GMP Definitions
A.
Accelerated testing: 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.
Acceptance criteria: The product specifications and acceptance/rejection criteria, such as acceptable quality limit and unacceptable quality limit, 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)
Acceptable Carryover Quantity (ACQ): The ACQ is the potential maximum allowable quantity of the previous product, which may be carried over to any subsequent product during manufacture.
The maximum allowable quantity of a guiding substance that can be carried over into subsequent manufacture. The guiding substance is generally the contaminant within the equipment train.
Accuracy: 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
Action limit: 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)
Actual yield: 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).
Adjustment: The adjustment of an instrument to improve accuracy so it shows the correct value. It is recommended to calibrate before and after adjustment. See also calibration.
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.
Aerobes: An organism that requires (for growth) a level of oxygen equal to, or greater than that present in the atmosphere.
Air changes: 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.
Air classifications: 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.
Air diffuser: A plate in the ceiling where the air is forced through. A diffuser may direct the air throughout the room
Air handling unit (AHU): An integrated piece of equipment consisting of fans, heating and cooling coils, air-control dampers, filters and silencers.
Air lock: 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.
Alert limit: 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.
Air samplers: 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.
Algae: Any member of a heterogeneous group of eucaryotic (cells that possess a definitive or true nucleus), photosynthetic, and unicellular or multicellular organisms.
Anaerobes: An organism that does not use oxygen to obtain energy and cannot grow in an air atmosphere and for which oxygen is toxic.
Analyte: 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.
Analytical Procedure: 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).
Analytical 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.
Annual Product Review (APR): An evaluation, conducted at least annually, to assess the quality standard of each drug product with the objective of verifying the consistency of existing processes and the appropriateness of current specifications, and highlighting any trends, in order to determine the need for changes in drug product specifications or manufacturing or control procedures.
Ancillary system: 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 – Active Pharmaceutical Ingredient: Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product that when used in the production of a drug becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure and function of the body.
API Intermediate (INT): 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.
API starting material (Contributory Raw Material): A raw material, intermediate, or 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 material purchased from one or more suppliers under contract or commercial agreements, or produced in-house.
API packaging material: Any material intended for protect an intermediate or API during storage and transport.
Artwork: A combination of a physical pack design, graphic design and approved text which gives a complete definition for printing of a package component.
“As-built” drawings: 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.
As found: The condition or status of equipment, instrumentation or systems prior to calibration or maintenance activities.
As left: The condition or status of equipment, instrumentation or systems following calibration or maintenance activities.
Asepsis: Prevention of microbial contamination of living tissues or sterile materials by killing, removing or excluding spores.
Aseptic filling: A process by which the drug or biological product, container, and closure are sterilized separately then assembled under strict environmental conditions.
Authorized person: Person recognized by the authority as having the necessary basic scientific and technical background and experience.
Audit: Note that, audits may assess: systems, processes, procedures, facilities, products, studies, reports, records, and/or data for compliance with policies, standards, procedures, guidelines, regulations, or regulatory submissions. Audits may assess both in-house and external activities. Audits may be planned, or undertaken on a ‘for-cause’ basis.
Auditee: The firm that is being audited.
Automated System: Includes (but is not limited to) automated manufacturing equipment, process control systems, automated laboratory systems, manufacturing execution systems, and, manufacturing and laboratory database systems. The automated system consists of the hardware, software, and if applicable, network components, together with the controlled functions and associated documentation.
Note: Automated systems are a type of computerized system.
Atypical result: See out-of-trend (OOT) result.
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B.
Bacteria: 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 number (or lot number): A specific quantity or lot of a test or control article that has been characterized according to Sec. 58.105(a). (From FDA CFR 58).
A distinctive combination of numbers and/or letters which specifically identifies a batch.
Batch Production record: The document used for each individual batch of API, based on the master production instruction.
Beta-Lactams: A major class of antibiotics that includes pencillins, cephalosporins and carbapenems.
Bias: 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.
Binary fission: The process whereby a single cell divides to form two cells of equal size.
Bioburden: The number of micro-organisms that an object is contaminated with.
Biocidal: Action which kills micro-organisms (irreversible).
Biological contamination: Refers to contamination by bacteria, yeasts, moulds, viruses, or any other micro-organisms that may be present in product.
