Measurable terms under which a test result will be considered acceptable.
active pharmaceutical ingredient (API)
A raw material, intermediate or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement or produced in-house.
active pharmaceutical ingredient (API) starting material
A raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house.
active pharmaceutical ingredient master file (APIMF) procedure
The APIMF procedure is one of four ways to provide information on the preparation control and stability of an API intended for use in a prequalified finished pharmaceutical product (FPP). The other three options are: the use of a prequalified API; use of a certificate of suitability (known as a CEP) issued by the European Directorate for the Quality of Medicines; or the submission of complete API information as part of the FPP dossier.
The person or entity who, by the deadline mentioned in the invitation, submits an expression of interest (EOI) to participate in this procedure in respect of the product(s) listed in the invitation, together with the required documentation on such product(s).
batch (or lot)
A defined quantity of starting material, packaging material, or product processed in a single process or series of processes so that it is expected to be homogeneous. It may sometimes be necessary to divide a batch into a number of sub-batches, which are later brought together to form a final homogeneous batch. In the case of terminal sterilization, the batch size is determined by the capacity of the autoclave. In continuous manufacture, the batch must correspond to a defined fraction of the production, characterized by its intended homogeneity. The batch size can be defined either as a fixed quantity or as the amount produced in a fixed time interval.
batch number (or lot number)
A distinctive combination of numbers and/or letters which uniquely identiﬁes a batch on the labels, its batch records and corresponding certiﬁcates of analysis, etc.
All documents associated with the manufacture of a batch of bulk product or ﬁnished product. They provide a history of each batch of product and of all circumstances pertinent to the quality of the ﬁnal product.
The rate and extent to which the active moiety is absorbed from a pharmaceutical dosage form and becomes available at the site(s) of action. Reliable measurements of active pharmaceutical ingredient (API) concentrations at the site(s) of action are usually not possible. The substance in the systemic circulation, however, is considered to be in equilibrium with the substance at the site(s) of action. Bioavailability can therefore be defined as the rate and extent to which the API or active moiety is absorbed from a pharmaceutical dosage form and becomes available in the systemic circulation. Based on pharmacokinetic and clinical considerations it is generally accepted that in the same subject an essentially similar plasma concentration time-course will result in an essentially similar concentration time-course at the site(s) of action.
The batch used to establish bioequivalence or similarity to the comparator product as determined in bioequivalence or biowaiver studies, respectively.
The level and type (objectionable or not) of microorganisms present in raw materials, media, biological substances, intermediates or finished products. Regarded as contamination when the level and/or type exceed specifications.
Two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives, and their bioavailabilities, in terms of rate (Cmax and tmax) and extent of absorption (area under the curve), after administration of the same molar dose under the same conditions, are similar to such a degree that their effects can be expected to be essentially the same.
A test that determines the equivalence between the multisource product and the comparator product using in vivo and/or in vitro approaches.
Biopharmaceutics Classification System (BCS)
The BCS is a scientific framework for classifying active pharmaceutical ingredients based upon their aqueous solubility and intestinal permeability. When combined with the dissolution of the pharmaceutical product, the BCS takes into account three major factors that govern the rate and extent of drug absorption (exposure) from immediate-release oral solid dosage forms: dissolution, solubility and intestinal permeability.
Biopharmaceutics Classification System (BCS) highly soluble
An active pharmaceutical ingredient (API) for which the highest dose recommended by WHO (if the API appears on the WHO Model List of essential medicines (EML)) or highest dose strength available on the market as an oral solid dosage form (if the API does not appear on the EML) is soluble in 250 ml or less of aqueous media over the Ph range of 1.2–6.8 at 37 °C (8).
The term biowaiver is applied to a regulatory drug approval process when the efficacy and safety part of the dossier (application) is approved based on evidence of equivalence other than through in vivo equivalence testing.
A multi-dose container consisting of two layers, of which one is shaped to contain the individual doses. Strips are excluded.
Any pharmaceutical product that has completed all processing stages up to, but not including, final packaging.
The set of operations that establish, under specified conditions, the relationship between values indicated by an instrument or system for measuring (especially weighing), recording, and controlling, or the values represented by a material measure, and the corresponding known values of a reference standard. Limits for acceptance of the results of measuring should be established.
calibration of equipment
The documented act of proving that the equipment is performing to predefined tolerances or criteria.
certificate of a pharmaceutical starting material
A document containing the information that is validated and issued for a specific starting material by the competent authority of the exporting country and intended for use by the competent authority in the importing country or in the absence of such an authority by, for example, the manufacturer of the finished product when exporting.
certificate of analysis
The list of test procedures applied to a particular sample with the results obtained and the acceptance criteria applied. It indicates whether or not the sample complies with the specification.
