The 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). (FDA 21 CFR 210.3)
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 Q2). The degree of closeness of the determined value to the nominal or known true value under prescribed conditions. This is sometimes termed trueness.
The accuracy of an analytical method is the closeness of test results obtained by that method to the true value. Accuracy can often be expressed as percent recovery by the assay of known, added amounts of analyte. Accuracy is a measure of the exactness of the analytical method.
% Accuracy = (Xbar – Target / Target) * 100
Established criteria, requiring immediate follow-up and corrective action if exceeded.
Active pharmaceutical ingredient:
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. (FDA 21 CFR 210.3)
The quantity that is actually produced at any appropriate phase of manufacture, processing, or packing of a particular drug product. (FDA 21 CFR 210.3).
Adverse Event (AE):
The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product.
An undesirable medical condition can be symptoms (e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged liver) or the abnormal results of an investigation (e.g. laboratory findings, electrocardiogram). In clinical studies an AE can include an undesirable medical condition occurring at any time, including run-in or wash-out periods, even if no study treatment has been administered. An adverse event can also be failure of expected pharmacological action.
An organism that requires (for growth) a level of oxygen equal to, or greater than that present in the atmosphere.
Air handling unit (AHU):
An integrated piece of equipment consisting of fans, heating andcooling coils, air-control dampers, filters and silencers.
The frequency (minutes, hours, etc) with which the air in a controlled environment (classified area) is replaced. The air can be recirculated partially or totally replaced.
Classification of processing rooms or areas based on the allowed number of particles per cubic foot of air (USA) e.g. class 100, or particles per cubic meter (EU) depending on level of activity in the processing room. The EU refers to these air classifications as Grades A through D, with A being the cleanest during normal activity.
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. (PIC/S)
Alert levels (environmental monitoring):
established static and operational 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.
Alert levels (media fill):
an established number of media filled units which indicate the presence of microbial growth (e.g. positive units). The cause of the growth should be investigated, but is not necessarily a reason for definitive corrective action.
Established criteria giving early warning of potential drift from normal conditions which are not necessarily grounds for definitive corrective action but which require follow-up investigation.
A calibrated piece of equipment that samples air by impacting a calculated amount of air onto a solid or semi-solid microbial growth media over a specified period of time. These samplers are used to determine the viable (microbiological) content of the air in the processing room. Some accepted samplers are Slit-To-Agar (STA) samplers, Centrifugal Samplers (CS), and Sieve Microbial Atrium (SMA) samplers.
Any member of a heterogeneous group of eucaryotic (cells that possess a definitive or true nucleus), photosynthetic, and unicellular or multicellular organisms.
A system that is not directly part of the equipment undergoing qualification. An example is a compressed air system that may be used in packaging to remove dust and other contaminants.
API starting material:
A raw material, intermediate, or an API that is used in the production of an API, which is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a materials purchased from one or more suppliers under contract of commercial agreements, or produced in-house.
API packaging material:
Any material intended for protect an intermediate or API during storage and transport.
Drawings of the equipment, indicating utilities etc. placement of equipment components, completed as the equipment was being built or manufactured.
“As is “drawings:
Drawings of the equipment as it has been placed/modified within the final location.
The condition or status of equipment, instrumentation or systems prior to calibration or maintenance activities.
The condition or status of equipment, instrumentation or systems following calibration or maintenance activities.
Prevention of microbial contamination of living tissues or sterile materials by killing, removing or excluding spores.
A process by which the drug or biological product, container, and closure are sterilized separately then assembled under strict environmental conditions.
An organism that does not use oxygen to obtain energy and cannot grow in an air atmosphere and for which oxygen is toxic.
A specific chemical moiety being measured, which can be intact drug, biomolecule or its derivative, metabolite, and/or degradation product in a biologic matrix.
Analytical run (or batch):
A complete set of analytical and study samples with appropriate number of standards and QCs for their validation. Several runs (or batches) may be completed in one day, or one run (or batch) may take several days to complete.
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 Q2)
Person recognised by the authority as having the necessary basic scientific and technical background and experience.
The firm that is being audited.
See out-of-trend (OOT) result.
A class of microscopic single cell organisms containing nuclear material within the cell wall (and not within a distinct nucleus, as for fungi). They can be found in almost every imaginable environment on the planet.
Batch (or lot):
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. (FDA 21 CFR 210.3)
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 subbatches, 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 the control of the finished product, a batch of a medicinal products 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. (PIC/S).
Batch Production record:
The document used for each individual batch of API, based on the master production instruction.
Batch number (or lot number):
A distinctive combination of numbers and/or letters which specifically identifies a batch.
An effect which deprives a statistical result of representativeness by systematically distorting its accuracy, as distinct from a random error which may distort in one action but balances out on the average.
Bias of Estimate:
The deviation of the expectation of an estimate of a parameter from the true value of the parameter.
Action which kills micro-organisms (irreversible).
Refers to contamination by bacteria, yeasts, moulds, viruses, or any other micro-organisms that may be present in product.
Microorganisms, including genetically engineered microorganisms, cell cultures and endoparasites, whether pathogenic or not.
A discrete material of biological origin that can be sampled and processed in a reproducible manner. Examples are blood, serum, plasma, urine, feces, saliva, sputum, and various discrete tissues.
Action which inhibits growth (reversible on removal of the biostatic agent from the organisms).
The process whereby a single cell divides to form two cells of equal size.
a chemical that acts to hold granules in a tablet together.
The number of micro-organisms that an object is contaminated with.
The process of combining materials, each within the same specification, to produce a homogeneous intermediate or API.
the processed material that is removed from the blender after the processing operation has been completed.
The design of a stability schedule such that only samples on the extremes of certain design factors (for example, 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 (for example, 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.
Any product which has completed all processing stages up to, but not including, final packaging.
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.
Comparison of a measurement standard or instrument of known accuracy with another standard or instrument to detect, correlate, report or eliminate by adjustment any variation in the accuracy of the item being compared with the standard traceable to a Recognised National Standard.
A biological matrix to which a known amount of analyte has been added or spiked . Calibration standards are used to construct calibration curves from which the concentrations of analytes in QCs and in unknown study samples are determined. (Source: Guidance for Industry Bioanalytical Method Validation 2001- CDER)
A process that performs within specification limits.
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 (fully characterised for identity and absence of contamination). 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.
Cell wall structure:
Another way to classify bacteria is based on their cellular structure. They can be either Gram-positive (blue) or Gram-negative (red) depending on how they react when stained with Gram Stain. Gram Stain is a differential stain by which bacteria are classified depending on whether they retain or lose the primary stain when treated with a decolourising agent.
A method of separating a solid/liquid mixture by rotating it at high speed in a cylindrical container. The solid will remain on the sides (through centrifugal force) while the liquid goes to drain.
