map procedural sequences in the process control system. They manage formulations which produce the connection between the manufacturers instructions from the ERP system and the technical equipment of the process facility. Likewise, the MES provides parameters based on the raw materials.
A system produced for a customer, specifically to order, to meet a defined set of user requirements.
1. Total number of viable microorganisms on or in pharmaceutical product prior to sterilisation. (PIC/S PI 007, see chapter F.2.)
2. The level and type (e.g. objectionable or not) of micro-organisms that can be present in raw materials, API starting materials, intermediates or APIs. Bioburden should not be considered contamination unless the levels have been exceeded or defined objectionable organisms have been detected. (EU GMP Guide, Part II, see chapter C.5)"
A contained system, such as a fermenter, into which biological agents are introduced along with other materials so as to effect their multiplication or their production of other substances by reaction with the other materials. Biogenerators are generally fitted with devices for regulation, control, connection, material addition and material withdrawal. (EU GMP Guide)
Micro-organisms, including genetically engineered micro-organisms, cell cultures and endoparasites, whether pathogenic or not. (EU GMP Guide)
Biological Indicator (BI)
A population of microorganisms inoculated onto a suitable medium (e.g., solution, container or closure) and placed within appropriate sterilizer load locations to determine the sterilization cycle efficacy of a physical or chemical process. The challenge microorganism is selected based upon its resistance to the given process. Incoming lot D-value and microbiological count define the quality of the BI.
A method of verifying an individual
A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s). Single-blinding usually refers to the subject(s) being unaware, and doubleblinding usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment assignment(s). In relation to an investigational medicinal product, blinding shall mean the deliberate disguising of the identity of the product in accordance with the instructions of the sponsor. Unblinding shall mean the disclosure of the identity of blinded products. (Annex 13, see chapter C.6.13.)
Whole blood collected from a single donor and processed either for transfusion or further manufacturing (Annex 14, see chapter C.6.14.)
Therapeutic components of blood (red cells, white cells, plasma, platelets), that can be prepared by centrifugation, filtration and freezing using conventional blood bank methodology (Annex 14, see chapter C.6.14.)
Blow the pressure down to atmospheric pressure. (Annex 6, chapter C.6.6.)
Filling of primary packages with bulk product.
The design of a stability schedule such that only samples on the extremes of certain design factors, e.g., 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. Where a range of strengths is to be tested, bracketing is applicable if the strengths are identical or very closely related in composition (e.g., for a tablet range made with different compression weights of a similar basic granulation, or a capsule range made by filling different plug fill weights of the same basic composition into different size capsule shells). Bracketing can be applied to different container sizes or different fills in the same container closure system. (ICH Q 1A, see chapter E.1.A.)
A manifestation of an error in software (a fault).
Any gas intended for medicinal use, which has completed all processing up to but not including final packaging. (Annex 6, chapter C.6.6).
Any product which has completed all processing stages up to, but not including, final packaging. (EU GMP Guide )
Bulk production batch
A batch of product, of a size described in the application for a marketing authorisation, either ready for assembly into final containers or in individual containers ready for assembly to final packs. (A bulk production batch may, for example, consist of a bulk quantity of liquid product, of solid dosage forms such as tablets or capsules, or of filled ampoules). (Annex 16, see chapter C.6.16.)
1. The determination and documentation of the difference between the displayed value and the correct applicable value without technical intervention. (DIN 31051) In measuring technology, adjustment involves the setting and balancing of a measuring instrument to prevent deviations in measurements exceeding the margin of error. Adjustment therefore requires intervention on the part of the measuring instrument, normally by making a permanent change. (DIN 1319/Part 1)
2. The demonstration that a particular instrument or device produces results within specified limits by comparison with those produced by a reference or traceable standard over an appropriate range of measurements. (EU GMP Guide, Part II, see chapter C.5)
3. The set of operations which establish, under specified conditions, the relationship between values indicated by a measuring instrument or measuring system, or values represented by a material measure, and the corresponding known values of a reference standard. (EU GMP Guide )"
Corrective Action and Preventive Action
The pharmaceutical company should have a system for implementing corrective actions and preventive actions resulting from the investigation of complaints, product rejections, non-conformances, recalls, deviations, audits, regulatory inspections and findings, and trends from process performance and product quality monitoring. A structured approach to the investigation process should be used with the objective of determining the root cause. The level of effort, formality, and documentation of the investigation should be commensurate with the level of risk, in line with ICH Q9. CAPA methodology should result in product and process improvements and enhanced product and process understanding. (ICH Q10 Pharma Quality System)
Cell bank system
A cell bank system is a system whereby successive batches of a product are manufactured by culture in cells derived from the same master cell bank. A number of containers from the master cell bank are used to prepare a working cell bank. The cell bank system is validated for a passage level or number of population doublings beyond that achieved during routine production.
The result from the in-vitro growth of cells isolated from multi cellular organisms. (EU GMP Guide )
Certification of the finished product batch
The certification in a register or equivalent document by a Q.P., as defined in Article 51 of Directive 2001/83/EC and Article 55 of Directive 2001/82/EC, before a batch is released for sale or distribution. (Annex 16, see chapter C.6.16.)
This includes all changes that are planned and known in advance. This means targeted and desired changes to sequences, processes and, in many cases, also to the products themselves, which have some influence on quality.
A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect a validated status of facilities, systems, equipment or processes. The intent is to determine the need for action that would ensure that the system is maintained in a validated state. (Annex 15, see chapter C.6.15.)
A less formal approach to change control that is generally utilised during the preliminary planning and design stage of a project. (Many companies will elect to move straight to a change control system in a design stage of a complex project. This has the advantage of formality, more accurate records and documentation as well as a strong traceability and accountability feature).
Chemical development studies
Studies conducted to scale-up, optimise, and validate the manufacturing process for a new drug substance. (ICH Q3A)
Not super imposable with its mirror image, as applied to molecules, conformations, and macroscopic objects, such as crystals. the term has been extended to samples of substances whose molecules are chiral, even if the macroscopic assembly of such molecules is racemic. (ICH Q6A)
An area with defined environmental control of particulate and microbial contamination, constructed and used in such a way as to reduce the introduction, generation and retention of contaminants within the area. (EU GMP Guide )
Clean in Place (CIP)
Cleaning involving cleaning equipment without first disassembling the equipment. Usually performed with a spray device.
Clean Out of Place (COP)
Cleaning involving disassembling the equipment before cleaning it elsewhere.
An area constructed and operated in such a manner that will achieve the aims of both a clean area and a contained area at the same time. (EU GMP Guide )
Chemical Agent or solution used for cleaning, may be aqueous or solvent based
Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products. (Annex 15, see chapter C.6.15.)
A room designed, maintained, and controlled to prevent particle and microbiological contamination of drug products. Such a room is assigned and reproducibly meets an appropriate air cleanliness classification.
The four zones in the world that are distinguished by their characteristic prevalent annual climatic conditions. (ICH Q 1A, see chapter E.1.A.)
Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamik effects of an investigational product(s) and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of one or more investigational medicinal product(s) with the object of ascertaining its/their safety and/or efficacy. (Annex 13, see chapter C.6.13.)
An environment in which system access is controlled by persons who are responsible for the content of electronic records that are on the system. (CFR, see chapter D.)
Colony Forming Unit (CFU)
A microbiological term that describes the formation of a single macroscopic colony after the introduction of one or more micro organisms to microbiological growth media. One colony forming unit is expressed as 1 CFU.
A drug product which contains more than one drug substance.
Commercial off-the-shelf (COTS)
An engineering term that covers all aspects of bringing a system or sub-system to a position where it is regarded as being ready for use in pharmaceutical manufacture. Commissioning involves all the basis requirements of Installation Qualification (IQ) and Operational Qualification (OQ).
Production batches of a drug substance or drug product for which the stability studies are initiated or completed post approval through a commitment made in the registration application. (ICH Q 1A)
Comparability bridging study
A study performed to provide non-clinical or clinical data that allows extrapolation of the existing data from the drug product produced by the current process to the drug product from the changed process.
The activities, including study design, conduct of studies, and evaluation of data, that are designed to investigate whether the products are comparable.
A conclusion that products have highly similar quality attributes before and after manufacturing process changes and that no adverse impact on the safety or efficacy, including immunogenicity, of the drug product occurred. This conclusion can be based on an analysis of product quality attributes. In some cases, nonclinical or clinical data might contribute to the conclusion.
An investigational or marketed product (i.e. active control), or placebo, used as a reference in a clinical trial. (Annex 13, see chapter C.6.13.)
Dealing with defects in drug products. The defect may mean that the intended healing effect does not occur as expected, and in the worst case that it has no healing effect or causes other medical problems. (EU GMP Guide )
Any ingredient intended for use in the manufacture of a drug product, including those that may not appear in the final drug product.
A process wherein bulk drug substance is combined with another bulk drug substance and/or one or more excipients to produce a drug product. (PIC/S PI 007, see chapter F.2.)
A gas which when packaged under pressure is entirely gaseous at
Various pieces of equipment in the computer system, including the central processing unit, the printer, the modem, the cathode ray tube (CRT), and other related apparatus.
A group of hardware components and associated soft ware, designed and assembled to perform a specific function or group of functions. (EU GMP Guide, Part II, see chapter C.5)
A system including the input of data, electronic processing and the output of information to be used either for reporting or automatic control. (EU GMP Guide, Part II, see chapter C.5)
Concentrated form of formulated cleaning agent. A concentrate is usually diluted with water for use.
Validation carried out during routine production of products intended for sale. (Annex 15, chapter C.6.15.)
The documented physical and functional characteristics of a particular item, or system, e.g. software, computerised system, hardware, firmware and operating system. A change converts one configuration into a new one.