A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect a validated status. The intent is to determine the need for action that would ensure that the system is maintained in a validated state.
chemical reference substance
The term chemical reference substance, as used in this text, refers to an authenticated, uniform material that is intended for use in speciﬁed chemical and physical tests, in which its properties are compared with those of the product under examination, and which possesses a degree of purity adequate for its intended use.
The zones into which the world is divided based on the prevailing annual climatic conditions
Any systematic study on pharmaceutical products in human subjects, whether in patients or other volunteers, in order to discover or verify the effects of, and/or identify any adverse reaction to, investigational products, and/or to study the absorption, distribution, metabolism and excretion of the products with the object of ascertaining their efficacy and safety. Clinical trials are generally divided into Phases I–IV. It is not possible to draw clear distinctions between these phases, and different opinions about details and methodology do exist. However, the individual phases, based on their purposes as related to the clinical development of pharmaceutical products, can be briefly defined as follows:
Phase I. These are the first trials of a new active ingredient or new formulations in humans, often carried out in healthy volunteers. Their purpose is to make a preliminary evaluation of safety, and an initial pharmacokinetic/ pharmacodynamic profile of the active ingredient.
Phase II. The purpose of these therapeutic pilot studies is to determine activity and to assess the short-term safety of the active ingredient in patients suffering from a disease or condition for which it is intended. The trials are preformed in a limited number of subjects and are often, at a later stage, of a comparative (e.g. placebo-controlled) design. This phase is also concerned with the determination of appropriate dose ranges/regimens and (if possible) the clarification of dose–response relationships in order to provide an optimal background for the design of extensive therapeutic trials.
Phase III. This phase involves trials in large (and possibly varied) patient groups for the purpose of determining the short- and long-term safety-efficacy balance of formulation(s) of the active ingredient, and assessing its overall and relative therapeutic value. The pattern and profile of any frequent adverse reactions must be investigated, and special features of the product must be explored (e.g. clinically relevant drug interactions, factors leading to differences in effect, such as age). The trials should preferably be randomized double-blind, but other designs may be acceptable, e.g. long-term safety studies. In general, the conditions under which the trials are conducted should be as close as possible to the normal conditions of use.
Phase IV. In this phase studies are performed after the pharmaceutical product has been marketed. They are based on the product characteristics on which the marketing authorization was granted and normally take the form of post-marketing surveillance, and assessment of therapeutic value or treatment strategies. Although methods may differ, the same scientific and ethical standards should apply to Phase IV studies as are applied in premarketing studies. After a product has been placed on the market, clinical trials designed to explore new indications, new methods of administration or new combinations, etc., are normally regarded as trials of new pharmaceutical products.
Procedure for collaboration between the World Health Organization (WHO) Prequalification Team (WHO/PQT) and interested national regulatory authorities (NRAs) in the assessment and accelerated national registration of WHO prequalified pharmaceutical products and vaccines.
The finished pharmaceutical product with which a fixed-dose combination finished pharmaceutical product (FPP) is to be compared. The comparison may be by means of bioequivalence studies or clinical studies of safety and/or effectiveness. A single study may use more than one comparator, for example several single entity FPPs. A comparator may be a placebo.
The comparator product is a pharmaceutical product with which the multisource product is intended to be interchangeable in clinical practice. The comparator product will normally be the innovator product for which efficacy, safety and quality have been established. If the innovator product is no longer marketed in the jurisdiction, the selection principle as described in Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) products (WHO Technical Report Series, No. 992, Annex 8 (2015)) should be used to identify a suitable alternative comparator product.
A manufacturer performing some aspect of manufacturing on behalf of the original manufacturer.
contract research organization (CRO)
A scientific organization (commercial, academic or other) to which a sponsor may transfer some of its tasks and obligations. Any such transfer should be defined in writing. In the context of this guidance document, bioequivalence studies are often contracted by the sponsor to a CRO, which will perform some of the tasks of the sponsor, but which will also perform the trial. The investigator (clinical part of the study) and the study director (bioanalytical part of the study) are then employees of the CRO.
contract research organization master file (CROMF)
A CROMF is a document prepared by the CRO containing specific and factual information about the CRO, the conduct of clinical studies as well as the analyses of samples and related operations (including clinical trials, clinical data management, pharmacokinetics and statistical analysis, regulatory affairs, etc.) carried out at the named site. If only part of the operations referred to below is carried out at the site, the site master file needs to be presented only for those operations.
A product consisting of two or more separate pharmaceutical products in their final dosage form that are packaged together for distribution to patients in the co-packaging.
Any action taken to eliminate a nonconformity. However, corrections do not address causes. When applied to pharmaceutical products, corrections can refer to reworking, reprocessing, or regrading of products, or assigning them to a different use, or simply destroying them.