Certificate of Analysis:
Document describing the quality and purity data from QC testing of a particular lot or batch.
A formal monitoring system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect the validation status of a system or process and cause corrective action, if any, to be taken that will ensure that the system or process retains, or is placed back into a validated state of control.
Occurs when product becomes contaminated with other materials or products.
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. Note: The different degrees of environmental control are defined in the Supplementary Guidelines for the Manufacture of sterile medicinal products.
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.
The removal of visible and microscopic contamination by dirt, extraneous matter, or product residues, by mechanical or physical means. Cleaning is usually followed by visual inspection to determine the effectiveness of the cleaning operation.
An automated cleaning process that relies on both chemical removal and physical agitation.
The four zones in the world that are distinguished by their characteristic, prevalent annual climatic conditions. This is based on the concept described by W. Grimm (Drugs made in Germany, 28:196-202, 1985 and 29:39-47, 1986)
Close out meeting/exit meeting/closing meeting:
The last formal meeting held between the auditee and the auditor(s) before the auditors leave the firm.
Coefficient of variation (cv):
The ratio of the standard deviation to the absolute value of the arithmetic mean. (Usually expressed as a percentage) Otherwise expressed as the relative standard deviation or RSD.
Refers to the storage of products requiring a storage temperature of 2oC-8oC, or requiring to be stored frozen.
Colony forming unit (cfu):
A microbiological term that describes the formation of a single macroscopic colony after the introduction of one or more microorganisms to microbiological growth media. One colony forming unit is expressed as 1 CFU.
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.
A complaint is any expression of dissatisfaction with a product or service marketed.
a. Critical Complaint:
A complaint that strongly indicates the purity, identity, safety or efficacy of a product may have been compromised and has the potential to cause
a life threatening or serious health situation.
b. Serious Complaint:
A complaint that indicates the purity, identity, safety or efficacy of a product may have been compromised, but does not present as a life
threatening or serious health risk.
c. Standard Complaint:
A complaint that is neither critical nor serious.
d. Justified Complaint:
A complaint where the investigation has shown the complaint to be valid and that it occurred under company control.
e. Non-Justified Complaint:
A complaint where the investigation has shown no valid reason for the complaint.
FDA defines this as any ingredient intended for use in the manufacture of a drug product, including those that may not appear in such drug product. The equivalent word in EU would be starting material. In this module the word component is used. The words are used interchangeably, depending on the stage of production, with a number of different terms such as: material, intermediate bulk, active pharmaceutical ingredient, excipient, starting material, raw material, goods.
a process in which one bulk drug substance is combined with another bulk drug substance and/or one or more excipients to produce a drug product.
Hardware components and associated software designed to perform specific functions.
A process where some or all actions are controlled by a computer. (FDA Guidance: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice)
A system including the input of data, electronic processing and the output of information to be used either for reporting or automatic control. . (From: PIC/S cGMP.)
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 (and other) manufacture. Commissioning involves all the basic requirements of Installation Qualification and Operational Qualification. (FDA Guidance: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice)
Equipment used for more than one type of product.
Any ingredient intended for use in the manufacture of a drug product, including those that may not appear in such drug product. (FDA 21 CFR 210.3)
Container closure system:
The sum of packaging components that contain and protect the dosage form. This includes primary packaging components and secondary packaging components (the latter are intended to provide additional protection to the drug product). A packaging system is equivalent to a container closure system.
Usually a plastic plate that has a raised surface composed of microbiological solid media. The media is then pressed or rolled upon a surface, transferring the content of the surface to the media. RODACs (Replicate Organism Direct Agar Contact) plates are one example.
The action of confining a biological agent or other entity within a defined space.
a. 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.
b. 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 sterilises for the exit of materials and secure operating
procedures. In many cases it may add to the effectiveness of primary containment.
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.
Refers to the presence of any foreign substance in a product, be it physical (e.g. foreign objects), chemical (e.g. degradation products), or microbiological (e.g. bacteria).
Ongoing sampling of environmental conditions throughout the period of operations, ensuring that update of data occurs constantly.
Provides a product/service to sponsoring organization (i.e. laboratory testing, producing an intermediate product and producing a finished product), that it cannot provide to other companies (e.g. making/packing products on which a firm owns the intellectual property).
Contributory raw materials:
A raw material used in the production of an API that contributes to the final molecular structure of an API.
Control article means any food additive, color additive, drug, biological product, electronic product, medical device for human use, or any article other than a test article, feed, or water that is administered to the test system in the course of a nonclinical laboratory study for the purpose of establishing a basis for comparison with the test article.
A statistical tool used to determine if a process performs within specification limits.
Any area in an aseptic process system for which airborne particulate and microorganism levels are controlled to specific levels that are appropriate to the activities conducted within that environment.
(see Lot number)
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.
Correction refers to repair, rework or adjustment and relates to the disposition of an existing non-conformity, defect, or other undesirable situation
Action to eliminate the causes of an existing non-conformity, defect or other undesirable situation in order to prevent recurrence.
A product that looks identical to an original product both in drug appearance and packaging, but does not contain any active ingredients.
Critical control points:
Particular areas in a process that, if not controlled, can affect product quality. In-process checks should be carried out here. Critical processing parameters defines the operating conditions under which production has been validated to work.
Items which have been assessed to impact on product quality, safety and efficacy or otherwise present an unacceptable hazard if the equipment or its protective system should fail and where failure or malfunction could lead to danger to life, significant harm to any person or to the environment.
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 the process.
Critical quality attributes:
Attributes the product is being specifically checked for when taking samples from the line.
The science which studies the separation of molecules based on differences in their structure and/or composition. Chromatography is also a method to separate components of an analyte involving a mobile phase moving through a stationary phase. Types of chromatography are thin layer chromatography, gas chromatography, liquid chromatography and paper chromatography.
a. Gas chromatography (GC):
A type of chromatography where a liquid sample is vaporized and then injected into a column on a carrier gas. Components of the analyte bind to the
column at different rates, with different parts of the analyte passing through the column at different times.
b. High performance liquid chromatography (HPLC):
A type of chromatography using relatively high pressures and small diameter column packings to achieve sharp and highly reproducible elution profiles.
The record of results for the process of chromatography that shows the response of each component as a function of time and concentration of the sample. The record may be the media itself, e.g. the paper or thin layer medium, a piece of paper (e.g. computer print out) or it may be retained in a computer and displayed on video display terminal.
Contamination of a starting material or of a product with another material or product.
A container designed to contain liquefied gas at extremely low temperature.
A list of observations, based on the GMP regulations, generated by the FDA during a plant inspection and given to management at the closing meeting. The observations are known as Cs” because the form that is used to record the observations is Form Number 483.
D. E. F.
An engineering term referring to a length of pipe, usually at right angles to the main pipe, that does not allow full flushing of the pipe to remove its contents. With a deadleg system residues or cleaning agents can remain in the “dead” area after the cleaning is completed.