The process of identifying and defining the configuration items in a system, controlling the release and change of these items throughout the system life cycle, recording and reporting the status of configuration items and change requests, and verifying the completeness and correctness of configuration items.
A signed statement that a process or test has been conducted in accordance with GMP and the relevant marketing authorisation, as agreed in writing with the Q.P. responsible for certifying the finished product batch before release. Confirm and confirmed have equivalent meanings. (Annex 16, chapter C.6.16.)
are those undertaken to establish photo stability characteristics under standardized conditions. These studies are used to identify precautionary measures needed in manufacturing or formulation and whether light resistant packaging and/or special labelling is needed to mitigate exposure to light. For the confirmatory studies, the batch(es) should be selected according to batch selection for long-term and accelerated testings. (ICH Q1B)
An area constructed and operated in such a manner (and equipped with appropriate air handling and filtration) so as to prevent contamination of the external environment by biological agents from within the area. (EU GMP Guide )
A container is a cryogenic vessel, a tank, a tanker, a cylinder, a cylinder bundle or any other package that is in direct contact with the medicinal gas. (Annex 6, see chapter C.6.6.)
Container closure system
The sum of packaging components that together contain and protect the dosage form. This includes primary packaging components and secondary packaging components, if the latter are intended to provide additional protection to the drug product. A packaging system is equivalent to a container closure system. (ICH Q1A, see chapter E.1.A)
1. Health protection for operators and as product protection in the pharmaceutical and API area. (EU GMP Guide )
2. The action of confining a biological agent or other entity within a defined space.
See Primary containment: A system of containment which prevents the escape of a biological agent into the immediate working environment. It involves the use of closed containers or safety biological cabinets along with secure operating procedures.
See Secondary containment: A system of containment which prevents the escape of a biological agent into the external environment or into other working areas. It involves the use of rooms with specially designed air handling, the existence of airlocks and/or sterilisers for the exit of materials and secure operating procedures. In many cases it may add to the effectiveness of primary containment.
The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or onto a raw material, inter mediate, or API during production, sampling, packaging or repackaging, storage or transport. (EU GMP Guide, Part II, see chapter C.5)
Continuous process verification
An alternative approach to process validation in which manufacturing process performance is continuously monitored and evaluated. (ICH Q8A, see chapter E.8)
A manufacturer performing some aspect of manufacturing on behalf of the original manufacturer. (EU GMP Guide, Part II, see chapter C.5)
An area constructed and operated in such a manner that some attempt is made to control the introduction of potential contamination (an air supply approximating to grade D may be appropriate), and the consequences of accidental release of living organisms. The level of control exercised should reflect the nature of the organism employed in the process. At a minimum, the area should be maintained at a pressure negative to the immediate external environment and allow for the efficient removal of small quantities of airborne contaminants. (EU GMP Guide )
Action for eliminating an identified fault.
Action taken to eliminate the cause of a detected fault or another undesired situation.
Small model surface used for either laboratory testing of cleaning performance, or for swab recovery studies.
"Central processing unit of a computer where the logic circuitry is located
Describes a process step, process condition, test requirement, or other relevant parameter or item that must be controlled within predator mined criteria to ensure that the product meets its specification. (EU GMP Guide, Part II, see chapter C.5)
An area designed to maintain sterility of sterile materials. Sterilized product, containers, closures, and equipment may be exposed in critical areas.
Surfaces that may come into contact with or directly affect a sterilized product 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 variable study
A study that serves to measure variables (parameters) critical to the satisfactory operation of a piece of equipment or plant and to assure their operation within monitored and controlled limits. Examples of variables would be pressure, temperature, flow rates, time etc.
1. Contamination of a material or of a product with another material or product. (EU GMP Guide, Part II, see chapter C.5)
2. Contamination of a starting material, intermediate product or finished product with another starting material or product during production."
Crude plant (vegetable drug)
Fresh or dried medicinal plant or parts thereof. (EU GMP Guide )
Gas which liquefies at 1.013 bar at temperature below
1. A container designed to contain liquefied gas at extremely low temperature. (EU GMP Guide )
2. A static or mobile thermally insulated container designed to contain liquefied or cryogenic gases. The gas is removed in gaseous or liquid form. (Annex 6, see chapter C.6.6.)"
Work done before the validation protocol to establish a cleaning SOP. May involve lab, pilot scale, as well as full process testing.
1. A container designed to contain gas at a high pressure. (EU GMP Guide)
2. A transportable pressure container with a water capacity not exceeding 150 litres. In this document when using the word cylinder it includes cylinder bundle (or cylinder pack) when appropriate. (Annex 6, chapter C.6.6.)"
A set assembly of cylinders, which are fastened together in a frame and interconnected by a manifold, transported and used as a unit. (Annex 6, see chapter C.6.6.)
The time (in minutes) of exposure at a given temperature that causes a one-log or 90 percent reduction in the population of a specific micro organism.
An area in process piping which leads nowhere (think of it as a dead-end street).
The process of locating, analysing, and correcting suspected faults.
Person(s) with the competence and authority to make appropriate and timely quality risk management decisions. (ICH Q9A)
A process that eliminates viable bioburden via use of sporicidal chemical agents.
Equipment only used for the manufacture of one product or one related product line
"A limit that is chosen as a minimum if scientifically justified calculations result in limit values that would be practically excessive. A typical default limit in the next product for finished drug products is 10 ppm
1. An impurity resulting from a chemical change in the drug substance brought about during manufacture and/or storage of the new drug product by the effect of, for example, light, temperature, pH, water, or by reaction with an excipient and/or the immediate container closure system. (3b)
2. A molecule resulting from a chemical change in the drug molecule brought about over time and/or by the action of e.g., light, temperature, pH, water, or by reaction with an excipient and/or the immediate container/closure system. Also called decomposition product. (ICH Q6A)"
A description of the degradation products observed in the drug substance or drug product. (ICH Q3b)
Release of a drug (or drugs) at a time other than immediately following oral administration. (ICH Q6A)
A process used to destroy or remove pyrogens (e.g., endotoxin).
Design Qualification (DQ)
The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose. (Annex 15, see chapter C.6.15.)
The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval. (ICH Q8A)
The ability to discover or determine the existence, presence, or fact of a hazard. (ICH Q9A)
The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value. (ICH Q2A, see chapter E.2.).
A type of cleaning agent, usually aqueous based and utilizing surfactants.
Studies conducted to scale-up, optimise, and validate the manufacturing process for a drug product. (3b)
Departure from an approved instruction or established standard. (EU-GMP-Guide Part II, see chapter C.5.)
Deviations are observed whenever an unplanned move away from a prescribed sequence or an established standard occurs.
Deionised water, or water from which all the ionized species have been removed.
Relating to separate and discrete information.
An electronic signature based upon cryptographic methods of originator authentication, computed by using a set of rules and a set of parameters such that the identity of the signer and the integrity of the data can be verified. (CFR, see chapter D.)
Direct contact test
Surface sampling procedure (e.g. by agar plates)
Process by which surface bioburden is reduced to a safe level or eliminated. Some disinfection agents are effective only against vegetative microbes, while others possess additional capability to effectively kill bacterial and fungal spores.
The working documents received from the PDG or one or more pharmacopoeial sources (USP, Ph. Eur., or JP) that contain the proposed pharmacopoeial text and any other support documents provided for Q4B evaluation. (ICH Q4A)
describe in detail the requirements with which the products or materials used or obtained during manufacture have to conform. They serve as a basis for quality evaluation. Manufacturing Formulae, Processing and Packaging Instructions state all the starting materials used and lay down all processing and packaging operations. Procedures give directions for performing certain operations e.g. cleaning, clothing, environmental control, sampling, testing, equipment operation. Records provide a history of each batch of product, including its distribution, and also of all other relevant circumstances pertinent to the quality of the final product. (EU GMP Guide )
A pharmaceutical product type (e.g., tablet, capsule, solution, cream) that contains a drug substance generally, but not necessarily, in association with excipients. (ICH Q1A, see chapter E.1.A)
Drug (medicinal) product
The dosage form in the final immediate packaging intended for marketing. (EU GMP Guide, Part II, see chapter C.5.)
A finished dosage form, for example, tablet, capsule, solution, etc., that contains an active drug ingredient generally, but not necessarily, in association with inactive ingredients. The term also includes a finished dosage form that does not contain an active ingredient but is intended to be used as a placebo. (ICH Q1A, chapter E.1.A)
The unformulated drug substance that may subsequently be formulated with excipients to produce the dosage form. Active Pharmaceutical Ingredient. (ICH Q1A, chapter E.1.A)
Conditions relating to clean area classification under conditions of normal production.
Computer-assisted, interactive learning programs. These software packages often contain small video units combined with text or audio teaching contents, allow knowledge to be tested via multiple choice tests or case studies, and thus enable online success monitoring.
"(CDI = Continuous Deionisation
Any combination of text, graphics, data, audio, pictorial, or other information representation in digital form that is created, modified, maintained, archived, retrieved, or distributed by a computer system. (CFR, see chapter D.)
1. An electronic measure that can be substituted for a handwritten signature or initials for the purpose of signifying approval, authorisation or verification of specific data entries. See also definition for
A system, usually microprocessor or PLC based, whose sole purpose is to control a particular piece of automated equipment. This is contrasted with a standalone computer system.
A compound with the same molecular formula as the drug substance that differs in the spatial arrangement of atoms within the molecule and is a non super imposable mirror image. (ICH Q3A, see chapter E.3.A)
Compounds with the same molecular formula as the drug substance, which differ in the spatial arrangement of atoms within the molecule and are non super imposable mirror images. (ICH Q6A, chapter E.6.A )
1. A pyrogenic product (e.g., lipopolysaccharide) present in the bacterial cell wall. Endotoxin can lead to reactions in patients receiving injections ranging from fever to death. 2. Components of the cell wall in gram-negative bacteria that cause fever on parenteral administration. Tested using the LAL test (Limulus Amebocyte Lysate test).