Biological agents: Microorganisms, including genetically engineered microorganisms, cell cultures and endoparasites, whether pathogenic or not.
Biological matrix: 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.
Biological Indicator (BI): A BI is a characterized preparation of a specific microorganism that provides a defined and stable resistance to a specific sterilization process.
Biostatic: Action which inhibits growth (reversible on the removal of the biostatic agent from the organisms).
Binder: A chemical that acts to hold granules in a tablet together.
Blank sample: A sample of a biological matrix to which no analytes have been added that is used to assess the specificity of the bioanalytical method.
Blending: The process of combining materials, each within the same specification, to produce a homogeneous intermediate or API.
Blender discharge: The processed material that is removed from the blender after the processing operation has been completed.
Bracketing: 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.
Bulk Formulated Product: A pharmaceutical product (Formulated Drug/Formulated Product) is held in large intermediate or shipping containers and ready to be filled into primary containers.
Bulk Intermediate: A material produced during steps of the processing of a Drug Substance/API, which must undergo further molecular change or purification before it becomes a Drug Substance/API.
Bulk product: Any product which has completed all processing stages up to, but not including, final packaging.
Bulk production batch: A batch of product, of a size described in the application for a Marketing Authorization, either ready for assembly into final containers or in individual containers ready for assembly to final packs. (A bulk production batch may, for example, consist of a bulk quantity of liquid product, of solid dosage forms such as tablets or capsules, or of filled ampoules.)
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C.
Certificate of Manufacture (C of M): A batch-specific document issued by a manufacturer, vendor, or exporter attests that the batch meets the specifications and has been produced in accordance with the requirements of the Regulatory Authority approval and with cGMP.
Certification: Is the act of approving (accepting) quality control results provided by the supplier in relation to a specific material, thereby eliminating the need to undertake some or all laboratory tests on receipt of that material at gmp site unless specifically required to meet regional/local GMP and/or import regulations.
Certification of a finished product batch: The certification, in a register or equivalent document by a QP, as defined in Article 51 of Directive 2001/83/EC before a batch is released for sale or distribution.
Certified materials: A certified material is a material provided to receiving site, by a supplier, that is released by a sister site, or released by a contractor directly into the site’s distribution chain, without repeat laboratory testing by the receiving site or an independent laboratory approved by the receiving site, unless such testing is necessary to meet cGMP requirements, e.g. identity testing and/or local import regulations.
A certified material may undergo additional laboratory testing by the receiving site, or an independent laboratory approved by the site if the supplier does not perform all tests required to release the material.
Certification Report: A compilation of all information gathered by the Receiving Site Supplier Certification Team supporting the award/re-assignment of certification status.
Classified Areas: Pharmaceutical facility areas that require validated and controlled environmental air systems.
Clean (Pure) Steam: High quality steam produced from purified water (or better) with a distribution system constructed of non-rusting materials and used in applications that may directly contact product contact surfaces.
Clinical Trial Application (CTA): An application to regulatory authority(ies) for the permission to perform a clinical study using an investigational product in subject/patients. Defined in ICH guideline for GCP, May 1996.
Cleaning Process Establishment: Cleaning carried out to establish an effective cleaning method for API or intermediate prior to formal cleaning validation.
Cleaning Validation: Establishing documented evidence that a specified cleaning procedure will provide a high degree of assurance that it can be used to consistently clean a piece of equipment or a facility to a predetermined acceptable level of cleanliness.
Commissioning: The process of verification that new or modified assets can meet their design intent, while bringing them from a constructed state into beneficial operation, as defined by the acceptance criteria and agreed with the Project Sponsor.
Compendial Water: Water covered by a compendial monograph. It contains no added substances.
Computerized System Validation: Establishing documented evidence which provides a high degree of assurance that a computerized system will consistently function in accordance with its pre-determined specifications and quality attributes throughout it’s lifecycle. (It applies to systems which can affect product quality.)
Concurrent Validation: The validation carried out during routine production of products for sale. (In exceptional circumstances it may not be acceptable to complete a validation program before routine production starts.)