Used to manufacture only one type of product, or for a run of batches (a campaign) of the same formulation.
Defined media characteristics:
When acid is produced, the resulting change in pH may cause the media to change colour. This colour change can aid in the identification of organisms.
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. This is considered to be 3 times the signal to noise ratio, within PAR&D.
A deviation is a departure from standard procedures or specifications resulting in non-conforming material &/or processes, or where there have been unusual or unexplained events which have the potential to impact on product quality, system integrity or personal safety.
a. Planned Deviation:
A deviation or change to test methods, laboratory or manufacturing procedures that has been planned and approved as part of temporary change.
b. Unplanned Deviation:
A deviation or change to test methods, laboratory or manufacturing procedures that was unplanned and was the result of an incident or error.
c. Critical deviation:
Deviation from Company Standards, and/or current regulatory expectations that provide immediate and significant risk to product quality, patient
safety or data integrity, or a combination /repetition of major deficiencies that indicate a critical failure of systems
d. Serious deviation:
Deviation from Company Standards and/or current regulatory expectations that provide a potentially significant risk to product quality, patient
safety or data integrity, or could potentially result in significant observations from a regulatory agency, or a combination /repetition of “other”
deficiencies that indicate a failure of system(s).”
e. Standard deviation:
Observations of a less serious or isolated nature that are not deemed Critical or Major, but require correction, or suggestions given on how to
improve systems or procedures that may be compliant, but would benefit from improvement (e.g. incorrect data entry).
Detection Limit (ICH Q2):
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.
A substance or preparation represented to be capable of killing pathogenic or food spoilage micro-organisms, excluding those for internal use, antiseptics and food additives. Note: A disinfectant is not necessarily expected to kill spores or viruses. A disinfectant is not expected to necessarily achieve sterility.
To remove a specific quantity of material from the primary material and portion into the individual secondary container for charging to a batch or prescription.
Must pass the Disinfectant Test:
disinfectants must kill the organisms in 10 minutes or less.
A pharmaceutical product type, for example tablet, capsule, solution, or cream. It usually contains a drug substance in association with excipients, but not always.
Due diligence audits:
Audits performed to evaluate if an external organization identified for in-licensing, acquisition, or collaboration is fit for purpose.
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. (FDA 21 CFR 210.3)
The unformulated drug substance that may subsequently be formulated with excipients to produce the dosage form.
The process during a chromatography run by which purified product is extracted from a column.
A test designed to determine if there are fever producing substances in the drug product. This substance can be produced by the degradation of gram negative bacteria from their cell walls. Endotoxin is harmful to humans.
Environmental monitoring program:
a defined documented program which describes the routine particulate and microbiological monitoring of processing and manufacturing areas and includes a corrective action plan when action levels are exceeded. This program provides meaningful information on the quality of the aseptic processing environment when a given batch is being manufactured as well as environmental trends of the manufacturing area. An adequate program identifies potential routes of contamination, allowing for implementation of corrections before contamination occurs.
Anything other than the drug substance in the dosage form.
A testing result that deviates from normal expectations defined by the firm.
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.
Expiry date (or Expiration Date):
Indicates the date after which the goods cannot be guaranteed to be safe for use.
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. Impurity: Any component present in the intermediate or API that is not the desired entity. (From: ICH Q7A – cGMPs for Active Pharmaceutical Ingredients).
The removal of a chemical from a mixture by the use of a selective solvent.
Factory Acceptance Testing (FAT):
Pre-delivery equipment testing and inspection performed at the factory.
An organism which does not require oxygen for growth but may use it if it is available. Grows well under both aerobic and anaerobic conditions.
FEFO (first-expiry, first-out):
A warehouse principle whereby the first stock due to time-expire is the first stock picked for use.
FIFO (first-in, first-out):
A warehouse principle whereby the first stock that arrives is the first stock picked for use.
A process in which an agent such as yeast, a bacterium, mold or enzyme causes an organic substance to break down into simpler substances.
The ability to support micro-organisms that the media is claimed to support.
The separation of a solid from a fluid by passing the liquid through a filter, cloth or other porous medium.
A medicinal products which has undergone all stages of production, including packaging in its final container.
Formal stability studies:
Long-term and accelerated (and intermediate) studies undertaken on primary and/or commitment batches according to a prescribed stability protocol to establish or confirm the re-test period of a drug substance or the shelf life of a drug product.
Freedom of information documents (FOI):
Documents that you, as a citizen, can access from the FDA website. Included are warning letters issued by the FDA. This can provide you with information about current audit areas the FDA is interested in.
Fungi are micro-organisms with a separate nucleus contained within a cell wall. Moulds and yeasts are typical examples of fungi.
G. H. I. J. K. L.
The time interval necessary for a cell to divide.
Good Distribution Practice (GDP):
Refers specifically to practices related to the transport and distribution of product.
Goods Inward Number (GIN):
See Unique Identifying Number (UIN).
Good Warehousing Practice (GWP):
Refers specifically to practices within the company warehouse.
Goods Received Register:
A register showing the receipt of starting materials.
Gram Stain is a differential stain by which bacteria are classified depending on whether they retain or lose the primary stain when treated with a decolorising agent.
Grade A area:
the normal air classification for an aseptic processing area. This classification means that there are not more than 3,500 particles measuring 0.5µm or larger in one cubic metre of air, when measure during activity. Grade A may be considered equivalent ISO class 5 and FDA class 100. Other grades/requirements can be found in the EU-GMP.
A particle that has been mixed or blended to achieve a certain size, shape and composition. The act or process of forming or crystallizing into grains; as, the granulation of powder and sugar.
The process of creating granules
Modification of the powder morphology using dry compaction forces.
Adding a liquid to a powder that causes particles to bind together through capillary forces.
Particle size profile:
The percentages of different sized particles that make up a passing granulation process
Herbal medicinal products:
Medicinal products containing, as active ingredients, exclusively plant material and/or vegetable drug preparations.
An expression used for build-up of material in equipment used for continous or campaign production leading to a risk of carry-over of contaminants (e.g. impurities or microorganisms). Examples of risks for significant carry-over between batches are filtration and micronisation.
Manufacture, processing, packing, or holding of a drug product includes packaging and labeling operations, testing, and quality control of drug products. (FDA 21 CFR 210.3).
High efficiency particulate air (HEPA) filter:
Retentive matrix designed to remove a defined percentage of particulate matter of a defined size.
Highly Purified Water (HPW):
Water produced from Potable Water by methods including, for example, double-pass reverse osmosis coupled with other suitable techniques such as ultrafiltration or deionisation. HPW (Highly Purified Water) meets the same quality standards as WFI (Water for Injections) but the production methods are considered less reliable than distillation and thus it is considered unacceptable for use as WFI. The specification for HPW is defined in the European Pharmacopoeia (EP) and HPW is a consideration only for certain products supplied to the European Union (EU).