Enterprise Resource Planning Systems (ERP)
ERP systems belong to the company management levels with strategic, commercial tasks with a longer-term time frame. The most widely used ERP system is SAP.
Environmental monitoring programme
Defined documented programme which describes the routine particulate and microbiological monitoring of processing and manufacturing areas, and includes a corrective action plan when action levels are exceeded. (PIC/S PI 007, see chapter F.2.)
All cases where individual items, or items that are connected with one another, are used to manufacture, process or package pharmaceutical products through direct or indirect contact with one another. Equipment may be driven manually or mechanically. Production machines, testing or control devices, as well as supply and disposal systems for air, water and other utilities, are also included under
Series of individual pieces of equipment linked together for a given process. May be cleaned individually or as a process train.
An independent body in a Member State, consisting of healthcare professionals and nonmedical members, whose responsibility it is to protect the rights, safety and wellbeing of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, expressing an opinion on the trial protocol, the suitability of the investigators and the adequacy of facilities, and on the methods and documents to be used to inform trial subjects and obtain their informed consent. (DIRECTIVE 2001/20/EC)
To remove the residual gas in a container by pulling a vacuum on it. (Annex 6, see chapter C.6.6.)
"A substance, other than the active ingredient, which has been appropriately evaluated for safety and is included in a drug delivery system to: aid in the processing of the drug delivery system during its manufacture
A biological agent where either the corresponding disease does not exist in a given country or geographical area, or where the disease is the subject of prophylactic measures or an eradication programme undertaken in the given country or geographical area. (EU GMP Guide )
Expiry date (expiration date)
The date placed on the container/labels of an API designating the time during which the API is expected to remain within established shelf life specifications if stored under defined conditions, and after which it should not be used. (ICH Q1A, chapter E.1.A)
Products which are formulated to make the drug available over an extended period after administration. (ICH Q6A)
An impurity arising from any source extraneous to the manufacturing process. (ICH Q3A)
The total amount of heat that acts on the sterilisation goods during a sterilisation process, adjusted according to the relevant temperature (here 121
Factory acceptance test
The partial commissioning and qualification of equipment and/or systems prior to their shipment from the fabricators site (ISPE).
Any particulate contaminant with a length at least three times greater than its width. (CFR, see chapter D.) See also Non-fiber-releasing filter.
A medicinal product which has undergone all stages of production, including packaging in its final container. (EU GMP Guide )
Finished product batch
With reference to the control of the finished product, a finished product batch is defined in Part 1 Module 3 point 220.127.116.11 of Directive 2001/83/EC2 and in Part 2 section F 1 of Directive 2001/82/EC. In the context of this annex the term in particular denotes the batch of product in its final pack for release to the market. (Annex 16, see chapter C.6.16.)
A software program permanently recorded in a hardware device, such as an EPROM. (Note: EPROM stands for Erasable Programmable Read Only Memory)
Forced degradation testing studies
are those undertaken to degrade the sample deliberately. These studies, which may be undertaken in the development phase normally on the drug substances, are used to evaluate the overall photosensitivity of the material for method development purposes and/or degradation pathway elucidation. (ICH Q1B)
Formal experimental design
A structured, organized method for determining the relationship between factors affecting a process and the output of that process. Also known as
Formal stability studies
Long term and accelerated (and intermediate) studies undertaken on primary and/or commitment batches according to a pre scribed stability protocol to establish or confirm the re-test period of a drug substance or the shelf life of a drug product. (ICH Q1A, chapter E.1.A)
Functional requirements (ANSI/IEEE)
Statements that describe functions a computer-related system must be capable of performing.
Statements of how the computerised system will satisfy functional requirements of the computer-related system.
A process for verifying that software, a system, or a system component performs its intended functions.
Labelling derived from a sheet of material on which more than one item of labelling is printed. (CFR, see chapter D.)
A substance or a mixture of substances that is completely gaseous at 1,013 bar (101,325 kPa) and +15
The gauging of a balance involves testing and stamping by the relevant gauging authority in accordance with the regulations.
Documents that must be compiled within the scope of the production and control of medicinal products due to applicable GMP rules. Examples of GMP-mandatory documents: operating procedures, manufacturing/testing documentation, deviation reports, change control documentation, etc.
Good Clinical Practice (GCP)
A standard for the design, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical trials, that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity and confidentiality of trial subjects are protected. (ICH)
Good Laboratory Practices (GLP)
A quality assurance system based on national legal requirements (e.g.
A program that establishes, both initially and on a periodic basis, the capability of an individual to don the complete sterile gown in an aseptic manner.
Validation strategy for multiproduct equipment in which three PQ runs are performed on a representative product (usually the most difficult to clean), and that performance is considered to apply to the cleaning of all products within that defined group.
Growth promotion test
Test performed to demonstrate that media will support microbial growth. (PIC/S PI 007, see chapter F.2.)
The scripted name or legal mark of an individual handwritten by that individual and executed or adopted with the present intention to authenticate a writing in a permanent form. The act of signing with a writing or marking instrument such as a pen or stylus is preserved. The scripted name or legal mark, while conventionally applied to paper, may also be applied to other devices that capture the name or mark. (CFR, see chapter D.)
Physical electronic circuitry and associated equipment.
Hardware acceptance test specification
Statements for the testing of all key aspects of hardware installation to assure adherence to appropriate codes and approved design intentions and that the recommendations of the regulated user have been suitably considered.
Hardware design specification
Description of the hardware on which the software resides and how it is to be connected to any system or equipment.
Damage to health, including the damage that can occur from loss of product quality or availability. (ICH Q9A)
The potential source of harm (ISO/IEC Guide 51). (ICH Q9A)
High efficiency particulate air filter with minimum 0.3
Medicinal products containing, exclusively, plant material and/or vegetable drug preparations as active ingredients. In some traditions, materials of inorganic or animal origin can also be present. (ICH Q3A, chapter E.3.A)
High efficiency particulate air (HEPA) filter
Retentive matrix designed to remove a defined percentage of particulate matter of a defined size.
Highly purified water
Aqua valde purificata, low endotoxin water, reverse osmosis water . (Ph.Eur)
Highly water soluble drugs
Drugs with a dose/solubility volume of less than or equal to 250 mL over a pH range of 1.2 to 6.8. (Example: Compound A has as its lowest solubility at 37
Heating, ventilation and air conditioning (PIC/S PI 007, see chapter F.2.)
Systems utilising a combination of human actions together with other automated functions and a variety of media for GxP data processing, records and information. In such cases documented procedural controls with recorded links, by reference and signatures may have to be used to complete the audit trail across, for example, a mixture of paper based records and electronic files.
Hydrostatic pressure test
Test performed for safety reasons as required by national or international guideline in order to make sure that cylinders or tanks can withhold high pressures. (Annex 6, chapter C.6.6.)
Hygienic (sanitary) design
A term for easy-to-clean, self-contained facilities with little dead space.
A limit above (>) which an impurity should be identified. (ICH Q3A, see chapter E.3.A)
An impurity for which a structural characterization has been achieved. (ICH Q3A, see chapter E.3.A)
Immediate (primary) pack
is that constituent of the packaging that is in direct contact with the drug substance or drug product, and includes any appropriate label. (ICH Q1B, see chapter E.1.B)
The container or other form of packaging immediately in contact with the medicinal or investigational medicinal product. (Annex 13, see chapter C.6.13.)
Allows the drug to dissolve in the gastrointestinal contents, with no intention of delaying or prolonging the dissolution or absorption of the drug.
Containers that provide a permanent barrier to the passage of gases or solvents, e.g., sealed aluminium tubes for semi-solids, sealed glass ampoules for solutions. (ICH Q1A, chapter E.1.A)
Process of a cleaning solution striking a surface. Impingement usually occurs in a spray process, and helps dislodge soils from surfaces.
The holder of the authorisation required by Article 40.3 of Directive 2001/83/EC and Article 44.3 of Directive 2001/82/EC for importing medicinal products from third countries. (Annex 16, see chapter C.6.16.)
Any component of the new drug substance that is not the chemical entity defined as the new drug substance. (ICH Q3A) Any component present in the intermediate or API that is not the desired entity. (EU GMP Guide, Part II, see chapter C.5.)
A description of the identified and unidentified impurities present in a new drug substance.(ICH Q3A) A description of the identified and unidentified impurities present in an API. (EU GMP Guide, Part II, see chapter C.5)
The condition where the installation is functioning in the defined operating mode with the specified number of personnel working. See also At rest
Checks performed during production in order to monitor and if necessary to adjust the process to ensure that the product conforms to its specification. (EU GMP Guide, Part II, see chapter C.5.) The control of the environment or equipment may also be regarded as a part of in-process control.
Any material fabricated, compounded, blended, or derived by chemical reaction that is produced for, and used in, the preparation of the drug product.
Tests which may be performed during the manufacture of either the drug substance or drug product, rather than as part of the formal battery of tests which are conducted prior to release.
Any component other than an active ingredient.
Contaminated with extraneous biological agents and therefore capable of spreading infection. (EU GMP Guide )
Informed consent (IC)
Decision, which must be written, dated and signed, to take part in a clinical trial, taken freely after being duly informed of its nature, significance, implications and risks and appropriately documented, by any person capable of giving consent or, where the person is not capable of giving consent, by his or her legal representative. If the person concerned is unable to write, oral consent in the presence of at least one witness may be given in exceptional cases, as provided for in national legislation. (DIRECTIVE 2001/20/EC)
The act by a competent authority of conducting an official review of documents, facilities, records, quality assurance arrangements, and any other resources that are deemed by the competent authority to be related to the clinical trial and that may be located at the site of the trial, at the sponsors and/or contract research organisations facilities, or at other establishments which the competent authority sees fit to inspect. (DIRECTIVE 2001/20/EC)
Ascertain and assess the current status of a component.