Confirmation: An internal Certificate of Analysis or Certificate of Manufacture will be issued that confirms a process or test has been conducted in accordance with GMP and the relevant Marketing Authorization, as agreed in writing (QA Agreement) with the QP responsible for certifying the finished product batch before release.
Consumable: A consumable is a material or item of disposable equipment used in the manufacture of an API or finished product that is not a process chemical (solvent), API raw material/intermediate, excipient or packaging material. Examples are filters, and disposable tubing used in the manufacturing process. A GMP critical consumable is defined as where failure to specify and control quality requirements could adversely affect product quality/patient safety.
Containment: The action of confining a chemical entity within a defined space.
i. Primary containment: A system of containment, which prevents the escape of a chemical entity into the immediate working environment. It involves the use of closed containers or safety cabinets along with secure operating procedures.
ii. Secondary containment: A system of containment, which prevents the escape of a chemical entity from a system of primary containment into the external environment or into other working areas. It involves the use of localized extract booths or rooms with specially designed air handling, the existence of airlocks and secure operating procedures. In many cases it may add to the effectiveness of primary containment.
Contract Acceptor (“ACCEPTOR”): A person or entity who agrees to provide the contract giver with a service, product, project or study according to the givers specified requirements.
Contract Giver (“GIVER”): A person or entity who on behalf of the site, commissions a service, product, project or study.
Critical: A process step, process condition, test requirement or any other relevant parameter or item that must be controlled within predetermined criteria to ensure that the API meets its specification.
Critical Activity: An activity that will prevent the Active Pharmaceutical Ingredient or intermediate from meeting its specification when omitted or carried out incorrectly.
Critical Effect: This is the first significant adverse effect(s), which occurs as the dose increases from zero. It is determined after consideration of all the available data. For pharmacologically active compounds, the critical effect may be the pharmacological effect but this is not necessarily the case.
Critical Observation: “Deficiencies with 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.” Immediate corrective action and reporting to Management is required.
Critical Parameter: A process parameter that must be controlled within an established range to ensure that the Active Pharmaceutical Ingredient or intermediate will meet specification.
Crystallization: The formation of pure to nearly pure crystals of small or big molecules. Often used to purify a substance; crystallization of proteins is used to obtain their three-dimensional structure by x-ray analysis.
Critical Process Parameters: A process step, process condition, or any other relevant parameter or item that must be controlled within predetermined criteria to ensure that the API meets its specification. The requirements or specifications of an API or API process that can be measured and controlled to produce the desired quality of the API.
Cytotoxic: A substance that kills or damages cells if the exposure is high enough.
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D. E. F.
D value: The time in minutes at a specific temperature required to reduce a surviving microbial population by 90%, i.e. a one-logarithm reduction.
De-certification: Is the act of reverting back to full or partially increased testing of a specific material on its receipt from the supplier.
De-certified material: A de-certified material is a material that has had its ‘certified’ status revoked.
For the purpose of cleaning, equipment/plant shall be considered dedicated when it is used for the production of one API or intermediate and the potential for cross contamination does not exist.
Design Qualification: Documented verification that the proposed design of the facilities, equipment, or systems is suitable for the in-tended purpose.
Direct Impact System / Component: This is a system / component that is expected to have a direct impact on product quality. These systems / components are subject to qualification.
In some instances, Direct Impact Systems / Components will depend on Indirect Impact Systems / Components for effective operation and therefore, any interfaces need to be carefully assessed.
Dynamic / “in-operation” testing: Testing performed during processing operations or within an active shift (as applicable) with personnel present to confirm that the environment remains under control during these conditions.
Endotoxins: Toxic molecules consisting of lipopolysaccharide originating from the outer cell wall of Gram-negative bacteria. Endotoxins may cause fever reactions in humans.
Endotoxin-Controlled Purified Water: Water that, as a minimum, meets the requirements of Purified Water with the addition of the Bacterial Endotoxin Test.
Equilibration Time: The period of time which elapses between the attainment of the sterilizing temperature in the chamber and the attainment of the sterilization temperature in all parts of the load. This period of time is an indication of the ability to properly remove air from the load items; consequently it should only be evaluated for heat penetration probes placed in porous loads. It is not applicable to heat penetration measurements in liquid loads.