Corrective actions are steps that are taken to eliminate the causes of existing nonconformities in order to prevent recurrence. The corrective action process tries to make sure that existing nonconformities and potentially undesirable situations do not happen again. While corrective actions prevent recurrence, preventive actions prevent occurrence. Both types of actions are intended to prevent nonconformities.
corrective and preventive action (CAPA, also sometimes called corrective action/preventive action)
Refers to the actions taken to improve an organization's processes and to eliminate causes of non-conformities or other undesirable situations. CAPA is a concept common across the GXPs (good laboratory practices, good clinical practices and good manufacturing practices), and numerous International Organization for Standardization business standards. The process focuses on the systematic investigation of the root causes of identified problems or identified risks in an attempt to prevent their recurrence (for corrective action) or to prevent occurrence (for preventive action).
counterfeit pharmaceutical product
A pharmaceutical product which is deliberately and fraudulently mislabelled with respect to identity and/or source. Counterfeiting can apply to both branded and generic products, and counterfeit pharmaceutical products may include products with the correct ingredients, with the wrong ingredients, without active ingredients, with an incorrect quantity of active ingredient or with fake packaging.
A critical observation observed by the WHO inspection group during inspection of a contract research organization, manufacturing site or quality control laboratory indicates that it considers that the product as manufactured risks causing harm to the user.
Data integrity is the degree to which data are complete, consistent, accurate, trustworthy and reliable and that these characteristics of the data are maintained throughout the data life cycle. The data should be collected and maintained in a secure manner, such that they are attributable, legible, contemporaneously recorded, original or a true copy and accurate. Assuring data integrity requires appropriate quality and risk management systems, including adherence to sound scientific principles and good documentation practices.
date of manufacture
A date fixed for the individual batch, indicating the completion date of the manufacture. It is normally expressed by a month and a year. The date of the release analysis may be taken as a date of manufacture, provided that the period between the beginning of production and the release of the product is not longer than one-twentieth of the shelf life.
Departure from an approved instruction or established standard.
The form of the completed pharmaceutical product, e.g. tablet, capsule, elixir, injection, suppository.
Any substance or pharmaceutical product for human or veterinary use that is intended to modify or explore physiological systems or pathological states for the benefit of the recipient. The terms drug, medicine and pharmaceutical product are commonly used interchageably.
drug master file
Detailed information concerning a specific facility, process or product submitted to the medicines regulatory authority, intended for incorporation into the application for marketing authorization.
essential pharmaceutical products
Those pharmaceutical products that satisfy the health care needs of the majority of the population. WHO’s Expert Committee on the Selection and Use of Essential Medicines updates the WHO Model List of Essential Medicines at two-year intervals. Each country may use this model to generate its own list of essential pharmaceutical products.
established multisource (generic) product
A multisource product that has been marketed by the applicant or manufacturer associated with the dossier for at least five years and for which at least 10 production batches were produced over the previous year, or, if less than 10 batches were produced in the previous year, not less than 25 batches were produced in the previous three years.
A substance or compound, other than the active pharmaceutical ingredient and packaging materials, that is intended or designated to be used in the manufacture of a pharmaceutical product.
The date after which a compounded preparation should not be stored, transported or used; the date is determined from the date or time the preparation is compounded. It is also known as beyond-use date.
finished pharmaceutical product (FPP)
A finished dosage form of a pharmaceutical product that has undergone all stages of manufacture, including packaging in its final container and labelling.
fixed-dose combination (FDC)
A combination of two or more active pharmaceutical ingredients (APIs) in a fixed ratio of doses. This term is used generically to mean a particular combination of APIs irrespective of the formulation or brand. It may be administered as singleentity products given concurrently or as a finished pharmaceutical product.
The term generic product has somewhat different meanings in different jurisdictions. The use of this term is therefore avoided as much as possible, and the term multisource pharmaceutical product (see below) is used instead. Generic products may be marketed either under the approved nonproprietary name or under a brand (proprietary) name. They may be marketed in dosage forms and/or strengths different from those of the innovator products (see below). Where the term generic product is used, it means a pharmaceutical product, usually intended to be interchangeable with the innovator product, which is usually manufactured without a license from the innovator company and marketed after expiry of the patent or other exclusivity rights. The term should not be confused with generic names for active pharmaceutical ingredients.
good clinical practices (GCP)
A standard for clinical studies which encompasses the design, conduct, monitoring, termination, audit, analysis, reporting and documentation of the studies and which ensures that the studies are scientifically and ethically sound and that the clinical properties of the pharmaceutical product (diagnostic, therapeutic or prophylactic) under investigation are properly documented.
good laboratory practices (GLP)
A quality system concerned with the organizational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported.
good manufacturing practice (GMP)
That part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization.
Acronym for the group of good practice guides governing the preclinical, clinical, manufacturing, testing, storage, distribution and post-market activities for regulated pharmaceuticals, biologicals and medical devices, such as good laboratory practices, good clinical practices, good manufacturing practices, good pharmacovigilance practices and good distribution practices.
innovator pharmaceutical product
Generally the pharmaceutical product which was first authorized for marketing (normally as a patented product) on the basis of documentation of efficacy, safety and quality according to requirements at the time of the authorization. When a substance has been available for many years, it may not be possible to identify an innovator pharmaceutical product.