Installation Qualification (IQ)1.
The documented verification that the facilities, systems and equipment, as installed or modified, comply with the approved design and the manufacturers recommendations. (Annex 15, see chapter C.6.15.) 2. Part of validation which documents that the cleaning equipment is installed correctly. 3. Establishing confidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. (CFR, see chapter D.)
Integrated circuit (IC)
"Small wafers of silicon etched or printed with extremely small electronic switching circuits
Integration testing (IEEE)
An orderly progression of testing in which software elements, hardware elements, or both are combined and tested until the entire system has been integrated.
Test to determine the functional performance of a filter system. (PIC/S PI 007, see chapter F.2.)
An application in which each entry calls forth a response from a system or program, as in a ticket reservation system.
Where such status is indicated, any of the official texts from JP, EP, or USP can be substituted one for the other (appropriately referenced) in the ICH regions for purposes of the pharmaceutical registration/approval process. Using any of the interchangeable methods, an analyst will reach the same accept or reject decisions irrespective of which PDG pharmacopoeia is used. (ICH Q4A)
A device which permits two or more devices to communicate with each other.
A shared boundary. To interact or communicate with another system component.
Something in an analyzed sample which causes analytical results for the target analyte which are less precise, less accurate, or just less applicable.
Intermediate (for APIs)
A material produced during steps of the processing of an API that undergoes further molecular change or purification before it becomes an API. Intermediates may or may not be isolated. (EU GMP Guide, Part II, see chapter C.5)
Intermediate precision expresses within laboratories variations: different days different analysts, different equipment, etc. (ICH Q2A, see chapter E.2.)
Partly processed material which must undergo fur there manufacturing steps before it becomes a bulk product. (EU GMP Guide )
A program which translates a high level language into machine code one instruction at a time. Each instruction in the high level language is executed before the next instruction is interpreted.
An aseptic manipulation or activity that occurs at the critical area.
Investigational medicinal product
A pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorisation but used or assembled (formulated or packaged) in a way different from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form.(DIRECTIVE 2001/20/EC)
A doctor or a person following a profession agreed in the Member State for investigations because of the scientific background and the experience in patient care it requires. The investigator is responsible for conducting a clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the leader responsible for the team and may be called the principal investigator. (DIRECTIVE 2001/20/EC)
A compilation of the clinical and non-clinical data on the investigational medicinal product or products which are relevant to the study of the product or products in human subjects. (DIRECTIVE 2001/20/EC)
A decontaminated unit, supplied with Class 100 (ISO 5) or higher air quality, that provides uncompromised, continuous isolation of its interior from the external environment (e.g., surrounding cleanroom air and personnel). There are two major types of isolators: Closed isolator systems exclude external contamination from the isolator
Job descriptions define the tasks, competencies and responsibilities of an employee. They must be available in written and up-to-date form, and must be approved.
The action involving the selection of the correct label, with the required information, followed by line clearance and application of the label.
Laboratory Information Management Systems (LIMS)
LIMS, like MES, belong to the plant management levels. They are used to record and document quality-related values e.g. for inspection of incoming goods or so-called In-Process Controls (IPC) for the process running time.
An airflow moving in a single direction and in parallel layers at constant velocity from the beginning to the end of a straight line vector.
The visual representation of machines inside rooms and also the arrangement and shape of rooms within a building.
Legacy computerized systems
These are regarded as systems that have been established and in use for some considerable time. For a variety of reasons, they may be generally characterised by lack of adequate GMP compliance related documentation and records pertaining to the development and commissioning stage of the system. Additionally, because of their age there may be no records of a formal approach to validation of the system.
Life cycle concept
An approach to computer system development that begins with identification of the user
All phases in the life of a product from the initial development through marketing until the product
An agent with a strong affinity to a metal ion. (ICH Q3A)
Limit of detection (LOD)
The lowest amount of analyte in a sample which can be detected but not quantitated as an exact value. The Limit of Detection is mostly a parameter of limit tests.
Limit of quantification (LOQ)
Lowest level of analyte that can be reliably measured with acceptable accuracy and precision.
The linearity of an analytical procedure is its ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample. (ICHQ2A)
Those which, at the normal filling temperature and pressure, remain as a liquid in the cylinder. (EU GMP Guide )
A gas which when packaged under pressure, is partially liquid (gas over a liquid) at
Long term testing
Stability studies under the recommended storage condition for the re-test period or shelf life proposed (or approved) for labelling. (ICH Q1A, chapter E.1.A)
Checking the installed combination of elements characterising each type of input/output loop.
"A batch, or a specific identified portion of a batch, having uniform character and quality within specified limits
Lot number, control number, or batch number
Any distinctive combination of letters, numbers, or symbols, or any combination of them, from which the complete history of the manufacture, processing, packing, holding, and distribution of a batch or lot of drug product or other material can be determined.
In accordance with, the entirety of all measures carried out to preserve and restore the required status and to ascertain and assess the actual status of a systems technical means. Maintenance includes measures such as Inspection (tech.), repair and servicing. (DIN 31051) The terms servicing and maintenance are often used as synonyms in practice, but are differentiated in literature.
"1. Equipment or apparatus designed to enable one or more gas containers to be filled simultaneously from the same source. (EU GMP Guide )
2. Equipment or apparatus designed to enable one or more gas containers to be emptied and filled at a time. (Annex 6, chapter C.6.6.)"
All operations of purchase of materials and products, Production, Quality Control, release, storage, distribution of medicinal products and the related controls. (EU GMP Guide ) For API: All operations of receipt of materials, production, packaging, repackaging, labelling, relabelling, quality control, release, storage, and distribution of APIs and related controls.
Holder of a Manufacturing Authorisation as described in Article 40 of Directive 2001/83/EC. (EU GMP Guide )
Manufacturer/importer of Investigational Medicinal Products
Any holder of the authorisation to manufacture/import referred to in Article 13.1 of Directive 2001/20/EC. (Annex 13, see chapter C.6.13.)
The terms are used simultaneously at individual companies: Manufacturing formula, Processing instruction, Batch processing record (EU GMP Guide ) or Master formula and Manufacturing description, Master production record, Batch production record (21CFR211, see chapter D.1)
Manufacturing Execution Systems (MES)
MES belong to the plant management level. They produce the connection between the process control level and the company management level. On the one hand, this includes functions such as production planning, requirements determination within a mid-term time frame and, on the other hand, it includes extensive search options for batch tracing or fault analysis.
is the combination of immediate pack and other secondary packaging such as a carton. (ICH Q1B)
The process of adding together the assay value and levels of degradation products to see how closely these add up to 100% of the initial value, with due consideration of the margin of analytical error. (ICH Q1A, chapter E.1.A.)
Master cell bank
A culture of [fully characterised] cells distributed into containers in a single operation, processed together in such a manner as to ensure uniformity and stored in such a manner as to ensure stability. A master cell bank is usually stored at 70
Document which describes overall philosophy and manner of cleaning validation in a given facility.
A general term used to denote raw materials (starting materials, reagents, solvents), process aids, intermediates, APIs and packaging and labelling materials. (WHO)
The interlinking of all operations relevant to sourcing, processing and treatment, as well as the distribution of material goods within specified areas. This specifically involves: processing, handling, transportation, testing, stopovers and storage. See also Personal Flow.
The design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations is tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations is tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point. The differences in the samples for the same drug product should be identified as, for example, covering different batches, different strengths, different sizes of the same container closure system, and, possibly in some cases, different container closure systems. (ICH Q1A, chapter E.1.A)
Maximum theoretical residual impurity
Gaseous impurity coming from a possible retropollution and remaining after the cylinders pre-treatment before filling. The calculation of the maximum theoretical impurity is only relevant for compressed gases and supposes that these gases act as perfect gases. (Annex 6, chapter C.6.6.)
Mean kinetic temperature
A single derived temperature that, if maintained over a defined period of time, affords the same thermal challenge to a drug substance or drug product as would be experienced over a range of both higher and lower temperatures for an equivalent defined period. The mean kinetic temperature is higher than the arithmetic mean temperature and takes into account the Arrhenius equation. When establishing the mean kinetic temperature for a defined period, the formula of J. D. Haynes (J. Pharm. Sci., 60:927-929, 1971) can be used. (ICH Q1A, chapter E.1.A)
Method of evaluating an aseptic process using a microbial growth medium. (Media fills are understood to be synonymous to simulated product fills, broth trials, broth fills etc.). (PIC/S PI 007, see chapter F.2.)
Any Type B or Type C medicated feed as defined in
A Type A medicated article as defined in
Any gas or mixture of gases intended to be administered to patients for therapeutic, diagnostic or prophylactic purposes using pharmacological action and classified as a medicinal product. (Annex 6, chapter C.6.6.)
The whole or part of which is used for medicinal purpose. (EU GMP Guide )
Any substance or combination of substances presented for treating or preventing disease in human beings or animals. Any substance or combination of substances which may be administered to human beings or animals with a view to making a medical diagnosis or to restoring, correcting or modifying physiological functions in human beings or in animals is likewise considered a medicinal product. (EU GMP Guide )
Medicinal product derived from blood or plasma
Same meaning as that given in Directive 89/381/EEC (Annex 14, chapter C.6.14.)
"Usually a single integrated circuit on a chip
Minimum pressure retention valve
Valve equipped with a non-return system which maintains a definite pressure (about 3 to 5 bars over atmospheric pressure) in order to prevent contamination during use. (Annex 6, see chapter C.6.6.)