Equipment Train: All process equipment, including flexible hoses and pipe work, that is in direct contact with the product during manufacture of a specific product, e.g. granulation, drying, milling, mixing, compaction and coating. Used to identify the total surface area potentially at risk to cross-contaminate a product. Disposable or dedicated product specific parts are excluded.
F0: The time required at any given temperature between 100°C -140°C that is equivalent to the sterilization effect of steam at 121.1°C (250°F). Assumes a Z value of 10°C.
For cause audit: An extraordinary audit focused to find the cause of a problem that is probably related to gaps/deficiencies in the quality system. It may be performed for critical issues or bad performance. It could affect the routine scheduled audit frequency.
Formulated Product: A finished dosage form, for example tablet, capsule, solution, suppository, that contains an API usually, but not necessarily, in association with inactive ingredients. It also includes a finished dosage form used as a placebo.
Free From Gross Contamination: A state of cleanliness in which the equipment train may not be visibly clean but is free from any large quantities of material hold up. The amount of solid/liquid remaining in the equipment is not quantified but is assessed by visual inspection (e.g., through a sight glass on a reactor). Typically equipment is cleaned free from gross contamination through a single rinse and residual material is estimated at less than 5%.
For pressure filters free from gross contamination normally requires the heel to be removed.
Functional Specification (FS): A document which records and approves the proposed solution to the User Requirement Specification prior to detailed design.
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G. H. I. J. K. L.
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.
GMP Documentation: GMP documentation is any procedure, control, record, distribution or related record, or electronic file that is required to be retained as evidence of compliance with GMP.
GMP Master Document: An approved, version controlled GMP document is any policy, procedure, guideline, protocol, report, controlled form or template in paper or electronic form that is required for compliance with the GMP codes of practice and/or company Standards.
Good Engineering Practice: Established engineering methods and standards that are applied throughout the project lifecycle to deliver appropriate, cost-effective solutions
Guiding Substance: The guiding substance is generally the contaminant within the equipment train that is considered to have the greatest potential impact on patient safety. This is assessed by taking into consideration information on toxicity, ease of removal and pharmacological activity. Often the guiding substance will be the final product from the equipment train, but it may be a reagent or intermediate in the synthesis if it is known to be highly toxic.
A guiding substance (or substances) should be selected such that verification of the removal of the guiding substance to an acceptable level will assure that any residual contamination from other materials in the contamination matrix is also below an acceptable level.
There may be a need to define more than one guiding substance if there is more than one potential contaminant with significant toxicological/pharmacological activity that is removed by a different cleaning method (e.g. a heavy metal from a catalyst may be considered as a guiding substance along with the final product from the equipment train).
Hazard (toxic): Any substance, which has the potential to cause harm to people.
HEPA filter: High efficiency particulate air filter with a minimum 0.3 micron particle retaining efficiency of 99. 97 percent.
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.
Hot Spot: A surface that is judged to be hard to clean or has the potential for hold up of materials.
House Steam: Steam produced from potable, softened or deionized water with a distribution system made of iron or steel and treated with additives to minimize corrosion and only used in applications with non-product contact.
HVAC: Integrity test: 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.
Incident rates: The rate or frequency at which contamination is observed in an environment. Typically expressed as a percentage of samples in which contamination is observed per unit time.
Indirect Impact System / Component: This is a system / component that is not expected to have a direct impact on product quality, but typically will support a Direct Impact System / Component.
These systems / components are not subject to qualification, but are subject to Good Engineering Practice (GEP).
Installation Qualification (IQ): Documented verification that all physical aspects of a facility or system, which affect product quality, adhere to the approved specification and are correctly installed.
Japanese New Drug Application (JNDA): Application to be submitted for regulatory drug approval to the Japanese Ministry of Health, Labor and Welfare (MHLW).
LD50 value: The LD50 (Lethal Dose, 50%) value is typically expressed in mg of material per kg of subject-body-weight, and indicates the quantity of material that, if administered to a population of subjects, will cause 50% of the subjects to perish.
Lead Audit Site: The site/function that is accountable for conducting quality audits of suppliers.
Level 1 Deviation: A deviation that may have an actual or potential adverse effect on product quality (inc. purity and identity) safety or efficacy. Alternatively, a level 1 deviation may arise as a consequence of numerous repeated level 2 deviations.