Those activities designed to keep a facility in a clean, sanitary and well-maintained condition.
Any component present in the intermediate or API that is not the desired entity.
A description of the identified and unidentified impurities present in an API.
A container that provides a permanent barrier to the passage of gases or solvents. For example, sealed aluminum tubes for semi-solids, and sealed glass ampoules for solutions.
Any component other than an active ingredient. (FDA 21 CFR 210.3)
Contaminated with extraneous biological agents and therefore capable of spreading infection.
A small quantity of a microbiological organism transferred into a large volume of culture media to grow large quantities of the microbiological organism.
Checks performed during production in order to monitor and if necessary to adjust the process to ensure that the product conforms to its specification. The control of the environment or equipment may also be regarded as a part of inprocess control.
Any material fabricated, compounded, blended, or derived by chemical reaction that is produced for, and used in, the preparation of the drug product. (FDA 21 CFR 210.3).
The list of equipment for a facility, organized in a convenient hierarchy, with equipment identified at the level at which the maintenance history will be documented and maintained.
A test to determine the functional performance of a filter or filter system and detect the presence of individual leaks in the filter media, frame, and seal.
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. (Note: this guidance only addresses those intermediates produced after the point that a company has defined as the point at which the production of the API begins.)
Studies conducted at 30°C/65% RH and designed to moderately increase the rate of chemical degradation or physical changes for a drug substance or drug product intended to be stored long-term at 25°C.
Partly processed material which must undergo further manufacturing steps before it becomes a bulk product.
Test compound(s) (e.g. structurally similar analog, stable labeled compound) added to both calibration standards and samples at known and constant concentration to facilitate quantification of the target analyte(s).
A formal and documented review of a deviation, issue, incident or problem, to identify its root cause and determine the actions required to address it.
Investigational Medicinal Product:
A pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including already with a marketing authorization but use or assembled (formulated or packaged) in a way different from the authorized form, or when used for an unauthorized indication or when used to gain further information about the authorized form.
Known Laboratory Error:
A laboratory test result that is attributable to an event or incident that is known to be caused by an instrument, environmental, analyst or other source that has an assignable cause.
Laboratory Information Management System (LIMS):
A system which can be used to schedule and record analytical data.
An airflow moving in a single direction and in parallel layers at a constant velocity from the beginning to the end of a straight-line vector. However, true laminarity is not achievable in clean room applications. “Unidirectional flow” is the more accurate description for clean room applications and is defined as; 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 areas.
Limit of detection (LOD):
The lowest concentration of an analyte that the bioanalytical procedure can reliably differentiate from background noise.
Linearity (ICH Q2):
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. (Source: Guideline for Industry Text on Validation of Analytical Procedures ICH-Q2A – March 1995)
Before starting a packaging and labelling operation, the line clearance includes cleaning the area and machines, removing all previous product and waste from the area and machines, and reconciling all printed material and product from the previous batch. See Line setup.
Before starting a packaging and labelling operation, separate to a “line clearance”, this involves verifying that the line has been cleared; assembling the materials needed for the new operation; verifying that each container of bulk material is approved for use; verifying that printed matter conforms to descriptions in the batch record; and labelling the line with the product name and strength.
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. For those analytical procedures which are not linear, another mathematical relationship (proportionality) must be demonstrated.
Stability studies under the recommended storage conditions for the re-test period or shelf life proposed (or approved) for labeling.
A batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits. (FDA 21 CFR 210.3).(see also Batch for PIC/S definition).
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. (FDA 21 CFR 210.3)
A distinctive combination of numbers and/or letters which specifically identifies a batch. (PIC/S)
Lower limit of quantification (LLOQ):
The lowest amount of an analyte in a sample that can be quantitatively determined with suitable precision and accuracy.
In the printing industry, this refers to the first few sheets or labels to pass through a printing machine before the actual run starts. Make ready materials should be discarded at each step in the run.
The combination of all technical, administrative and managerial actions during the lifecycle of an item intended to retain it in or restore it to a state in which it can reliably perform a required function. Maintenance can be planned or unplanned.
All operations of purchase of materials and products, Production, Quality Control, release, storage, distribution of medicinal products and the related controls. (PIC/S)
Holder of a manufacturing authorization.
Manufacturing formulae, Processing and Packaging Instructions:
State all the starting materials used and lay down all processing and packaging operations.
The process of adding together the assay value and levels of degradation products to see how closely they add up to 100 percent of the initial value, with due consideration of the margin of analytical error.
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°C or lower.
Master production instruction:
The approved process document or “recipe” that is used for preparing every batch of the intermediate and API.
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°C. A freeze-dried master seed lot is stored at a temperature known to ensure stability. Working seed lot: A culture of a micro-organism derived from the master seed lot and intended for use in production.
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.
The direct or indirect alteration or interference in response due to the presence of unintended analytes (for analysis) or other interfering substances in the sample.
A general term used to denote raw materials (starting materials, reagents, solvents), process aids, intermediates, APIs, and packaging and labeling materials
Material item code:
An extra level of identification on a material’s label used in the Master Batch Record and formulation. This code also corresponds to the barcode, and usually helps identify the approved supplier and grade of the material.
Any medicine or similar product intended for human use, which is subject to control under health legislation in the manufacturing or importing State.
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.
A substrate for growing microorganisms. If the tests are compendial tests, the type of growth media (e.g. trypticase soybean casein digest, blood, etc.) will be suggested. Different media are used to characterize different microorganisms based on nutritional requirements/preferences.
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. The term “process simulation” is sometimes used interchangeably with media fill).
Media growth promotion test:
a test performed to demonstrate that microbial growth media will support microbial growth.
A comprehensive description of all procedures used in sample analysis. (Source: Guidance for Industry Bioanalytical Method Validation 2001- CDER).
Microbial limits testing:
A test used to determine the quantity of organisms in a pharmaceutical raw material, in process sample, or finished sample and indicator organisms for a particular drug product.
The growing of microorganisms, tissue cells, or other living matter in a specially prepared nutrient media.
The ability of media to selectively support growth of specific organisms, whilst selectively inhibiting the growth of other micro-organisms.
Occurs when labelling and packaging information does not accurately reflect the contents of a container.
A fungus characterised by a filamentous structure (mycelium).
MSDS (Material Data Safety Sheet):
A document provided by a material supplier indicating the proper safety procedures for handling or working with a particular substance.
New molecular entities:
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 ICH Q1A(R2).
Negative room pressure:
Pressures that contain dust within a room and prevent dust from getting into other rooms.