Dosage forms whose drug-release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release dosage form. Modified release solid oral dosage forms include both delayed and extended release drug products. (ICH Q6A)
Process of routinely evaluating cleaning process during and after cleaning. It may include measuring of process as well as performance characteristics.
The residual liquid which remains after the crystallization or isolation processes. A mother liquor may contain unreacted materials, intermediates, levels of the API and/or impurities. It may be used for further processing. (EU GMP Guide, Part II, see chapter C.5)
Multi-centre clinical trial
A clinical trial conducted according to a single protocol but at more than one site, and therefore by more than one investigator, in which the trial sites may be located in a single Member State, in a number of Member States and/or in Member States and third countries. (DIRECTIVE 2001/20/EC)
Mutual Recognition Agreement (MRA)
The appropriate arrangement between the Community and an exporting third country mentioned in Article 51(2) of Directive 2001/83/EC and Article 55(2) of Directive 2001/82/EC. (Annex 16, see chapter C.6.16.)
"1. An interconnected, or interrelated group of nodes.
2. An interconnected communications facility. A Local Area Network (LAN) is a high bandwidth (allowing a high data transfer rate) computer network operating over a small area such as an office or group of offices."
Process of changing the pH of a used aqueous cleaning solution to the neutral range of approximately 6-10 so it can be discharged into a waste treatment system.
New drug product
A pharmaceutical product type, for example, tablet, capsule, solution, cream, etc., which has not previously been registered in a region or Member State, and which contains a drug ingredient generally, but not necessarily, in association with excipients. (ICH Q6A)
New drug substance
The designated therapeutic moiety that has not been previously registered in a region or member state (also referred to as a new molecular entity or new chemical entity). It can be a complex, simple ester, or salt of a previously approved drug substance. (ICH Q6A)
New molecular entity
An active pharmaceutical substance not previously contained in any drug product registered with the national or regional authority concerned. A new salt, ester, or non-covalent-bond derivative of an approved drug substance is considered a new molecular entity for the purpose of stability testing under this guidance. (ICH Q1A, chapter E.1.A)
Any filter, which after any appropriate pre-treatment such as washing or flushing, will not release fibers into the component or drug product that is being filtered. All filters composed of asbestos are deemed to be fiber-releasing filters. See also Fiber.
A study where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of collected data. (DIRECTIVE 2001/20/EC)
A training usually assigned to the foremen. The employee to be instructed should learn how to carry out and document his tasks based on the relevant (standard) operating procedures. The method is carried out according to the following principle:
CIP cleaning process, or part of a CIP cleaning process, in which the cleaning solution or rinse water goes directly to the drain after passing through the equipment to be cleaned.
An environment in which system access is not controlled by persons who are responsible for the content of electronic records that are on the system.
Those conditions and activities interfacing directly or indirectly with the system of concern, control of which can affect the systems validated state.
Operating Procedure (SOP) - (Standard)
An approved, written specification which regulates a specific procedure that is repeated on a regular basis. It regulates individual processes and is relevant to sections of an organisational structure. The term operating procedure has a variety of synonyms: operational procedure (EU GMP Guideline), written procedure (21 CFR 211, see chapter D.1), standard operating procedure (SOP), standard procedure instruction, procedure instruction, manufacturing instructions, test instructions, test procedure, operational instructions, etc.
A set of software programs provided with a computer that function as the interface between the hardware and the applications pro gram.
Operational Qualification (OQ)
The documented verification that the facilities, systems and equipment, as installed or modified, perform as intended throughout the anticipated operating ranges. (Annex 15, see chapter C.6.15.)
Any individual participating in the aseptic processing operation, including line set-up, filler, maintenance, or other personnel associated with aseptic line activities.
Instruction to process, package and/or ship a certain number of units of investigational medicinal product(s). (Annex 13, see chapter C.6.13.)
Out of Specification (OOS) results
Include all suspect results that fall outside the specifications or acceptance criteria established in new drug applications, official compendia, or by the manufacturer. (FDA Draft Guidance for Industry)
Out of trend (OOT) results
Result within the specifications but also conspicuous because it is not in keeping with the trend observed over a longer period of time.
The packaging into which the immediate container is placed. (Annex 13, see chapter C.6.13.)
Overkill sterilization process
A process that is sufficient to provide at least a 12 log reduction of microorganisms having a minimum D value of 1 minute.
All operations, including filling and labelling, which a bulk product has to undergo in order to become a finished product. Note: Sterile filling would not normally be regarded as part of packaging, the bulk product being the filled, but not finally packaged, primary containers.
Any material employed in the packaging of a medicinal product, excluding any outer packaging used for transportation or shipment. Packaging materials are referred to as primary or secondary according to whether or not they are intended to be in direct contact with the product. (EU GMP Guide, Part II, see chapter C.5.)
A system of release that gives the assurance that the product is of the intended quality based on information collected during the manufacturing process and on the compliance with specific GMP requirements related to Parametric Release.
Percentage of theoretical yield
The ratio of the Actual yield (at any appropriate phase of manufacture, processing, or packing of a particular drug product) to the theoretical yield (at the same phase), stated as a percentage.
Performance Qualification (PQ)
The documented verification that the facilities, systems and equipment, as connected together, can perform effectively and reproducibly, based on the approved process method and product specification. (Annex 15, see chapter C.6.15.)
All possible and different transfer routes to the layout and the functions of individual persons. See also Material Flow.
Any medicine intended for human use or veterinary product administered to food-producing animals, presented in its finished dosage form or as a starting material for use in such a dosage form, that is subject to control by pharmaceutical legislation in both the exporting state and the importing state.
Pharmacopoeial Discussion Group (PDG)
"The three-party Pharmacopoeial Discussion Group consisting of representatives from the European Directorate for the Quality of Medicines (EDQM) in the Council of Europe
The pharmacopoeial monographs, general test chapters, and analytical methods emanating from the three regional pharmacopoeias.
Pilot scale batch
A batch of a drug substance or drug product manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch. For solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger. (ICH Q1A, chapter E.1.A)
Piping & Instrument Diagrams (P&IDs)
Engineering schematic drawings that provide details of the interrelationship of equipment, services, material flows, plant controls and alarms. The P&ID also provide the reference for each tag or label used for identification.
Slope of pipes in the equipment train. A desirable pitch is a least 1/16 inch per foot (about 5 mm per meter) of length of pipe.
Method of sampling that uses the manufacture of a product placebo to sample the cleaned equipment.
Plant functional specifications
Specifications that document functions, standards and permitted tolerances of systems (plant) or system components (equipment) and which define the operating capabilities of the equipment.
The occurrence of different crystalline forms of the same drug substance. This may include solvation or hydration products (also known as pseudopolymorphs) and amorphous forms. (ICH Q3A, ICH Q6A)
Feed water, public water supply, service water, city water. (Ph.Eur)
An impurity that theoretically can arise during manufacture or storage. It may or may not actually appear in the new drug substance. (ICH Q3A)
Pre-determined acceptance criteria
The criteria assigned, before undertaking testing, to allow evaluation of test results to demonstrate compliance with a test phase of delivery requirement.
A water flush of the equipment train prior to applying the cleaning solution. Also called a
The precision of an analytical procedure expresses the closeness of agreement (degree of scatter) between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions. Precision may be considered at three levels: repeatability, intermediate precision and reproducibility. Precision should be investigated using homogeneous, authentic samples. However, if it is not possible to obtain a homogeneous sample it may be investigated using artificially prepared samples or a sample solution. The precision of an analytical procedure is usually expressed as the variance, standard deviation or coefficient of variation of a series of measurements. (ICH Q2A, see chapter E.2.)
Work done before approval of the validation protocol. Includes cycle development, determination of residue limits, and selection of analytical and sampling methods.
Action taken to eliminate the cause of a possible fault (3.6.2) or another undesired possible situation.
A batch of a drug substance or drug product used in a formal stability study, from which stability data are submitted in a registration application for the purpose of establishing a re-test period or shelf life, respectively. A primary batch of a drug substance should be at least a pilot scale batch. For a drug product, two of the three batches should be at least pilot scale batch, and the third batch can be smaller if it is representative with regard to the critical manufacturing steps. However, a primary batch may be a production batch. (ICH Q1A, chapter E.1.A)
A containment system that prevents the escape of a biological agent into the immediate working environment. This includes the use of closed containers or biological safety workstations together with safe working procedures.
Primary packaging materials
They come into direct contact with the product and as containers, they protect the product. They include jars (sometimes dyed for UV absorption) and foil (e.g. for tablets, granulates or suppositories). These materials come into contact with the product and are therefore subject to specific requirements. The process is described as primary packaging. See also Secondary packaging materials.
The responsible leader of the team if a trial is conducted by a team of individual investigators at a trial site Investigator. (Annex 13, see chapter C.6.13.)
Description of the operations to be carried out, the precautions to be taken and measures to be applied directly or indirectly related to the manufacture of a medicinal product, an intermediate or API. (EU GMP Guide, Part II, see chapter C.5)
Materials, excluding solvents, used as an aid in the manufacture of an intermediate or API that do not themselves participate in a chemical or biological reaction (e.g. filter aid, activated carbon, etc). (EU GMP Guide, Part II, see chapter C.5)
Process Analytical Technology (PAT)
A system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality. (ICH Q8A)
Process Capability Index (CpK)
A process capability index CpK represents the true measure of process capability CpK = (X LSL)/3s or = (USL
Process capability study
A process capability study is a statistical method that compares process information (e.g. X and s) to the upper and lower specification limits.
Process control system
Takes into account the entirety of all tasks (functions) that are required for controlling a process. In addition to the functions of the respective automatic procedures that are established in its programming, all decision processes of the person who monitors the process are also taken into account, including his resulting direct intervention in the process.