Level 2 Deviation: An isolated event or deviation from an agreed/approved procedure or process that normally results in a rapid corrective action or establishment of such corrective actions. Alternatively, a level 2 deviation may arise as a consequence of numerous repeated level 3 deviations.
Level 3 Deviation: A deviation from GMP or procedure with no impact on product quality.
Lead Site: The Lead Site is the site reflected in the Vendor and Contractor Database to be accountable for conducting specified material related QA activities. If no Quality Assurance Agreement Coordination site is assigned, the Lead Site would be responsible for GMP related interactions and issues, conducting audits, and development of the Quality Assurance Agreement.
Limit of Quantification: The lowest amount of a given substance in a sample that can be quantified with suitable accuracy and precision with the selected analysis procedure.
Local Exhaust/Extract System: Consists of a control exhaust hood, duct work, exhaust, filter and controls used to control an air contaminant by collecting it at source. A local hood/booth is the point of entry of air to the system.
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M.N.O.
Major Observation: “Deficiencies with 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).”
Manometer: A device that measures the difference in pressure between two points.
Market Specific Requirements: These are the market specific requirements for the provision of BSD to customers and are held as an appendix to this guideline (Appendix VIII). These requirements are for customers external to the company, they are not for internal Operations supply – when bulk finished products are shipped between Operations manufacturing sites for further processing CofA are always needed.
Marketing Authorization Application (MAA): Application for authorization to place medicinal products on market. This is a specific term for the EU/EAA markets.
Material Safety Data Sheet (MSDS): A Material Safety Data Sheet provides information on the hazards to health, safety and environment inherent in a chemical substance.
Materials Validation: Provides documented evidence that all the necessary qualification associated with materials used during manufacture have been generated and approved as appropriate. It includes specifications, vendor audits/ vendor rating, purchase standards for Raw Materials and Excipients, Primary Packaging Materials, Processing Aids.
Maximum Daily Dose (MDD): The maximum dose of active substance (usually mg or g) typically administered to a patient in any 24hr period (e.g. as referenced in the Core Data Sheet).
Medical Device: Any instrument, appliance, material or other article, whether used alone or in combination, including the software necessary for its proper application, intended by the manufacturer to be used for human beings for the purposes of diagnosis, prevention, monitoring, treatment or alleviation of disease.
Medical Device Documentation: Medical Device Documentation is any procedure, control record, distribution or related record, or electronic file that is required to be retained as evidence of compliance to Medical Device Legislation.
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.
Microbiological (BIO): Is a material from an animal or plant source that is used to grow and/or culture microorganisms and to monitor the production and quality assurance of sterile products (i.e. culture media).
Minimal Effect Dose (MED): The minimum dose at which there is an observable pharmacological effect in man. Note: The MED is expressed as a weight of active substance (usually mg or g) per day.
Minimum Therapeutic Dose (MTD): The minimum amount of active substance typically given to a patient on each occasion as referenced in the Core Data Sheet. Note: The MTD differs to the MED when the lowest observable pharmacological effect is not the desired therapeutic effect.
Minor Observation: 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. Good Practice seen elsewhere).
Mobile Equipment: Items of product contact equipment that are routinely disconnected and reconnected to plant to enable processing steps as part of an equipment train. This excludes small, easily inspected or disposable items and spares (e.g. sight glasses, small flexible lines, filter bags etc.).
Multi-Market Pack: A finished product pack that is designed for supply to two or more specified markets.
Multi-purpose Equipment/Plant: Non-dedicated plant or equipment used for the production of more than one intermediate or API where the potential for cross-contamination exists.
National Drug Code (NDC): Product identifiers for human drugs, which include a unique NDC number (US term).
Network Diagrams: A network diagram is a comprehensive, detailed view of the infrastructure. It should include both physical and logical components at a Local Area Network and Wide Area Network level.
New Drug Application (NDA): Application to the US regulatory agency (FDA) to allow the sponsor to market a drug product in the US.
Nil Effect Dose (NED): Based on human data, is the maximum (single or repeated) dose at which there are no observable pharmacological effects in man.
No Observable Effect Level (NOEL): The dose level (usually mg or g) at which no toxicological effects are observed.