An inspection observation is a finding or a statement of fact made during an inspection and substantiated by objective evidence. Such findings may be positive or negative. Positive observations should take the form of a description of the processes that the firm is carrying out particularly well and that may be considered examples of particularly good practice. Negative observations are findings of non-compliance with requirements.
interchangeable pharmaceutical product
An interchangeable pharmaceutical product is one which is therapeutically equivalent to a comparator product and can be interchanged with the comparator in clinical practice.
A material produced during steps of the processing of an active pharmaceutical ingredient (API) that undergoes further molecular change or purification before it becomes an API. Intermediates may or may not be isolated.
international chemical reference substance (ICRS)
ICRSs are primary chemical reference substances established on the advice of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. They are supplied primarily for use in physical and chemical tests and assays described in the specifications for quality control of drugs published in The International Pharmacopoeia or proposed in draft monographs. They may be used to calibrate secondary standards.
International Nonproprietary Name (INN)
The shortened scientific name based on the active ingredient. WHO is responsible for assigning INNs to pharmaceutical substances.
investigational product (synonym: study product)
Any pharmaceutical product (see definition) or placebo being tested or used as a reference in a clinical trial.
invitation for expression of interest (EOI)
Invitation calling upon interested parties (e.g. manufacturers or other applicants) to submit an expression of interest (EOI) to WHO by a specified deadline for the purpose of participating in the WHO prequalification procedure in respect of the product(s) listed/laboratories defined in the invitation. Such an EOI should be accompanied by the required documentation on the product(s) in question.
Process of identifying a pharmaceutical product including the following information, as appropriate: name of the product; active ingredient(s), type and amount; batch number; expiry date; special storage conditions or handling precautions; directions for use, warnings and precautions; names and addresses of the manufacturer and/or the supplier.
Information to the user provided on the package label or in the patient information leaflet.
laboratory information file (LIF)
A LIF is a document prepared by the laboratory. It contains specific and factual information about the operations carried out at the named site and any closely integrated operations of the laboratory. If only some of the operations are carried out on the site, the LIF needs to describe only those operations, e.g. sampling, chemical analysis or stability testing.
An individual or a corporate entity possessing a marketing authorization for a pharmaceutical product.
long-term stability studies
Experiments on the physical, chemical, biological, biopharmaceutical and microbiological characteristics of an active pharmaceutical ingredient or finished pharmaceutical product, during and beyond the expected shelf life and storage periods of samples under the storage conditions expected in the intended market. The results are used to establish the re-test period or the shelf life, to confirm the projected re-test period and shelf life, and to recommend storage conditions.
A major deviation from good manufacturing practice has been observed by the WHO inspection group during inspection of a contract research organization, manufacturing site or quality control laboratory.
All operations of purchase of materials and products, production, quality control, release, storage and distribution of pharmaceutical products, and the related controls.
A company that carries out operations such as production, packaging, repackaging, labelling and relabelling of pharmaceuticals.
Also referred to as product licence or registration certificate. A legal document issued by the competent medicines regulatory authority that authorizes the marketing or free distribution of a medical product in the respective country after evaluation of safety, efficacy and quality. In terms of quality it establishes inter alia the detailed composition and formulation of the medical product and the quality requirements for the product and its ingredients. It also includes details of the packaging, labelling, storage conditions, shelf life and approved conditions of use.
marketing authorization holder
For the purposes of this document, the term marketing authorization holder refers to any person or entity that holds the legal responsibility for the product on the market by submission of the required documentation on a product that has been listed after evaluation as registered or approved.
A general term used to denote raw materials (starting materials, reagents, solvents), process aids, intermediates, active pharmaceutical ingredients and packaging and labelling materials.
Any substance or pharmaceutical product for human or veterinary use that is intended to modify or explore physiological systems or pathological states for the benefit of the recipient. On ths website, the terms medicine and pharmaceutical product (see below) are used interchangeably.
medicines regulatory authority
A national body that administers the full spectrum of medicine regulatory activities, including at least all of the following functions in conformity with national medicine legislation:
- marketing authorization of new products and variations of existing products
- quality control laboratory testing
- monitoring of adverse drug reactions
- provision of information on medicines and promotion of rational use of medicines
- good manufacturing practice inspections and licensing of manufacturers, wholesalers and distribution channels
- enforcement operations
- monitoring of drug use.
A branch of science that refers to microbes of all of types, including bacteria, viruses, rickettsia, protozoa, fungi and prions. Derived words (such as microbiological) have a similar meaning.
multisource (generic) pharmaceutical product
Multisource pharmaceutical products are pharmaceutically equivalent products that may or may not be therapeutically equivalent. Multisource pharmaceutical products that are therapeutically equivalent are interchangeable.
new chemical (or biological) entitities
Actives that have not previously been authorized for marketing as a drug for use in humans in the country in question.