Nonclinical laboratory study:
Nonclinical laboratory study means in vivo or in vitro experiments in which test articles are studied prospectively in test systems under laboratory conditions to determine their safety. The term does not include studies utilizing human subjects or clinical studies or field trials in animals. The term does not include basic exploratory studies carried out to determine whether a test article has any potential utility or to determine physical or chemical characteristics of a test article.
Means the non-fulfilment of a specified “material/product” requirement – (usually to a specification) A non-conformance usually leads to rejection or reworking of the item.
The distribution of a random continuous variable whose variability is due to the summed effect of many random independent causes. When plotted, this distribution has a single mode from which the curve falls away symmetrically on two sides, making the mode, median and mean all the one value.
Micro-organisms which normally inhabit a healthy human body or other natural environment.
Normal Operating Range:
The normal operating limits of the instrument, equipment or system as required for operation within a process.
Micro-organisms which may present a health risk to consumers and which, for that reason, must be excluded from products. A microorganism that has been shown to cause harm to humans. Depending on the route of administration and the type of drug product, these organisms will be different for different products
GMP controls enacted during the packaging and labelling operation. Also called “in-process controls”.
Open ended question:
A question in which respondents are free to reply in their own words rather than being limited to choosing from among a set of alternatives. Example: How do you check in material coming into the plant site? An open-ended question is usually followed by a probing question to clarify or amplify information.
A micro-organism that is not normally pathogenic, but which can cause disease if host defence mechanisms are decreased.
A dosage form taken by mouth that may include tablets, gelatin capsules, chewable tablets, or a form of sustained release delivery.
A liquid dosage form taken by mouth containing an active drug product that is given to a patient. It may be a solution, elixir, or a suspension.
Out of Specification (OOS) Result:
A finished product or raw material test result that falls outside approved, registered or official specifications or acceptance criteria. A validated OOS results in Non-conforming product.
Out of Trend (OOT) or Atypical Result:
A result that is within specifications but is “atypical” or out of trend based on experience or systematic/statistical review of historical data. Typically OOT results would fall outside the alert limit but within the action limit.
A symbol for the degree of acidity or alkalinity of a solution. The pH of the media is important because some bacteria will only grow well in a narrow pH range.
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. (PIC/S)
Any material employed in the packaging of a medicinal products, 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.
Manufacture, processing, packing, or holding of a drug product includes packaging and labeling operations, testing, and quality control of drug products. (FDA 21 CFR 210.3)
A quantity associated with a population. (See statistic).
The chemical treatment of stainless steel with a mild oxidant, such as a nitric acid solution, for the purpose of enhancing the spontaneous formation of the protective passive film. This process is designed to remove foreign metals, oxides, and corrosion from the surface of stainless steel and corrosion resistant steels, which allows water to move through the pipes and improves corrosion resistance.
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. (FDA 21 CFR 210.3).
A pharmaceutical term used to describe a drug product that is sterile and delivered through injection/infusion.
Testing of the processing air for various sizes of viable and non-viable particles. Continuous monitoring is required in grade A and recommended for grade B by EU. FDA is less prescriptive and only state that such monitoring be frequent.
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 larger.
Positive room pressure:
Pressures that exclude outside air from entering a facility.
Water, that as a minimum, meets national standards for water intended for human consumption that have been documented as at least equivalent to World Health Organization (WHO) guidelines, the national standards for the USA, Europe and Japan meet or exceed the WHO guidelines. Potable Water is also known as Drinking Water.
Precision (ICH Q2):
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.
Repeatability expresses the precision under the same operating conditions over a short interval of time. Repeatability is also termed intra-assay precision
b. Intermediate precision:
Intermediate precision expresses within laboratories variations: different days different analysts, different equipment, etc.
Reproducibility expresses the precision between laboratories (collaborative studies usually applied to standardization of methodology).
The closeness of agreement (degree of scatter ) between a series of measurements obtained from multiple sampling of the same homogenous sample
under the prescribed conditions.
An audit performed by QA to determine if a site is prepared for a regulatory Pre Approval Inspection (PAI). This audit usually takes place prior to the submission of a regulatory filing.
Action taken to eliminate the cause of a potential non-conformity, defect, or other undesirable situation in order to prevent occurrence.
Preventive Maintenance System (PMS):
This system brings together people, equipment and procedures (including scheduled maintenance plans) to ensure that an asset is available for operation in accordance with its functional specification.
A question used to clarify answers or discover more in-depth information. It is usually specific, focused and used after a general question has been asked. Example: You mentioned that you documented the arrival of raw materials, what do you record on that documentation?
A statistical indicator that measures how well a given process is running. It compares the actual variability in the process to the process specification.
The limits within which a process parameter should be maintained to ensure adequate product quality.
A batch of a drug substance or drug product used in a formal stability study, from which stability data is 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.
Primary reference standard:
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: (1) obtained from an officially recognized source, (2) prepared by independent synthesis, (3) obtained from existing production material of high purity, or (4) prepared by further purification of existing production material. (From: ICH Q7A – cGMPs for Active Pharmaceutical Ingredients)
Includes labels for containers, package leaflets, labels for cartons or packaging, and printed containers.
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 products. (PIC/S)
The final extract (prior to instrumental analysis) of a sample that has been subjected to various manipulations (e.g., extraction, dilution, concentration).
Manufacture, processing, packing, or holding of a drug product includes packaging and labeling operations, testing, and quality control of drug products. (FDA 21 CFR 210.3)
All operations involved in the preparation of a medicinal products, from receipt of materials, through processing and packaging, to its completion as a finished product. (PIC/S)
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.
Protozoa are micro-organisms that have some animal characteristics – such as the way they ingest food.
Water produced by a suitable method (e.g., deionization, reverse osmosis, distillation, etc.) from potable water to meet specifications as defined by a compendial monograph.
A substance that induces a febrile reaction in a patient.
Action of proving that any equipment works correctly and actually leads to the expected results. The word validation is sometimes widened to incorporate the concept of qualification.
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.
a. Design Qualification:
Documented verification that the proposed design of the facilities, equipment, or systems is suitable for the in-tended purpose.
b. Installation Qualification (IQ):
Provides evidence (documentation of tests) that the system has been installed correctly and safely, according to the manufacturers instructions
and that installation can be repeated in support of disaster recovery. Also it ensures that the system work in accordance with established
c. Operational Qualification (OQ):
Provides documented evidence that functionality of the system meets the purchase specification requirements or performs as intended in its
normal operating environment and range.
d. Performance Qualification (PQ):
Provide documented evidence that the performance of the system under process conditions will consistently meet the specification and the
products manufacturing process requirements.
Qualification Audit (Retrospective Review):
An audit carried out to confirm that a piece of equipment or a service has been satisfactorily qualified. This will be confirmed via a qualification audit checklist.
Qualified Person (QP):
EU requirement, a person who is held legally accountable for ensuring that all Quality conditions are met before releasing each batch of drug product.