Process Data Acquisition system (PDA)
Records various measurable values from production. These can be the temperature flow, counter statuses, revolutions, etc. Depending on the relevance of the value, a relationship can be established between the measuring point (sensor, balance, etc.) and the order or batch number.
Process performance qualification
Establishing confidence that the process is effective and reproducible. (CFR, see chapter D.)
Ability of a process to tolerate variability of materials and changes of the process and equipment without negative impact on quality. (ICH Q8A)
The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes. (Annex 15, see chapter C.6.15.)
Process visualisation and control
These systems show the current status of each individual element of the technical equipment and make it possible to control these elements. A drive can, for example, be activated or deactivated, and at the same time the operating hours of the drive and the storage temperatures of heavily burdened gear parts can be recorded.
Deviation of an analytical result from the true value due to insufficient product quality as a consequence of failure in manufacturing. A differentiation is made between errors that are not related to the manufacturing process (e.g. incorrect initial weight, incorrect mixing time, operating error) and those that are related to the manufacturing process (e.g. insufficient validation of procedure, imprecise/incorrect formulation of manufacturing procedure).
All phases in the life of the product from the initial development through marketing until the products discontinuation.
Product performance qualification
Establishing confidence through appropriate testing that the finished product produced by a specified process meets all release requirements for functionality and safety. (CFR, see chapter D.)
Product Quality Review (PQR)
Regular periodic or rolling quality reviews of all licensed medicinal products, including export only products, should be conducted with the objective of verifying the consistency of the existing process, the appropriateness of current specifications for both starting materials and finished product to highlight any trends and to identify product and process improvements. Such reviews should normally be conducted and documented annually, taking into account previous reviews. (EU GMP Guide, Part I) Regular quality reviews of APIs should be conducted with the objective of verifying the consistency of the process. Such reviews should normally be conducted and documented annually. (EU GMP Guide, Part II, see chapter C.5.)
Product specification file
A reference file containing, or referring to files containing, all the information necessary to draft the detailed written instructions on processing, packaging, quality control testing, batch release and shipping of an investigational medicinal product. (Annex 13, see chapter C.6.13.)
All operations involved in the preparation of a medicinal product, from receipt of materials, through processing and packaging, to its completion as a finished product.
A batch of a drug substance or drug product manufactured at production scale by using production equipment in a production facility as specified in the application. (ICH Q1A, chapter E.1.A)
1. Establishing documented evidence that a process, procedure, system, equipment or mechanism used in manufacture does what it purports to do based on a pre-planned validation protocol. 2. Validation conducted prior to the distribution of either a new product, or product made under a revised manufacturing process, where the revisions may affect the products characteristics. (CFR, see chapter D.) 3. Carried out before routine production of products intended for sale. (Annex 15, see chapter C.6.15.)
A document that describes the objective(s), design, methodology, statistical considerations and organisation of a trial. The term protocol refers to the protocol, successive versions of the protocol and protocol amendments. (DIRECTIVE 2001/20/EC)
Public Key Infrastructure (PKI)
"Provides a framework for secure communication, using a combination of public-key cryptography and Digital Certificates.
PKIs can exist within many different domains but essentially there are two types:
- A Private PKI is deployed by a corporation for the benefit of its business and any related parties (e.g. customers, suppliers).
- Public PKIs (using Trusted Third Parties) are deployed on open systems, such as the Internet and facilitate security between previously unrelated parties. "
To empty and clean a cylinder y blowing down and evacuating or by blowing down, partial pressurisation with the gas in question and then blowing down. (Annex 6, see chapter C.6.6.)
Demineralised water, deionised water . (Ph.Eur)
Any substances (chemical, microbiological) that cause fever on parenteral administration. Tested using the rabbit test.
"Produced by the Q4B evaluation process
1. Identification of equipment attributes related to the performance of a particular function or functions and allocation of certain limits or restrictions to those attributes. 2. The process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified. (ICH Q3A) 3. Action of proving and documenting that equipment or ancillary systems are properly installed, work correctly, and actually lead to the expected results. Qualification is part of validation, but the individual qualification steps alone do not constitute process validation. (EU GMP Guide, Part II, see chapter C.5.)
Qualification means the theoretical knowledge, practical skills and professional and business experience of the employee.
A limit above (>) which an impurity should be qualified. (ICH Q3A)
Qualified Person (Q.P.)
The person defined in Article 48 of Directive 2001/ 83/EC and Article 52 of Directive 2001/82/EC. (Annex 16, chapter C.6.16.)
"1. The suitability of either a drug substance or drug product for its intended use. This term includes such attributes as the identity, strength, and purity (from ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances) (ICH Q8A).
2. The nature of a drug product, which is determined by the identity, content, purity, and other chemical, physical and biological properties or by the manufacturing procedure.
3. The degree to which a set of inherent properties of a product, system or process fulfils requirements (see ICH Q6A definition specifically for
Quality assurance (QA)
The sum total of the organised arrangements made with the object of ensuring that all products are of the quality required for their intended use and that quality systems are maintained. (EU GMP Guide, Part II, see chapter C.5.)
A molecular or product characteristic that is selected for its ability to help indicate the quality of the product. Collectively, the quality attributes define identity, purity, potency and stability of the product, and safety with respect to adventitious agents. Specifications measure a selected subset of the quality attributes.
Quality Control (QC)
Checking or testing that specifications are met. (EU GMP Guide, Part II, see chapter C.5.)
Quality control unit
-An organizational element with authority and responsibility as defined by 211.22. -Any person or organizational element designated by the firm to be responsible for the duties relating to quality control. (CFR, see chapter D.)
Quality risk management
A systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle. (ICH Q9A)
The sum of all aspects of a system that implements quality policy and ensures that quality objectives are met. (ICH Q9A)
An organizational unit independent of production which fulfils both Quality Assurance and Quality Control responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization. (EU GMP Guide, Part II, see chapter C.5.)
The quantization limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy. The quantization limit is a parameter of quantitative assays for low levels of compounds in sample matrices, and is used particularly for the determination of impurities and/or degradation products. (ICH Q2A, see chapter E.2.)
The status of starting or packaging materials, intermediate, bulk or finished products isolated physically or by other effective means whilst awaiting a decision on their release or refusal. (EU GMP Guide, Part II, see chapter C.5.)
A composite (solid, liquid, gaseous, or in solution) of equimolar quantities of two enantiomeric species. It is devoid of optical activity. (ICH Q6A)
means any medicinal product which, when ready for use, contains one or more radionuclides (radio active isotopes) included for a medicinal purpose (Article 1(6) of Directive 2001/83/EC.
The process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias. (Annex 13, see chapter C.6.13.)
A listing in which the treatment assigned to each subject from the randomisation process is identified. (Annex 13, see chapter C.6.13.)
The range of an analytical procedure is the interval between the upper and lower concentration (amounts) of analyte in the sample (including these concentrations) for which it has been demonstrated that the analytical procedure has a suitable level of precision, accuracy and linearity. (ICH Q2A, see chapter E.2.)
Rapidly dissolving products
An immediate release solid oral drug product is considered rapidly dissolving when not less than 80% of the label amount of the drug substance dissolves within 15 minutes in each of the following media: (1) pH 1.2, (2) pH 4.0, and (3) pH 6.8. (ICH Q6A)
Is a representative of one of the six ICH parties, who is designated by the Steering Committee when a new topic is formally adopted. The Rapporteur is responsible for leading a working group (EWG/IWG) and ensuring that the group keeps an up-to-date action plan and timetable, with clear deliverables and deadlines. The Rapporteur shall regularly present reports to the Steering Committee, focusing in particular on the timelines and milestones.
Any work-sheets, records, memoranda, notes, or exact copies thereof, that are the result of original observations and activities and which are necessary for the reconstruction and evaluation of a work project, process or study report, etc. Raw data may be hard/paper copy or electronic but must be known and defined in system procedures.
A general term used to denote starting materials, reagents, and solvents intended for use in the production of intermediates, APIs or medicinal products. (EU GMP Guide, Part II, see chapter C.5.)
A substance other than a starting material, intermediate, or solvent that is used in the manufacture of a new drug substance. (ICH Q6A)
CIP cleaning process, or part of a CIP cleaning process, in which the cleaning solution or rinse water passes through the CIP control unit, spray devices, and equipment multiple times. Typically used for the cleaning cycle of a CIP process.
Due to the information technology (IT) nature of the M2 EWGs work on Electronic Standards for the Transfer of Regulatory Information (ESTRI), some of their activities result in Recommendations. These Recommendations do not undergo the ICH step process so as to allow for flexible change as both science, and technologies evolve. They are agreed in the EWG, signed by all parties of the EWG, and are approved and signed off by the ICH Steering Committee. Current M2 Recommendations are posted on the ESTRI website: http://estri.ich.org.
A comparison, making due allowance for normal variation, between the amount of product or materials theoretically and actually produced or used. (EU GMP Guide)
The introduction of all or part of previous batches of the required quality into another batch at a defined stage of manufacture. (EU GMP Guide )
Reference standard, primary
A substance that has been shown by an extensive set of analytical tests to be authentic material that should be of high purity. This standard can be obtained from an officially recognised source or prepared by independent synthesis, or obtained from existing production materials of high purity, or prepared by further purification of existing production material. (EU GMP Guide, Part II, see chapter C.5.)
Reference standard, secondary
A substance of established quality and purity, as shown by comparison to a primary reference standard, used as a reference standard for routine laboratory analysis. (EU GMP Guide, Part II, see chapter C.5.)
Regional Harmonisation Initiatives (RHI)
Regional Harmonisation Initiatives founded on the principle of harmonising drug regulation across a defined group of non-ICH countries.
The regulated Good Practice entity, that is responsible for the operation of a computerised system and the applications, files and data held thereon. (See also User)
Eliminates a fault and thus restores the required status. A distinction is also made between preventative and fault-based repair.