Nonconformity refers to a failure to comply with requirements. A requirement is a need, expectation or obligation. It can be stated or implied by an organization, its customers or other interested parties. There are many types of requirements. These include quality requirements, customer requirements, management requirements, product requirements, process requirements and legal requirements. Whenever an organization fails to meet one of these requirements, a nonconformity occurs.
normal storage conditions
Storage in dry, well-ventilated premises at temperature of 15–25 °C or,depending on climatic conditions, up to 30 °C. Extraneous odours, other indications of contamination, and intense light have to be excluded.
Verifiable information or records pertaining to the quality of an item or service or to the existence and implementation of a quality system element, which is based on visual observation, measurement or test.
officially recognized pharmacopoeia (or compendium)
Those pharmacopoeias recognized by the national regulatory agencies (e.g. national pharmacopoeia (if applicable), the British Pharmacopoeia, the European Pharmacopoeia, The International Pharmacopoeia, the Japanese Pharmacopoeia and the United States Pharmacopeia).
Use of a medicine outside the scope of regulatory authorization.
ongoing stability study
The study carried out by the manufacturer on production batches according to a predetermined schedule in order to monitor, confirm and extend the projected re-test period (or shelf life) of the active pharmaeutical ingredient, or confirm or extend the shelf life of the finished pharmaceutical product.
oral solid dosage (OSD)
Usually refers to an OSD plant that manufactures medicinal products such as tablets, capsules and powders to be taken orally.
An “other observation” observed by the WHO inspection group during inspection of a manufacturing site, quality control laboratory or contract research organization indicates that a minor lapse or minor deviation from good manufacturing practice has been observed in the case of a manufacturing site, and from good clinical practice in the case of a contract research organization.
All operations, including filling and labelling, that a bulk product has to undergo in order to become a finished product. Filling of a sterile product under aseptic conditions or a product intended to be terminally sterilized, would not normally be regarded as part of packaging.
Any material, including printed material, employed in the packaging of a pharmaceutical, but 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.
Products are pharmaceutical alternative(s) if they contain the same active pharmaceutical moiety or moieties but differ in dosage form (e.g. tablets versus capsules), strength, and/or chemical form (e.g. different salts or different esters). Pharmaceutical alternatives deliver the same active moiety by the same route of administration but are otherwise not pharmaceutically equivalent. They may or may not be bioequivalent or therapeutically equivalent to the comparator product.
pharmaceutical dosage form
The physical form in which a medicine is presented; the name of a dosage form combines its physical form and the intended route of administration, e.g. a tablet (to be swallowed), oral suspension (liquid suspension of solid particles intended for oral intake and swallowing).
Products are pharmaceutical equivalents if they contain the same molar amount of the same active pharmaceutical ingredients (APIs) in the same dosage form, if they meet comparable standards and if they are intended to be administered by the same route. Pharmaceutical equivalence does not necessarily imply therapeutic equivalence, as differences in the API solid state properties, the excipients and/or the manufacturing process and other variables can lead to differences in product performance.
A substance, other than the active pharmaceutical ingredient, which has been appropriately evaluated for safety and is included in a medicines delivery system to:
- aid in the processing of the medicines delivery system during its manufacture
- protect, support or enhance stability, bioavailability or patient acceptability
- assist in pharmaceutical product identification
- enhance any other attribute of the overall safety and effectiveness of the medicine during its storage or use.
Any substance or combination of substances marketed or manufactured to be marketed for treating or preventing disease in human beings, or with a view to making a medical diagnosis in human beings, or to restoring, correcting or modifying physiological functions in human beings.
pharmaceutical starting material
Any substance of a defined quality used in the production of a pharmaceutical product, but excluding packaging materials. This includes active pharmaceutical ingredients and pharmaceutical excipients.
pharmacopoeial reference standards
The specificity of pharmacopoeial reference substances has been addressed in the introduction of ISO Guide: General requirements for the competence of reference material producers. “Pharmacopoeial standards and substances are established and distributed by pharmacopoeial authorities following the general principles of this Guide. It should be noted, however, that a different approach is used by the pharmacopoeial authorities to give the user the information provided by certificate of analysis and expiration dates” (*).
*International Organization for Standardization. General requirements for the competence of reference material producers. 2006, ISO Guide 34.
A batch of an active pharmaceutical ingredient or finished pharmaceutical product manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch. For example, for solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100 000 tablets or capsules, whichever is the larger; unless otherwise adequately justified.