Quality Assurance (QA):
The sum total of the organized arrangements made with the object of ensuring that all APIs are of the quality required for their intended use and that quality systems are maintained.
A wide ranging concept which covers all matters which individually or collectively influence the quality of a product. It is the sum total of the organised arrangements made with the object of ensuring that medicinal products are of the quality required for their intended use. (PIC/S, 1.2).
The activity of providing evidence that all the information necessary to determine that the product is fit for the intended use is gathered, evaluated and approved. The Quality Assurance department executes this function.
Quality assurance unit:
Quality assurance unit means any person or organizational element, except the study director, designated by testing facility management to perform the duties relating to quality assurance of nonclinical laboratory studies.
Quality Control (QC):
Checking or testing that specifications are met.
That part of Good Manufacturing Practice which is concerned with sampling, specifications and testing, and with the organization, documentation and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory. (PIC/S, 1.4).
The activity of measuring process and product parameters for comparison with specified standards to assure that they are within predetermined limits and therefore, the product is acceptable for use. The Quality Control department executes this function.
Quality Control Unit:
An organizational element with authority and responsibility as defined by 211.22.
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.
An organizational unit independent of production that fulfills 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.
The range of concentration, including ULOQ and LLOQ, that can be reliably and reproducibly quantified with accuracy and precision through the use of a concentration-response relationship.
A set of minimum specifications and testing methods for raw materials, packaging components, chemical intermediates, active substance or drug products as established by official compendia and/or registered requirements.
Quantitation Limit (ICH Q2):
The quantitation 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 quantitation 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.
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. (PIC/S)
An area of the warehouse reserved for storing goods that have not yet been inspected or tested.
Raw data means any laboratory worksheets, records, memoranda, notes, or exact copies thereof, that are the result of original observations and activities of a nonclinical laboratory study and are necessary for the reconstruction and evaluation of the report of that study. In the event that exact transcripts of raw data have been prepared (e.g., tapes which have been transcribed verbatim, dated, and verified accurate by signature), the exact copy or exact transcript may be substituted for the original source as raw data. Raw data may include photographs, microfilm or microfiche copies, computer printouts, magnetic media, including dictated observations, and recorded data from automated instruments.
A general term used to denote starting materials, reagents, and solvents intended for use in the production of intermediates or APIs.
Range (ICH Q2):
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.
Reanalysis (New Initial Test):
A test performed on the original sample (where possible) following invalidation of a test for a determinant error.
Real-time studies are performed over the entire shelf life of the product, at temperatures and humidity in line with maximum storage claims. These studies are performed to give a confirmation of stability over the real shelf-life time.
A Major Quality Incident that leads to the removal of the entire affected batch or batches of material from the market or if clinical trials, from a study.
Recalled Goods store:
An area of the warehouse reserved for isolating faulty or recalled goods, ensuring that they are not issued or sold by mistake.
A comparison, making due allowance for normal variation, between the amount of product or materials theoretically and actually produced or used. Record See Chapter 4 of the PICS cGMP.
A way of looking at material balance, focusing on losses or gains of materials. Reconciliation compares the amount of material going into a process with the amount coming out of the process.
Provides a history of each batch of product, including its distribution, and also of all other relevant circumstances pertinent for the quality of the final product. (PIC/S, 4.1)
The introduction of all or part of previous batches of the required quality into another batch at a defined stage of manufacture.
The extraction efficiency of an analytical process, reported as a percentage of the known amount of an analyte carried through the sample extraction and processing steps of the method.
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: (1) obtained from an officially recognized source, (2) prepared by independent synthesis, (3) obtained from existing production material of high purity, or (4) prepared by further purification of existing production material.
Reference / reserve samples:
Term used for samples taken for retention
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. (From: ICH Q7A – cGMPs for Active Pharmaceutical Ingredients)
An area of the warehouse reserved for rejected batches.
Relative standard deviation (RSD):
The internal correlation of the standard deviation of a set of specific numbers. The RSD is the sample SD divided by the sample Mean. The RSD is usually expressed as a percentage. The higher the percentage is, the worse the correlation. The RSD is also known as 100 times the Coefficient of Variation (CV).
An area of the warehouse reserved for batches or materials that have been tested and passed for use.
Larger containers or material being distributed into smaller order quantities.
A deviation that re-occurs after the identification of actions identified from a previous deviation. This would indicate that the root cause of the previous incident had not been correctly identified and/or that the actions determined had either not been taken in a timely manner, or had not effectively addressed the root cause.
The inherent variation in measurements due to the equipment. Causes include noise in electronics, variation in chemical solutions used in the measurement and other causes of random system fluctuations.
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. (FDA 21 CFR 210.3)
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.
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 is not reprocessing.
Taking the same material and repeating steps that are already part of the normal process.
The precision between two laboratories. It also represents precision of the method under the same operating conditions over a short period of time. The variation due to the effect of different operators using the same equipment. In this case excessive reproducibility signals a need for training and consistent procedures.
To take additional test samples from the same lot of material previously tested.
To perform additional testing on the original sample (where possible) or new original sample according to an investigative plan, when no determinant error is found.
The date when a material should be re-examined to ensure that it is still suitable for use. Reworking: 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).
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 retested 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 retest, 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 retest period. The same may be true for certain antibiotics.
Sending back to the manufacturer or distributor of a medicinal products which may or may not present a quality defect.
Taking already manufactured material and performing steps that are not part of the normal process
An assessment of the risk associated with the non-conformity, defect, or other undesirable situation based on both safety and business components. The output is categorised into Major, Moderate, Minor or Incidental ratings.
Robustness (ICH Q2):
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.
The basic cause of a deviation, from which effective actions can be defined to prevent recurrence.
Used to monitor manufacturing processes, a run chart specifies the target fill, lower and upper specification limits, and the actual volumes dispensed over time.
A generic term encompassing controls, blanks, unknowns, and processed samples, as described below:
A sample of a biological matrix to which no analytes have been added that is used to assess the specificity of the bioanalytical method.
Quality control sample (QC):
A spiked sample used to monitor the performance of a bioanalytical method and to assess the integrity and validity of the results of the unknown samples analyzed in an individual batch.
A biological sample that is the subject of the analysis. (Source: Guidance for Industry Bioanalytical Method Validation 2001- CDER)
An area in the warehouse where starting and packaging materials are first sampled.
The reduction of microbiological contamination, usually achieved through cleaning as a preparation step, followed by the use of chemicals, biocides or disinfectants as sanitising agents. The reduction in microbial load (the bio burden) by chemical means. The end result of sanitation does not guarantee the complete absence of micro-organisms.
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.
A small amount of material used to start a chemical reaction, typically an approved lot of the material containing the desired crystal form which is added to start a crystallization process.
An action by authorities, taken to remove a product from commerce because it is in violation of the law.