Repeatability expresses the precision under the same operating conditions over a short interval of time. Repeatability is also termed intra-assay precision. (ICH Q2A, see chapter E.2.)
Repetition of sampling (re-sampling)
"Repetition of sampling of one batch in accordance with a predetermined plan
Repetition of the analysis (retesting)
Repetition of the analysis using the same sample or quantity of samples.
Repetition of the injection (re-injection)
Repetition of the injection (in an analytical apparatus) from a test solution that is still available.
A limit above (>) which an impurity should be reported. Reporting threshold is the same as reporting level in Q2B. (ICH Q3A)
A sample that consists of a number of units that are drawn based on rational criteria such as random sampling and intended to assure that the sample accurately portrays the material being sampled. (CFR, see chapter D.)
The reworking of all or part of a batch of product of an unacceptable quality from a defined stage of production so that its quality may be rendered acceptable by one or more additional operations. (EU GMP Guide )
Reprocessing (for APIs)
Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process. Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process, and not reprocessing. (EU GMP Guide, Part II, see chapter C.5.)
Reproducibility expresses the precision between laboratories (collaborative studies usually applied to standardization of methodology). (ICH Q2A, see chapter E.2.)
"The explicit or implicit needs or expectations of the patients or their surrogates (e.g., health care professionals, regulators and legislators). In this document, ""requirements"" refers not only to statutory, legislative, or regulatory requirements, but also to such needs and expectations. "
Materials left behind after the cleaning process. May be chemical or microbiological in nature.
The date after which samples of the drug substance should be examined to ensure that the material is still in compliance with the specification and thus suitable for use in the manufacture of a given drug product. (ICH Q1A, chapter E.1.A)
The period of time during which the drug substance is expected to remain within its specification and, therefore, can be used in the manufacture of a given drug product, provided that the drug substance has been stored under the defined conditions. After this period, a batch of drug substance destined for use in the manufacture of a drug product should be re-tested for compliance with the specification and then used immediately. A batch of drug substance can be retested multiple times and a different portion of the batch used after each re-test, as long as it continues to comply with the specification. For most biotechnological/biological substances known to be labile, it is more appropriate to establish a shelf life than a re-test period. The same may be true for certain antibiotics. (ICH Q1A, chapter E.1.A.)
Validation of a process for a product which has been marketed based upon accumulated manufacturing, testing and control batch data. (Annex 15, see chapter C.6.15.)
Sending back to the manufacturer or distributor of a medicinal product which may or may not present a quality defect. (EU GMP Guide )
Repetition of the process validation to provide an assurance that changes in the process/equipment introduced in accordance with change control procedures do not adversely affect process characteristics and product quality. (Annex 15, see chapter C.6.15.)
Subjecting an intermediate or API that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain acceptable quality intermediate or API (e.g., recrystallizing with a different solvent). (EU GMP Guide, Part II, see chapter C.5.)
Process by which performance of a validated cleaning process is evaluated to ensure it is still under control. Might include re-validation upon significant change, or else validation confirmation upon review of appropriate documents, including original validation, change control, monitoring, and QC records.
Procedure for sampling involving flooding the surfaces with rinse solution to effectively remove target residues. The rinse solution is then analyzed for the target residue.
Combination of the probability of occurrence of harm and the severity of that harm (ISO/IEC Guide 51, ICH Q9A).
The decision to accept risk (ISO Guide 73). (ICH Q9A)
1. The estimation of the risk associated with the identified hazards. (ICH Q9A) 2. Method to assess and characterise the critical parameters in the functionality of equipment or process. (Annex 15, see chapter C.6.15.)
A systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards. (ICH Q9A)
The sharing of information about risk and risk management between the decision maker and other stakeholders. (ICH Q9A)
Actions implementing risk management decisions (ISO Guide 73). (ICH Q9A)
The comparison of the estimated risk to given risk criteria using a quantitative or qualitative scale to determine the significance of the risk. (ICH Q9A)
The systematic use of information to identify potential sources of harm (hazards) referring to the risk question or problem description. (ICH Q9A)
The systematic application of quality management policies, procedures, and practices to the tasks of assessing, controlling, communicating and reviewing risk. (ICH Q9A)
Actions taken to lessen the probability of occurrence of harm and the severity of that harm. (ICH Q9A)
Review or monitoring of output/results of the risk management process considering (if appropriate) new knowledge and experience about the risk. (ICH Q9A)
The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage. (ICH Q2A, see chapter E.2.)
Deviation of an analytical result from the true value due to a failure in sample preparation, e.g. sampling, sample mix-up, incorrect labelling, change in quality of samples.
Established period for collecting samples.
A system of containment which prevents the escape of a biological agent into the external environment or into other working areas. It involves the use of rooms with specially designed air handling, the existence of airlocks and/or sterilisers for the exit of materials and secure operating procedures. In many cases it may add to the effectiveness of primary containment.
Secondary packaging materials
They are added after the primary packaging to provide extra protection (e.g. folding cartons, paper board containers) and to comply with the legal obligation to identify the contents of the package (e.g. package inserts, folding cartons, brochures, seals). The process is described as secondary packaging.
The protection of computer hardware and software from accidental or malicious access, use, modification, destruction or disclosure. Security also pertains to personnel, data, communications and the physical protection of computer installations.
Seed lot system: A seed lot system is a system according to which successive batches of a product are derived from the same master seed lot at a given passage level. For routine production, a working seed lot is prepared from the master seed lot. The final product is derived from the working seed lot and has not undergone more passages from the master seed lot than the vaccine shown in clinical studies to be satisfactory with respect to safety and efficacy. The origin and the passage history of the master seed lot and the working seed lot are recorded. Master seed lot: A culture of a micro-organism distributed from a single bulk into containers in a single operation in such a manner as to ensure uniformity, to prevent contamination and to ensure stability. A master seed lot in liquid form is usually stored at or below 70
Containers that allow the passage of solvent, usually water, while preventing solute loss. The mechanism for solvent transport occurs by absorption into one container surface, diffusion through the bulk of the container material, and analytics from the other surface. Transport is driven by a partial-pressure gradient. Examples of semi-permeable containers include plastic bags and semirigid, low-density polyethylene (LDPE) pouches for large volume parenterals (LVPs), and LDPE ampoules, bottles, and vials. (ICH Q1A, chapter E.1.A)
Capacity of the test procedure to record small variations in concentration of a component, with a defined degree of precision.
Serious adverse event (SAE) or serious adverse reaction (SAR)
Any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or in a congenital anomaly or birth defect. (DIRECTIVE 2001/20/EC) See also Adverse event (AE).
Preserve the required status.
A measure of the possible consequences of a hazard. (ICH Q9A)
Any area that does not receive adequate cleaning solution from the spray device because of an impediment (agitator shaft, baffle, etc.) within the process vessel.
Shared product surface area
Surface area within the equipment train that contacts manufactured product. Residues on shared product surface area can be transferred to the next product.
(also referred to as expiration dating period) The time period during which a drug product is expected to remain within the approved shelf life specification, provided that it is stored under the conditions defined on the container label. (ICH Q1A, chapter E.1.A)
Scheduled periods of work or production, usually less than 12 hours in length, staffed by alternating groups of workers. (PIC/S PI 007, see chapter F.2.)
The operation of packaging for shipment and sending of ordered medicinal products for clinical trials. (Annex 13, see chapter C.6.13.)
The record of the individual who performed a particular action or review. This record can be initials, full handwritten signature, personal seal, or authenticated and secure electronic signature. (EU GMP Guide, Part II, see chapter C.5.)
A material that closely approximates the physical and, where practical, the chemical characteristics (e.g. viscosity, particle size, pH etc.) of the product under validation. In many cases, these characteristics may be satisfied by a placebo product batch. (Annex 15, see chapter C.6.15.)
Site Acceptance Test (SAT)
Final acceptance by customer.
Programs executable on a computer. Programs are written in any number of different languages.
Material in equipment train to be removed by the cleaning process.
1. An inorganic or organic liquid used as a vehicle for the preparation of solutions or suspensions in the manufacture of an intermediate or API. (EU GMP Guide Part II, see chapter C.5.) 2. An inorganic or an organic liquid used as a vehicle for the preparation of solutions or suspensions in the synthesis of a new drug substance or the manufacture of a new drug product. (ICH Q6A)
Source code (PMA CSVC)
An original computer program expressed in human-readable form (programming language), which must be translated into machine-readable form before it can be executed by the computer.
High level language program which the operator can read.
A test which is considered to be applicable to particular new drug substances or particular new drug products depending on their specific properties and/or intended use. (ICH Q6A)
A list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the test described. It establishes the set of criteria to which a material should conform to be considered acceptable for its intended use.
The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of a drug product at the time of its release. (ICH Q1A, chapter E.1.A)
Specification shelf life
The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of a drug substance throughout its re-test period, or that a drug product should meet throughout its shelf life. (ICH Q1A, chapter E.1.A)
Specificity is the ability to assess unequivocally the analyte in the presence of components which may be expected to be present. Typically these might include impurities, degradants, matrix, etc. Lack of specificity of an individual analytical procedure may be compensated by other supporting analytical procedure(s). (ICH Q2A, see chapter E.2.)
1. An identified or unidentified impurity that is selected for inclusion in the new drug substance or new drug product specification and is individually listed and limited in order to assure the quality of the new drug substance or new drug product. 2. An impurity that is individually listed and limited with a specific acceptance criterion in the new drug substance specification. A specified impurity can be either identified or unidentified. (ICH Q3A)
An individual, company, institution or organisation which takes responsibility for the initiation, management and/or financing of a clinical trial. (Annex 13, see chapter C.6.13.
