Glossary

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.

The documented act of proving that the equipment is performing to predefined tolerances or criteria.

A collection of vials of cells of uniform composition (though not necessarily clonal) derived from a single tissue or cell, and used for the production of a vaccine directly or via a cell bank system. The following terms are used in these Guidelines – master cell bank (MCB): a bank of a cell substrate from which all subsequent cell banks used for vaccine production will be derived. The MCB represents a well characterized collection of cells derived from a single tissue or cell; and working cell bank (WCB): a cell bank derived by propagation of cells from an MCB under defined conditions and used to initiate production of cell cultures on a lot-by-lot basis. Also referred to as “manufacturer’s working cell bank” in other documents.

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.

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.

Refers to a change that includes, but is not limited to, the product composition, manufacturing process, quality controls, equipment, facilities or product labelling information made to an approved MA or licence by the MA holder. Also referred to as “variation” in other documents.

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.

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.

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 mechanism which prevents the temperature inside a cold room from dropping below +2°C under low ambient temperature conditions, down to the temperature specified by the employer at the time of procurement, subject to a minimum ambient of -15°C.

Any mechanism which prevents the temperature inside a refrigerated vehicle from dropping below +2°C under low ambient temperature conditions, down to the temperature specified by the employer at the time of procurement, subject to a minimum of -10°C.

The cold climate freeze protection life is measured from the moment when the container is closed until the temperature of the coldest point inside the vaccine storage compartment first reaches 0°C at a constant ambient temperature of -20°C.

The empty container is stabilized at +43°C and loaded with coolant-packs that have been prepared in accordance with the manufacturer’s coolant recharging instructions. Cold life is measured from the moment when the container lid is closed until the temperature of the warmest point in the vaccine storage compartment first reaches +10°C (after initially cooling to below +10°C during cool down), at a constant ambient test temperature +43°C.  The vaccine storage compartment must remain above 0°C.

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.

Head-to-head comparison of a biotherapeutic product with a licensed reference biotherapeutic product (RBP) with the goal of establishing similarity in quality, safety and efficacy. Products should be compared in the same study using the same procedures.

Establishes the tests to be done and acceptable limits to be achieved to demonstrate the lack of a negative effect of specific manufacturing changes on the safety or effectiveness of the product. A comparability protocol is a highly specific, well defined plan for the future implementation of a quality (that is, manufacturing) change. Also referred to as “post-approval change management protocol” in other documents

The activities, including study design, conducting of studies and data evaluation that are designed to investigate whether the pre- and post-change products are comparable. In addition to routine analysis performed during production and control of the antigen or final product, these evaluations typically include a comparison of manufacturing process steps and parameters impacted by the change, characterization studies and an evaluation of product stability following the change. In some cases, nonclinical or clinical data might contribute to the conclusion reached.

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.

A comparator for a clinical study for a human insulin product (biotherapeutic product) is an established human insulin product approved by a stringent regulatory authority that has a pharmacological profile similar to that of the product to be assessed for prequalification.

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 frozen coolant-pack that has been allowed to warm at ambient temperature until some water is present inside the pack. The pack is correctly conditioned as soon as the ice core is able to move inside the pack when it is shaken. The effective temperature of a conditioned icepack in this state is 0°C.

The systematic examination of evidence generated and procedures undertaken by the manufacturer, under requirements established by the regulatory authority, to determine that a medical device is safe and performs as intended by the manufacturer and, therefore, conforms to the Essential Principles of Safety and Performance of Medical Devices.

A body engaged in the performance of procedures for determining whether the relevant requirements in technical regulations or standards are fulfilled. A CAB is authorized to undertake specified conformity assessment activities by a regulatory authority that will ensure that performance of the CAB is monitored and, if necessary, withdraw designation.

Refers to the following components: (a) a primary container closure system is a packaging component (for example, a vial or pre-filled syringe) that is in, or may come into, direct contact with the final Annex 4 183 product dosage form, or components that contribute to the container/closure integrity of the primary packaging material for a sterile product; and (b)  a secondary container closure system is a packaging component (for example, a carton or tray) that is not, and will not be, in direct contact with the dosage form.

A manufacturer performing some aspect of manufacturing on behalf of the original manufacturer.

An organization (commercial, academic or other) to which an applicant may transfer some of its tasks and obligations in relation to the conduct of clinical studies with which the product submitted to WHO for assessment for prequalification. Any such transfer should be defined in writing. Bioequivalence studies are often contracted by the sponsor to a CRO, which will perform some of the tasks of the applicant, 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.

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 coolant-pack cooled to a temperature between + 2°C to +8°C before use.

Any substance that can be transported and repeatedly used to absorb energy in a long-term storage cold box and that is non-hazardous, non-corrosive and non-flammable.

A standard procedure that supports the sustained operation of the long-term storage cold box, for example the freezing of coolant packs. Coolant preparation and the equipment needed for this task may be located away from the site where the long-term storage cold box is used.

A purpose-designed, leak-proof container filled with coolant. 

This is measured from the moment when the appliance lid is closed until the temperature of the warmest point in the vaccine storage compartment first goes below +10°C, at a constant ambient test temperature of +43°C. 

The time in hours required for the appliance to cool, starting from the time the device is switched on and ending when stabilized temperatures are measured at all locations inside the vaccine storage area.

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.

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).

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.