The ability of the bioanalytical method to measure and differentiate the analytes in the presence of components that may be expected to be present. These could include metabolites, impurities, degradants, or matrix components.
A container that allows the passage of solvent, usually water, while preventing solute loss. Examples of semipermeable containers include plastic bags and semirigid, low-density polyethylene (LDPE) pouches for large volume parenterals (LVPs), and LDPE ampoules, bottles, and vials.
Settling or settle plates:
Usually petri dishes containing a microbial growth media, like agar, which are distributed throughout an area, media side up, to measure the viable content of the air over a specified period of time. This is a passive system that catches microorganisms as they fall onto plates.
Inwards goods that have been separated on the basis of having different manufacturers’ batch or lot numbers and different delivery dates. Each separate material is allocated a Unique Identifying Number.
(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.
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.
An inorganic or organic liquid used as a vehicle for the preparation of solutions or suspensions in the manufacture of an intermediate or API.
Describes 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. (PIC/S, 4.1). Means a document which defines official tests, test methods and limits. Specifications usually relate to starting materials, components, bulk product and finished products but may also apply to critical steps of manufacture where failure to meet the acceptance criteria would result in defective product. Failure to meet specification results in Non-conforming product, formal QA investigations, rejection of material or product or reprocessing, and probably corrective action.
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.
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.
Specificity (ICH Q2):
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). This definition has the following implications:
To ensure the identity of an analyte.
To ensure that all the analytical procedures performed allow an accurate statement of the content of impurities of an analyte, i.e., related substances test, heavy metals, residual solvents content, etc.
Assay (content or potency):
To provide an exact result which allows an accurate statement on the content or potency of the analyte in a sample.
Provides evidence that the software has been designed, installed, and tested that ensures its performance meets its intended purpose, and that the system can be reinstalled in support of disaster recovery.
Confirmation by examination and provision of objective evidence that (software) specifications conform to user needs and intended uses, and that the particular requirements implemented (through software) can be consistently fulfilled.
Verification provides objective evidence that design outputs of design development meet all specified requirements. (Software) verification looks for consistency, completeness (of software) and its supporting documentation.
Specimen means any material derived from a test system for examination or analysis
(1) A person who initiates and supports, by provision of financial or other resources, a nonclinical laboratory study;
(2) A person who submits a nonclinical study to the Food and Drug Administration in support of an application for a research or marketing permit; or
(3) A testing facility, if it both initiates and actually conducts the study.
A resistant body formed by certain micro-organisms.
Kills 100% of bacterial spores.
The chemical stability of an analyte in a given matrix under specific conditions for given time intervals. (Source: Guidance for Industry Bioanalytical Method Validation 2001- CDER). The variation in accuracy with respect to time. This might be due to wear in the standard or a function of environmental conditions.
A validated quantitative analytical procedure that can detect the changes with time in the pertinent properties of the drug substance and drug product.
Measurement systems or artifacts, traceable to National or International Reference Standards, which are used to calibrate test equipment.
A name assigned to a starting material that uniquely identifies it within the manufacturing establishment. It is used to cite the material in specifications, on identity/status tags, in analytical reports, in stores records and in batch documents. It is chosen to avoid the possibility of confusion between similar-looking or similar-sounding names.
Standard Names Register:
A list containing the names used to label and identify starting materials during storage and manufacture.
The relationship between the experimental response value and the analytical concentration (also called a calibration curve ).
Any substance used in the production of a medicinal products, but excluding packaging materials.
Static /“at rest” testing:
Testing performed with equipment installed but no personnel present to ensure that the facility environment continues to perform as designed and is compliant during normal operation
A quantity associated with a sample taken from a population. (See parameter).
Statistical quality control:
The specialised field of quality control using statistical methods such as the use of frequency distribution, measures of central tendency and dispersion, control charts, acceptance sampling, regression analysis etc.
Physical or electronic identification of a material indicating its status as “Quarantine”, “Hold”, “Released”, “Approved”, or “Rejected”.
Sterility is the absence of living organisms. The conditions of the sterility tests are given in the European or other relevant Pharmacopoeia. The concept of the complete absence of living micro-organisms. The total elimination of any living organisms, usually by heat or chemical means, of any living organisms.
A test performed on a sample of the product lot to determine if viable microorganisms are present.
Sterility assurance level (SAL):
The SAL of a sterilising process is the degree of assurance with which the process in question renders a population of items sterile. The SAL for a given process is expressed as the probability of a non-sterile item in that population. An SAL of 10-6 for example, denotes a probability of not more than one viable micro-organism in 1 × 106 sterilised items of the final product. The SAL of a process for a given product is established by appropriate validation studies.
Free from all living organisms.
(1) A process intended to produce sterile goods. (2) Reduction of the probability of the presence of viable micro-organisms to an acceptable extent. Sterilisation is effected by moist or dry heat, by treatment with a gaseous sterilant such as ethylene oxide, by irradiation with ionising radiation or, where such processes are inapplicable to solutions, by filtration.
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.
Sterilizing grade filter:
A filter that, when appropriately validated, will remove all microorganisms from a fluid stream, producing a sterile effluent.
Pure microbial cultures that are kept for use in the lab. Sources of these cultures may be the American Type Tissue Collection or microorganisms isolated from the production environment.
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 conditions within the ranges defined in ICH Q1A(R2). The actual temperature and humidity (when controlled) 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.
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 of certain products (for example meered dose inhalers, creams, emulsions, refrigerated aqueous liquid products).
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.
Study director means the individual responsible for the overall conduct of a nonclinical laboratory study.
Study initiation date:
Study initiation date means the date the protocol is signed by the study director.
Study completion date:
Study completion date means the date the final report is signed by the study director.
An umbrella term that covers both Vendors and Contractors supplying API, intermediates, raw materials, packaging components, excipients, formulated products, packaged products and / or providing services, e.g. calibration, validation, laboratory testing etc. to the sponsoring firm.
System suitability testing:
The evaluation of the components of an analytical system to show that the performance of a system meets the standards required by the method.
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 includes (1) 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; (2) information regarding test results on containers; and (3) other scientific rationales.
Determination of instrument performance (e.g., sensitivity and chromatographic retention) by analysis of a reference standard prior to running the analytical batch.
T. U. V. W. X.Y. Z.
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).
Test article means any food additive, color additive, drug, biological product, electronic product, medical device for human use, or any other article subject to regulation under the act or under sections 351 and 354-360F of the Public Health Service Act.
Test system means any animal, plant, microorganism, or subparts thereof to which the test or control article is administered or added for study. Test system also includes appropriate groups or components of the system not treated with the test or control articles.
Measurement systems used to calibrate critical instrumentation.