Any individual, group or organization that can affect, be affected by, or perceive itself to be affected by a risk. Decision makers might also be stakeholders. For the purposes of this guideline, the primary stakeholders are the patient, healthcare professional, regulatory authority, and industry. (ICH Q9A)
A self-contained computer system, which provides data processing, monitoring or control functions but which is not embedded within automated equipment. This is contrasted with an embedded system, the sole purpose of which is to control a particular piece of automated equipment.
A material used in the synthesis of a new drug substance that is incorporated as an element into the structure of an intermediate and/or of the new drug substance. Starting materials are normally commercially available and of defined chemical and physical properties and structure. (ICH Q3A)
"The formal ICH procedure consists of 5 Steps:
Step 1: Consensus Building.
Step 2: Confirmation of six-party con
Free of any viable organisms. (In practice, no such absolute statement regarding the absence of microorganisms can be proven, see sterilisation.) (PIC/S PI 007, see chapter F.2.)
For purposes of this guidance, sterile product refers to one or more of the elements exposed to aseptic conditions and ultimately making up the sterile finished drug product. These elements include the containers, closures, and components of the finished drug product.
Sterilising grade filter
A filter that, when appropriately validated, will remove all microorganisms from a fluid stream, producing a sterile effluent.
Sterility is the absence of living organisms. The conditions of the sterility test are given in the European Pharmacopoeia. (EU GMP Guide )
Sterility assurance level (SAL)
Probability that a batch of product is sterile. (SAL is expressed as 10
Sterility assurance system
The sum total of the arrangements made to assure the sterility of products.
Test performed to determine if viable microorganisms are present. (PIC/S PI 007, see chapter F.2.)
Validated process used to render a product free of viable organisms. Note: In a sterilisation process, the nature of microbiological death of reduction is described by an exponential function. Therefore, the number of microorganisms which survive a sterilisation process can be expressed in terms of probability. While the probability may be reduced to a very low number, it can never be reduced to zero. (PIC/S PI 007, see chapter F.2.)
The storing of pharmaceutical products and materials up to their point of use.
Storage condition tolerances
The acceptable variations in temperature and relative humidity of storage facilities for formal stability studies. The equipment should be capable of controlling the storage condition within the ranges defined in this guideline. The actual temperature and humidity (when control led) should be monitored during stability storage. Short term spikes due to opening of doors of the storage facility are accepted as unavoidable. The effect of excursions due to equipment failure should be addressed, and reported if judged to affect stability results. Excursions that exceed the defined tolerances for more than 24 hours should be described in the study report and their effect assessed. (ICH Q1A, chapter E.1.A)
A unit into which a product can be placed, retained and retrieved.
"1. The concentration of the drug substance (for example, weight/ weight, weight/volume, or unit dose/volume basis), and/or
2. the potency, that is, the therapeutic activity of the drug product as indicated by appropriate laboratory tests or by adequately developed and controlled clinical data (expressed, for example, in terms of units by reference to a standard). (CFR, see chapter D.)"
Stress testing (drug product)
Studies undertaken to assess the effect of severe conditions on the drug product. Such studies include photostability testing (see ICH Q1B) and specific testing on certain products, (e.g., metered dose inhalers, creams, emulsions, refrigerated aqueous liquid products). (ICH Q1A, chapter E.1.A)
Stress testing (drug substance)
Studies undertaken to elucidate the intrinsic stability of the drug substance. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing. (ICH Q1A, chapter E.1.A)
An activity intended to produce documented assurance that software has appropriate structural integrity.
An individual who participates in a clinical trial as either a recipient of the investigational medicinal product or a control. (DIRECTIVE 2001/20/EC)
A person providing pharmaceutical products and materials on request. Suppliers may be agents, brokers, distributors, manufacturers or traders. Where possible, suppliers should be authorized by a competent authority.
"Data, other than those from formal stability studies, that support the analytical procedures, the proposed re-test period or shelf life, and the label storage statements. Such data include stability data on early synthetic route batches of drug substance, small scale batches of materials, investigational formulations not proposed for marketing, related formulations, and product presented in containers and closures other than those proposed for marketing
Sampling tool that comprises a textile, fiber, or foam on the end of a moderately flexible handle. Examples include cotton on a wooden handle (for microbiological sampling) and knit polyester on a polypropylene handle for chemical sampling.
Procedure for sampling surfaces involving wiping the surfaces with a swab, typically saturated with water or another sampling solvent, to remove residues from a surface. The swab is then desorbed, and a chemical analysis is performed on the desorbed material.
1. Is used in the sense of a regulated pattern of interacting activities and techniques which are united to form an organised whole. (EU GMP Guide ) 2. For computer systems: Term can refer to hardware or software. For hardware it is the collection of equipment that makes up the computer. For software it refers to an integrated number of computer programs to perform predefined tasks. (Annex 15, see chapter C.6.15.)
System acceptance test specification
The system acceptance test specification is a description of those tests to be carried out to permit acceptance of the system by the user. Typically it should address the following: System functionality, System performance, Critical parameters, Operating procedures. The tests should ensure that the product operates as indicated in the functional specification and meets the user requirements as defined in the URS. The tests typically include limit, alarms and boundary testing.
Static container for the storage of liquefied or cryogenic gas. (Annex 6, chapter C.6.6.)
Container fixed on a vehicle for the transport of liquefied or cryogenic gas. (Annex 6, see chapter C.6.6.)
A liner magnetic storage device rolled onto a reel or cassette.
Flat window frame device, usually made of PTFE (polytetrafluoroethylene), applied to a surface to restrict swab sampling to a defined area inside the window frame.
A device, usually equipped with a CRT display and keyboard, used to send and receive information to and from a computer via a communication channel.
The application of a lethal agent to sealed, finished drug products for the purpose of achieving a predetermined sterility assurance level (SAL) of usually less than 10-6 (i.e., a probability of a nonsterile unit of greater than one in a million).
The System Acceptance Test
Specification is a contractual document and, as such, should be approved by both the supplier/ developer/ integrator and the end user.
Topic leader / Deputy topic leader
Are the two officially nominated representatives that each of the six ICH parties will elect to represent their party in an EWG/IWG. It is the responsibility of the Topic Leader/Deputy Topic Leader to officially represent a consolidated view of their party during any ICH interaction.
Total Organic Carbone (TOC)
A nonspecific analytical procedure that involves oxidizing the residue to carbon dioxide, and then measuring the generated carbon dioxide.
A statistical term referring to the direction or rate of change of a variable(s). (ICH Q9A)
Ultra-low penetration air filter with minimum 0.3 m particle retaining efficiency of 99.999 percent.
Ultra filtration (UF)
A separation technology for separating particles with a size of 0.001 to 0.1 m. For ultra pure water production UF hollow fibre membranes are usually used.
Unexpected adverse reaction
An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g. investigators brochure for an unauthorised investigational product or summary of product characteristics for an authorised product). (DIRECTIVE 2001/20/EC)
1. An impurity for which a structural characterisation has not been achieved and that is defined solely by qualitative analytical properties (e.g., chromatographic retention time). (ICH Q3A) 2. An impurity which is defined solely by qualitative analytical properties, (e.g., chromatographic retention time).
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.
"A test which is considered to be potentially applicable to all new drug substances, or all new drug products
An impurity that is limited by a general acceptance criterion, but not individually listed with its own specific acceptance criterion, in the new drug substance specification. (ICH Q6A)
Dilute solution of a cleaning agent concentrate, as it is used for cleaning.
The company or group responsible for the operation of a system. (ICH Q6A) (see also Regulated User). The GxP customer, or user organisation, contracting a supplier to provide a product. In the context of this document it is, therefore, not intended to apply only to individuals who use the system, and is synonymous with Customer.
1. Establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes. For computer systems: The assurance, through testing, that hardware or software produces specified and predictable output for any given input. 2. 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. (EU GMP Guide, Part II, see chapter C.5.)
Validation master plan
A document providing information on the company
A written plan stating how validation will be conducted and defining acceptance criteria. For example, the protocol for a manufacturing process identifies processing equipment, critical process parameters/operating ranges, product characteristics, sampling, test data to be collected, number of validation runs, and acceptable test results. (EU GMP Guide, Part II, see chapter C.5.)
Document reporting the validation activities, the validation data and the conclusions drawn.
Device for opening and closing containers. (Annex 6, see chapter C.6.6.)
Non-shedding porous material capable of removing viable and non-viable particles from gases passing in and out of a closed vessel. (PIC/S PI 007, see chapter F.2.)
The air in the room is exchanged with external air.
Documented evidence that an individual cleaning event has produced product contact surfaces that are acceptably clean. Verification is typically done for infrequent or varying processes, such as clinical trial production or product made only every two years.
Water for injection
Aqua ad iniectabilia, ultra pure water, distilled water . (Ph.Eur)
An active pharmaceutical ingredient of established quality and purity, by comparison to the reference standard. The material is routinely used in the laboratory for analysing production batches of active pharmaceutical ingredients and drug products. A regular (e.g. annual) comparison with the reference standard will be necessary. (FDA)
A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure. (Annex 15, chapter C.6.15.)
The quantity that is actually produced at any appropriate phase of manufacture, processing, or packing of a particular drug product.
The quantity of material or the percentage of theoretical yield anticipated at any appropriate phase of production based on previous laboratory, pilot scale, or manufacturing data. (EU GMP Guide, Part II, see chapter C.5.)
The quantity that would be produced at any appropriate phase of production, based upon the quantity of material to be used, in the absence of any loss or error in actual production. (EU GMP Guide, Part II, see chapter C.5.)
Value in degrees Celsius that causes a change in the decimal D value (or: the change in temperature that causes the D value to change by a power of ten). The Z value is also defined as the relative resistance of a given microorganism against different temperatures. The Z value for Bacillus stearothermophilis is 10
The GMP-Glossary contains items and expressions you often hear in cGMP context.