No Impact System / Component: This is a system / component that will not have any impact, either directly or indirectly, on product quality. These systems / components are not subject to qualification, but are subject to Good Engineering Practice.
Non-Contributory Raw Material (NCRM): Is a raw material used in the production of an API that does not contribute to the final molecular structure of an API (e.g. catalyst, water/solvents that are dried off in process, cleaning fluids).
Non-Sterile Excipient : Is a material used to formulate API’s into pharmaceutical dosage forms suitable for administration to a patient. If sterile it is stored in a way that ensures its sterility for subsequent use in the preparation of a sterile formulated product that is not subjected to further aseptic or terminal sterilization.
Occupational Exposure Limit (OEL): An in-house Occupational Exposure Limit (OEL) is a health-based exposure limit. This is the concentration of an airborne substance, averaged over a reference period, at which, according to current knowledge, there is no evidence that it is likely to be injurious to employees if they are exposed by inhalation, day after day.
Occupational Hygiene: Occupational hygiene practice is the application of principles to ensure adequate control of exposure to hazards and to minimize the risk in the workplace to adverse health effects.
Occupational Hygiene Monitoring (OHM): Occupational hygiene monitoring is the measurement of airborne substances in the workplace to assess potential for exposure and assess effectiveness of controls.
Operational Qualification (OQ): Documented verification that all functional aspects of a facility or system, which affect product quality, perform as intended throughout all anticipated operating ranges.
Operations Sites: Each Operations site/plant shall put in place validated cleaning procedures and generate data to confirm the validation of all product/equipment changeovers.
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.
Opening meeting: A meeting is held between the auditee and auditors before the audit officially starts.
Overkill cycle: A sterilization cycle that provides a 12-log reduction of a resistant Biological Indicator (BI) with a known D value of not less than 1 minute. A typical cycle would provide a minimum of 15 minutes at or above 121.1°C. This method is appropriate for heat stable products and processing equipment and is the preferred cycle type.
Overkill Sterilization Method: For steam sterilization, this approach is a cycle that provides a minimum 12-log reduction of a resistant Biological Indicator (BI) with a known D value of not less than 1 minute.
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P. Q.
Packaging Component – Critical (PCC): Is any printed packaging component, primary (product contact) component or device. Furthermore any secondary packaging component critical to the microbiological integrity, stability and/or administration of the product (e.g. aluminum pillow packs around semi-permeable).
Packaging Component – Non-Critical (PCNC): Is any non-printed or secondary (non-product contact) packaging component or device that does not fall within the definition of a PCC.
Packaging Site: A site where the particular medicinal product is packaged and/or labeled to produce ‘finished product’. A packaging site packing a product for a particular Marketing Company may be one of the following:
– a part of that Marketing Company organization
– a part of another contracted Marketing Company organization
– a company contracted to one of the above.
In the case of a larger Marketing Company that may have more than one packaging site in its organization, some of the responsibilities and activities identified in this Guideline may be discharged through a single group that acts for some or all these packaging sites.
Packing Bay: This is the area within a packing facility that houses the group of equipment that make up the packing line, e.g., blister former, labeler, and end of line equipment.
Packing Facility: The building and services which house the hardware.
Packing Line: The combination of equipment receiving the bulk formulated product and generating the primary container and may also generate the final pack for shipping.
Part Finished production batch: In the context of this procedure the term means the different stages of manufacturing required to formulate a product batch prior to it being in its final pack for release to the market.
Particle size profile: The percentages of different sized particles that make up a passing granulation process.
Performance Qualification (PQ): A process which ensures /verifies that the facilities, utilities and equipment, as connected together, function as intended and produce intended results repeatedly and reliably.
Personal Protective Equipment (PPE): Any equipment worn by an operator or technician to minimize exposure to a drug or substance, e.g., to provide protection to hands, eyes, skin or to prevent inhalation.
Piping and installation drawings: Mechanical drawing or blueprints of the required piping system for installation of equipment.
Potent: A compound that is biologically active at low doses.
Pressure Regimes: A subdivision of a series of rooms into defined air pressure regimes. The pressure regimes are cascaded, with the lowest pressure at the point of highest risk of loss of contaminant, to prevent airborne material transmission from process rooms into adjacent transit areas.