Testing facility means a person who actually conducts a nonclinical laboratory study, i.e., actually uses the test article in a test system. Testing facility includes any establishment required to register under section 510 of the act that conducts nonclinical laboratory studies and any consulting laboratory described in section 704 of the act that conducts such studies. Testing facility encompasses only those operational units that are being or have been used to conduct nonclinical laboratory studies.
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.
The quantity that would be produced at any appropriate phase of manufacture, processing, or packing of a particular drug product, based upon the quantity of components to be used, in the absence of any loss or error in actual production. (FDA 21 CFR 210.3)
Reach the use-by date.
A plan established by site management for individual employees or employees within a single department stating what training (both regulatory and job skills training) is required for the employee to be considered competent in the job.
The ability to trace the history, application or location of that which is under consideration (ISO 9000:2000).
Traceability (with respect to calibration):
The ability to relate individual measurement results through a continuous sequence of measurement accuracy verifications, to nationally (or internationally) accepted measurement systems.
A determination that data is moving in a general direction based on the reoccurrence of events within a defined period of time.
A periodic review and analysis of the Environmental Monitoring Program results that can be related to time, shift, facility, etc. for patterns that may suggest underlying or developing problems.
Type or Class A glassware:
Glassware that conforms to applicable construction and accuracy requirements as certified by the American Society of Standards and Testing. This glassware is marked with the letter “A” on it.
Ultra-low penetration air filter with minimum 0.3 ºm particle retaining efficiency of 99.999 percent.
Undetermined laboratory error:
A situation where the laboratory investigation is inconclusive and the possibility remains that a laboratory error has eluded the investigation process.
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.
Unique Identifying Number (UIN):
A number or combination of numbers, symbols and letters which uniquely distinguishes a batch of product from all other batches of that product, or other products, at all stages of manufacture and permits a correspondence to be established between the batch and all tests carried out on it in the course of processing and quality control. The UIN for starting materials should be derived from a different system to that used for finished product batches. Alternately called the Goods Inward Number (GIN).
Upper limit of quantification (ULOQ):
The highest amount of an analyte in a sample that can be quantitatively determined with precision and accuracy.
Action of proving, in accordance with the principles of Good Manufacturing Practice, that any procedure, process, equipment, material, activity or system actually leads to the expected results (see also qualification).
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.
a. Prospective Validation:
Validation conducted prior to the distribution of either a new product or process. 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, are established.
b. Concurrent Process Validation:
Validation carried out during routine production of products intended for sale.
c. Retrospective Validation:
The conduct of validation studies performed after production has begun and designed to show that the processes and procedures etc are capable of
ensuring product consistently meets specification. Retrospective validation is often proceeded by retrospective review which involves the
assessment of accumulated manufacturing, testing and control data.Validation of a process for a product which has been marketed based upon
accumulated manufacturing testing and control batch data.
d. Revalidation / Requalification:
Routine activities undertaken to confirm that critical systems, equipment and processes continue to operate in a validated state and in conformance
with current GMPs.
e. Full validation
Establishment of all validation parameters to apply to sample analysis for the bioanalytical method for each analyte.
f. Partial validation:
Modification of validated bioanalytical methods that do not necessarily call for full revalidation.
Comparison validation parameters of two bioanalytical methodsh. Cleaning validation:
Sets out to prove that the documented cleaning procedure will consistently remove the previous product, cleaning agent, and reduce the microbial
population to a safe and acceptable level.
i. Method Validation:
The process by which it is established, by laboratory studies, that the performance characteristics of the analytical methods meet the requirements for the intended application.
Validation Deficiency or Deviation Report:
A form used to monitor and record circumstances which do not meet acceptance criteria or Code of Good Manufacturing Practice guidelines during the execution of validation.
A document which defines the specific validation scope and associated activities of a project
A written plan stating how validation will be conducted. Including test parameters, product characteristics, production equipment and decision points on what constitutes acceptable test results.
Validation Protocol Supplement:
A written document that presents supplementary information or planned changes to the original protocol..
Document reporting the validation activities, the validation data and the conclusion drawn.
A form developed to aid in the collection of the data specified in a Validation Protocol or Annual Review/Verification.
Validation Master File (Datapack):
A file or datapack which contains all documents, reports and information concerning a validation activity. It is the permanent record of the objective evidence generated to demonstrate that a process, system or piece of equipment is in control and has been validated satisfactorily.
Validation documentation includes:
- Overview and definition of the system (Requirements Specification)
- A Validation Master Plan or equivalent which provides schedules, standards, acceptance criteria, responsibilities for development and execution of protocols
- System design requirements (functional and technical specifications)
- Installation qualification protocols
- Operational and Performance qualifications that identify the critical parameters and functionalities to be qualified
- Worksheets that capture the test plan, test results and acceptance criteria
- Validation report that summarises the protocol objectives, testing results and acceptance/rejection criteria from the test plan and protocol(s) and astatement that accepts or rejects the system
- Change control records.Vegetative cells:A cell in the active stage of growing , as opposed to the resting or spore stage.Vendor:Provider of API, raw material, excipients and packaging components to sponsoring firm. A vendor supplies articles of commerce (i.e. available for purchase by other companies).Vent filter:a non-shedding porous material capable of removing viable and non-viable particles from gases passing in and out of a closed vessel.Viruses:Viruses are basically packages of genetic material wrapped in a protein coat. They are parasites and incapable of independent growth and replication outside a host cell.Violative product:A drug product produced or manufactured in violation of the Federal Food, Drug, and Cosmetic Act.Working cell bank:A culture of cells derived from the master cell bank and intended for use in the preparation of production cell cultures. The working cell bank is usually stored at -70°C or lower.Warning Letter:A letter sent by the Food and Drug Administration (FDA) to management of a company indicating that GMP violations were found in a recent inspection and what the violations were. The expectation is that the company will respond within a designated time period with an acceptable corrective action plan.Water for Injection:Water produced by a suitable method (e.g., distillation) from potable water, usually with an intermediate purification step(s), to meet specifications as defined by a compendial monograph.Worst case:A set of conditions encompassing upper and lower processing limits and circumstances, including those within standard operating procedures, that pose the greatest chance of process or product failure (when compared to ideal conditions). Such conditions do not necessarily induce product or process failure.Conditions within normal parameters most likely to give failure. For processing purposes, “worst case” means those values of normal operating parameters most likely to cause process failure. For sampling locations, “worst case” means those equipment locations most likely to have higher levels of residues after cleaning. For sampling recovery, “worst case” means those procedures, within normal sampling parameters, most likely to give poorer percentage recovery.Yeast:A type of fungus that is uni-cellular and lacks typical mycelia.Yield:A way of looking at material balance, focusing on acceptable product outputs. As opposed to reconciliations (used in packaging and labelling), yield calculations are usually used during production processes.Yield, actual:Actual yield is the quantity of acceptable material or product that is output at an intermediate or final stage of manufacture.Yield, expected: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.Yield, theoretical: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.