The activities undertaken in defining a product or service need, seeking expressions of interest from enterprises to supply the product or service, and examining the product or service offered against the specification and the facility where the product or service is prepared against common standards of good manufacturing practice. The examination of the product or service and of the facility where it is manufactured is performed by trained and qualified inspectors against common standards. Once the product is approved, and the facility is approved for the delivery of the specified product or service, other procurement agencies are informed of the approval. Prequalification is required for all pharmaceutical products regardless of their composition and place of manufacture or registration, but the amount and type of information requested from the supplier for use in the assessment by the procurement agency may differ.
Preventive actions are steps taken to eliminate the causes of undesirable nonconformities or situations that could occur, but have not yet done so. While corrective actions prevent recurrence, preventive actions prevent occurrence. See also corrective action. Both types of actions are intended to prevent nonconformities.
A batch of an active pharmaceutical ingredient or finished pharmaceutical product used in a stability study, from which stability data are submitted in a registration application for the purpose of establishing a retest peropd or shelf life.
The process of purchasing or otherwise acquiring any pharmaceutical product, vaccine, or nutraceuticals for human use. For the purpose of this website, procurement means the preselection of products and manufacturers through a procedure of qualification, including prequalification (see above) and continuous monitoring thereafter, purchase of the prequalified products from prequalified manufacturers (linked to the specific product) through defined purchasing mechanisms, storage and distribution.
Any organization which is purchasing or otherwise acquiring any pharmaceutical product, vaccine or nutraceutical for human use. In the context of these guidelines it will normally be a not-for-profit organization, a non governmental organization or a United Nations organization. A procurement agency in the context of this website is defined as any organization purchasing pharmaceutical products, vaccines, or other health sector goods or is otherwise involved in their prequalification (see above), purchasing, storage and distribution.
Information on pharmaceutical products submitted by manufacturers or suppliers in any of the formats specified in the procurement agency’s guidelines (including product dossiers, product questionnaires or other formats) to obtain prequalification for the products.
A process for withdrawing or removing a pharmaceutical product from the pharmaceutical distribution chain because of defects in the product, complaints of serious adverse reactions to the product and/or concerns that the product is or may be counterfeit. The recall might be initiated by the manufacturer, importer, wholesaler, distributor or a responsible agency.
All operations involved in the preparation of a pharmaceutical product, from receipt of materials, through processing, packaging and repackaging, labelling and relabelling, to completion of the finished product.
A batch of an active pharmaceutical ingredient or finished pharmaceutical product manufactured at production scale by using production equipment in a production facility as specified in the application.
A document which states the background, rationale and objectives of the trial and describes its design, methodology and organization, including statistical considerations, and the conditions under which it is to be performed and managed. The protocol should be dated and signed by the investigator, the institution involved and the sponsor. It can also function as a contract.
Action of proving and documenting that any premises, systems and equipment are properly installed and/or work correctly and lead to the expected results.Qualification is often a part (the initial stage) of validation, but the individual qualification steps alone do not constitute process validation. It is the work done to prove that the supply system will deliver products of the quality required and specified on a routine basis, meeting all the applicable quality requirements.
The suitability of either an active pharmaceutical ingredient or a pharmaceutical product for its intended use. This term includes such attributes as the identity, strength and purity.
“Quality assurance” is a wide-ranging concept covering all matters that individually or collectively influence the quality of a product. It is the totality of the arrangements made with the object of ensuring that pharmaceutical products are of the quality required for their intended use. Quality assurance therefore incorporates good manufacturing practice and other factors, including those outside the scope of this guide such as product design and development.
quality assurance relating to clinical trials
Systems and quality control procedures that are established to ensure that the trial is performed and the data are generated in compliance with good clinical practices and good laboratory practices. These include procedures to be followed which apply to ethical and professional conduct, standard operating procedures, reporting, and professional qualifications or skills of personnel.
All measures taken, including the setting of specifications, sampling, testing and analytical clearance, to ensure that raw materials, intermediates, packaging materials and finished pharmaceutical products conform with established specifications for identity, strength, purity and other characteristics.
quality management system
An appropriate infrastructure, encompassing the organizational structure, procedures, processes and resources, and systematic actions necessary to ensure adequate confidence that a product or service will satisfy given requirements for quality.
A member of staff who has a defined responsibility and authority for ensuring that the management system related to quality is implemented and followed at all times.
A handbook that describes the various elements of the quality management system for assuring the quality of the test results generated by a laboratory.
quality risk management
A systematic process for the assessment, control, communication, and review of risks to the quality of the pharmaceutical product across the product life-cycle.
Explicit written test procedures and requirements that must be met.
An appropriate infrastructure, encompassing the organizational structure, procedures, processes and resources, and systematic actions necessary to ensure adequate confidence that a product (or services) will satisfy given requirements for quality.
The status of starting or packaging materials, intermediates, or bulk or finished products isolated physically or by other effective means while a decision is awaited on their release, rejection or reprocessing.
Sample in which the different fractions of the material have an equal probability of being represented.