Primary containment: A system of containment, which prevents the escape of a chemical entity into the immediate working environment. It involves the use of closed containers or safety cabinets along with secure operating procedures.
Primary Packing: Any material employed in the packaging of a pharmaceutical product, excluding secondary packaging and any outer packaging used for transportation or shipment. Primary packaging material(s) form the container/closure system for the product and therefore may be in direct contact with the product. Examples include HDPE bottles/caps, blister strip packs, tubes/caps for ointments.
Primary Packing Equipment: The hardware used to put the product into its primary container, e.g., the blister former or bottle filler.
Printed Package Component: Printed packaging materials are printed and/or otherwise decorated packaging materials produced by a printer from an artwork. In the case of printed packaging components for finished products, the text, and in some cases the decoration, forms a part of the legal labelling and design of the finished products, (e.g. labels, leaflets, pre-printed ampoules, tubes, foils).Some package components are printed during the packaging process. Such components fall within this definition. Printed components added to packs to meet transport, hazard and other distribution requirements are excluded.
Probability of a Non Sterile Unit / Sterility Assurance Level: The Probability of a Non Sterile Unit (PNSU) establishes the target for the lethal treatment. That target is the probability of not more than 1 contaminated unit in 1million units or the probability of less than one chance in a million that a viable organism remains following the sterilization process. The PNSU is expressed as1x10-6 and represents the minimum target for a sterilization process. Another term, Sterility Assurance Level (SAL) is often used and expressed interchangeably with PNSU i.e. SAL of 1×10-6.
Process Validation: Establishing documented evidence, which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics.
Product Quality Complaint (PQC) Notification: Any report involving 1. The possible failure of a drug product to meet any of its specifications. 2. Non typical product characteristics: color, odor, embossing, labeling etc. 3. Dissatisfaction with the design of the product or the package or labeling.
Product Quality Review (PQR): Regular periodic review, normally conducted and documented annually, of an API, Bulk Formulated Product, Drug Product or Finished Product intended for the EU market or manufactured within EU but intended for export only, with the objective of verifying the consistency of existing process and the appropriateness of current specifications, to highlight any trends and to identify both product and process improvements.
For Bulk Formulated Product, Drug Product or Finished Product, the review includes verifying the appropriateness of current starting material specifications as well.
Product Specific Method: For steam sterilization, validation using this method relies on a thorough knowledge of the population and heat resistance of any product, items-to-be-sterilized, or environmental bioburden. The desired sterilization cycle lethality (Fvalue) as well as the attributes of the biological indicator used during validation are derived from knowledge of the bioburden population and resistance of the spore bioburden.
Prospective Validation: Establishing documented evidence that systems do what they purport to do prior to the commercial distribution of a new product or an existing product made by a new or modified process.
Pure Steam: Pure Steam is produced using an appropriate steam generator, from Potable Water, usually pre-treated with an intermediate purification step(s). The steam condensate should meet the appropriate quality requirements of the water used in the facility.
Pure Steam is also known as Clean Steam or Pyrogen Free Steam.
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R.
Rapid Microbial Identity Test: A commercially prepared test that is able to identify microorganisms through interactions with chemicals within a matter of hours instead of days.
Reportable Result: The final value(s) that will be reported as representing the outcome of the analysis derived from the data. It is the value compared to the specifications.
Reprocessing: Taking the same material and repeating steps that are already part of the normal process.
Reserve/ Reference samples: Term used for samples taken for retention.
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S.
Sanitization Schedules: Schedules established by the firm to sanitize the cleanroom facility surfaces, e.g., walls, ceilings, floors. Schedules may vary depending on the use and condition of the room. The schedule is to be part of an approved procedure for housekeeping and cleaning of the aseptic area.
Standard Deviation (SD): A measure of the dispersion of a series of results around their average, expressed as the square root of the variance.
Sterility test: A test performed on a sample of the product lot to determine if viable microorganisms are present.
Stop shipment: A drug shipment that is placed on hold pending investigation.
Supervisory control and data acquisition (SCADA): Application software used for process control and alarm management for the collection of data.
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T. U. V. W. X.Y. Z.
– Overview and definition of the system (Requirements Specification)
– A Master Validation 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
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