All records or certified copies of original observations, clinical findings or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Such material includes laboratory notes, memoranda, calculations and documents, as well as all records of data from automated instruments or exact, verified copies, e.g. in the form of photocopies or microfiches. Raw data can also include photographic negatives, microfilm or magnetic media (e.g. computer diskettes) and optical media (CD-ROMs).
A general term used to denote starting materials, reagents and solvents intended for use in the production of intermediates or active pharmaceutical ingredients.
real-time (long-term) stability studies
Experiments on the physical, chemical, biological, biopharmaceutical and microbiological characteristics of a drug, during and beyond the expected shelf life and storage periods of samples under the storage conditions expected in the intended market. The results are used to establish the shelf life, to confirm the projected shelf life, and to recommend storage conditions.
A process for withdrawing or removing a pharmaceutical material from the distribution chain because of defects in the materials or complaints of a serious nature. The recall might be initiated by the manufacturer/importer/distributor or a responsible agency.
A reference product is a pharmaceutical product with which the new product is intended to be interchangeable in clinical practice. The reference product will normally be the innovator product for which efficacy, safety and quality have been established. Where the innovator product is not available, the product which is the market leader may be used as a reference product, provided that it has been authorized for marketing and its efficacy, safety and quality have been established and documented.
A sample of a batch of starting material, packaging material, intermediate or finished product which is stored for the purpose of being analysed should the need arise during the shelf life of the batch concerned.
reference standard (primary)
A substance that has been shown by an extensive set of analytical tests to be authentic material that should be of high purity. This standard can be:
- obtained from an officially recognized source
- prepared by independent synthesis
- obtained from existing production material of high purity
- prepared by further purification of existing production material.
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.
reference substance (or standard)
Microorganisms defined at least to the genus and species level, catalogued and described according to its characteristics and preferably stating its origin. Normally obtained from a recognized national or international collection.
Any statutory system of approval required at national level as a precondition for introducing a pharmaceutical product on to the market.
The process whereby regulatory requirements, approaches and systems become more similar or aligned over time as a result of the adoption of internationally recognized technical guidance, standards and best practices.
The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of an API or FPP at the time of its release.
A sample of a fully packaged unit from a batch of finished product. It is stored for identification purposes (for example, of presentation, packaging, labelling, patient information leaflet, batch number and expiry date) should the need arise during the shelf life of the batch concerned.
Combination of the probability of occurrence of harm and severity of the harm.
The estimation of the risk associated with the identified hazards.
A systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the evaluation of risk associated with exposure to those hazards.
The sharing of information about risk and risk management between the decisionmaker and other stakeholders.
The comparison of the estimated risk to given risk criteria using a quantitative or qualitative scale to determine the significance of the risk.
The systematic use of information to identify potential sources of harm (hazards) referring to the risk question or problem description.
Review or monitoring of output or results of the risk management process considering (if appropriate) new knowledge and experience about the risk.
The ability of the procedure to provide analytical results of acceptable accuracy and precision under a variety of conditions.
sample collected in a quality survey
A product in a given presentation (identified by its name, content of active pharmaceutical ingredient(s) (API(s)), dosage form, strength, batch number, production date (if known), expiration date, collection date and name of manufacturer or labelled registration holder) collected at the specific sample collection site. It means that the same product characterized by the same name, content of APIs, dosage form, strength, batch, and from the same manufacturer collected in two different sites represents two samples. Each sample should consist of the number of dosage units (e.g. tablets, capsules, ampoules, vials or bottles) required by the sampling plan.
A portion of a material collected according to a defined sampling procedure. The size of any sample should be sufficient to allow all anticipated test procedures to be carried out, including all repetitions and retention samples. If the quantity of material available is not sufficient for the intended analyses and for the retention samples, the inspector should record that the sampled material is the available sample (see Sampling record) and the evaluation of the results should take account of the limitations that arise from the insufficient sample size.
Operations designed to obtain a representative portion of a pharmaceutical product, based on an appropriate statistical procedure, for a defined purpose, e.g. acceptance of consignments or batch release.
That part of the sampling procedure dealing with the method prescribed for withdrawing samples.
A plan that contains detailed identification of sites where samples will be collected, medicines to be sampled, minimum number of dosage units to be collected per sample, number of samples to be collected per medicine and total number of samples to be collected in the area for which the sampling plan is prepared. It also contains detailed instructions for sample collectors.
The complete sampling operations to be performed on a defined material for a specific purpose. A detailed written description of the sampling procedure is provided in the sampling protocol.
Written record of the sampling operations carried out on a particular material for a defined purpose. The sampling record should contain the batch number, date and place of sampling, reference to the sampling protocol used, a description of the containers and of the materials sampled, notes on possible abnormalities, together with any other relevant observations, and the name and signature of the inspector.
Discrete part of a consignment such as an individual package, drum or container.
secondary chemical reference substance
A secondary chemical reference substance is a substance whose characteristics are assigned and/or calibrated by comparison with a primary chemical reference substance. The extent of characterization and testing of a secondary chemical reference substance may be less than for a primary chemical reference substance.
secondary reference substance (or standard)
A substance whose characteristics are assigned and/or calibrated by comparison with a primary reference substance. The extent of characterization and testing of a secondary reference substance may be less than for a primary reference substance.
Note: Often referred to as an “in-house” working standard.
serious adverse advent
An event that is associated with death, admission to hospital, prolongation of a hospital stay, persistent or significant disability or incapacity, or is otherwise life threatening in connection with a clinical trial.
The period of time during which a pharmaceutical product, if stored as indicated on the label, is expected to comply with the specification as determined by stability studies on a number of batches of the product. The shelf life is used to establish the expiry date of each batch.
site master file
A site master file is a document prepared by the manufacturer containing information with respect to the production and/or control of pharmaceutical manufacturing operations carried out at a named site, and to any closely integrated operations at adjacent and/or nearby buildings. If only part of a pharmaceutical operation is carried out.
A list of detailed requirements with which the products or materials used or obtained during manufacture have to conform. They serve as a basis for quality evaluation.
A list of tests, references to analytical procedures and appropriate acceptance criteria that are numerical limits, ranges or other criteria for the test described. It establishes the set of criteria to which a material should conform to be considered acceptable for its intended use. “Conformance to specification” means that the material, when tested according to the listed analytical procedures, will meet the listed acceptance criteria.
The ability of a drug to retain its properties within specified limits throughout its shelf life. The following aspects of stability are to be considered: chemical, physical, microbiological and biopharmaceutical.
stability studies (stability testing)
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 retest period (or shelf life) of an active pharmaceutical ingredient or the shelf life of a finished pharmaceutical product.
A series of tests designed to obtain information on the stability of a pharmaceutical product in order to define its shelf life and utilization period under specified packaging and storage conditions.
standard operating procedure (SOP)
An authorized written procedure giving instructions for performing operations not necessarily specific to a given product or material (e.g. equipment operation, maintenance and cleaning; validation; cleaning of premises and environmental control; sampling and inspection). Certain SOPs may be used to supplement product-specific master and batch production documentation.
Any substances of a defined quality used in the production of a pharmaceutical product, but excluding packaging materials. In the context of biological products manufacturing, examples of starting materials may include cryo-protectants, feeder cells, reagents, growth media, buffers, serum, enzymes, cytokines, growth factors and amino acids.
A multi-dose container consisting of two layers, usually provided with perforations, suitable for containing single doses of solid or semi-solid preparations. Blisters are excluded.
subject matter expert
Commonly used term for employee of a manufacturing company that is undergoing inspection who is presented as possessing expertise in a particular area or subject and who can therefore answer related questions and requests for futher information made by the inspection team.
Substandard medicines are pharmaceutical products that fail to meet either their quality standards or their specifications, or both. Each pharmaceutical product that a manufacturer produces has to comply with quality assurance standards and specifications, at release and throughout its shelf life, according to the requirements of the territory of use. Normally, these standards and specifi cations are reviewed, assessed and approved by the applicable national or regional medicines regulatory authority before the product is authorized for marketing.
summary of product characteristics
Summary of product characteristics approved by the competent authority. The information may alternatively be presented in the container or package label.
A person providing pharmaceutical products and materials on request. Suppliers may be agents, brokers, distributors, manufacturers or traders. Where possible, suppliers should be authorized by a competent authority.
Therapeutic activity refers to the successful prevention, diagnosis and treatment of physical and mental illnesses; improvement of symptoms of illnesses; as well as beneficial alteration or regulation of the physical and mental status of the body and development of a sense of general well-being.
Two pharmaceutical products are considered to be therapeutically equivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and, after administration in the same molar dose, their effects, with respect to both efficacy and safety, are essentially the same when administered to patients by the same route under the conditions specified in the labelling. This can be demonstrated by appropriate equivalence studies, such as pharmacokinetic, pharmacodynamic, clinical or in vitro studies.
Traceability aims at ensuring that the results of laboratory measurements using procedures of lower metrological order are reproducible and scientifically acceptable by referring to an internationally agreed denominator by means of a reference procedure of highest metrological order and/or a primary reference material.
Defining policies and procedures in writing and publishing the written documentation, and giving reasons for decisions to the public.
Action of proving, in accordance with the principles of good manufacturing practice/good clinical practices/good laboratory practices, that any procedure, process, equipment, material, activity or system actually and consistently leads to the expected results (see also qualification).
A change to any aspect of a pharmaceutical product, including but not limited to, the change of use of a starting material, a change to formulation, method and site of manufacture, specifications for the finished product and ingredients, container and container labelling and product information.
A small container for parenteral medicinal products, with a stopper and overseal; the contents are removed after piercing the stopper. Both single-dose and multi-dose types exist.