Some Important Definitions

self-contained area

Premises which provide complete and total separation of all aspects of an operation, including personnel and equipment movement, with well established procedures, controls and monitoring. This includes physical barriers as well as separate air-handling systems, but does not necessarily imply two distinct and separate buildings.

specification

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.

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.

starting material

Any substance of a defined quality used in the production of a pharmaceutical

product, but excluding packaging materials.

validation

Action of proving, in accordance with the principles of GMP, that any procedure, process, equipment, material, activity or system actually leads to the expected results (see also qualification).

acceptance criteria

Measurable terms under which a test result will be considered acceptable.

action limit

The action limit is reached when the acceptance criteria of a critical parameter have been exceeded. Results outside these limits will require specified action and investigation.

air-handling unit (AHU)

The air-handling unit serves to condition the air and provide the required air

movement within a facility.

airlock

An enclosed space with two or more doors, which is interposed between two

or more rooms, e.g. of differing classes of cleanliness, for the purpose of

controlling the airflow between those rooms when they need to be entered. An

airlock is designed for and used by either people or goods (PAL, personnel

airlock; MAL, material airlock).

alert limit

The alert limit is reached when the normal operating range of a critical parameter has been exceeded, indicating that corrective measures may need to be taken to prevent the action limit being reached.

as-built

Condition where the installation is complete with all services connected and

functioning but with no production equipment, materials or personnel present.

at-rest

Condition where the installation is complete with equipment installed and

operating in a manner agreed upon by the customer and supplier, but with no

personnel present.

central air-conditioning unit (see air-handling unit)

change control

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.

clean area (clean room)1

An area (or room) with defined environmental control of particulate and microbial contamination, constructed and used in such a way as to reduce the introduction, generation and retention of contaminants within the area.

commissioning

Commissioning is the documented process of verifying that the equipment and

systems are installed according to specifications, placing the equipment into

active service and verifying its proper action. Commissioning takes place at the conclusion of project construction but prior to validation.

containment

A process or device to contain product, dust or contaminants in one zone,

preventing it from escaping to another zone.

contamination

The undesired introduction of impurities of a chemical or microbial nature, or

of foreign matter, into or on to a starting material or intermediate, during production, sampling, packaging or repackaging, storage or transport.

critical parameter or component

A processing parameter (such as temperature or humidity) that affects the

quality of a product, or a component that may have a direct impact on the

quality of the product.

cross-contamination

Contamination of a starting material, intermediate product or finished product

with another starting material or material during production.

design condition

Design condition relates to the specified range or accuracy of a controlled variable used by the designer as a basis for determining the performance requirements of an engineered system.

design qualification (DQ)

DQ is the documented check of planning documents and technical specifications

for conformity of the design with the process, manufacturing, GMP and

regulatory requirements.

1 Note: Clean area standards, such as ISO 14644-1 provide details on how to classify air cleanliness by

means of particle concentrations, whereas the GMP standards provide a grading for air cleanliness in

terms of the condition (at-rest or operational), the permissible microbial concentrations, as well as other

factors such as gowning requirements. GMP and clean area standards should be used in conjunction

with each other to define and classify the different manufacturing environments.

direct impact system

A system that is expected to have a direct impact on product quality. These

systems are designed and commissioned in line with good engineering practice

(GEP) and, in addition, are subject to qualification practices.

facility

The built environment within which the clean area installation and associated

controlled environments operate together with their supporting infrastructure.

good engineering practice (GEP)

Established engineering methods and standards that are applied throughout the

project life-cycle to deliver appropriate, cost-effective solutions.

indirect impact system

This is a system that is not expected to have a direct impact on product quality, but typically will support a direct impact system. These systems are designed and commissioned according to GEP only.

infiltration

Infiltration is the ingress of contaminated air from an external zone into a clean area.

installation qualification (IQ)

IQ is documented verification that the premises, HVAC system, supporting utilities and equipment have been built and installed in compliance with their

approved design specification.

no-impact system

This is a system that will not have any impact, either directly or indirectly, on product quality. These systems are designed and commissioned according to

GEP only.

non-critical parameter or component

A processing parameter or component within a system where the operation,

contact, data control, alarm or failure will have an indirect impact or no impact on the quality of the product.

normal operating range

The range that the manufacturer selects as the acceptable values for a parameter during normal operations. This range must be within the operating range.

operating limits

The minimum and/or maximum values that will ensure that product and safety

requirements are met.

operating range

Operating range is the range of validated critical parameters within which

acceptable products can be manufactured. operational condition

This condition relates to carrying out room classification tests with the normal production process with equipment in operation, and the normal staff present in the room.

operational qualification (OQ)

OQ is the documentary evidence to verify that the equipment operates in accordance with its design specifications in its normal operating range and performs as intended throughout all anticipated operating ranges.

oral solid dosage (OSD)

Usually refers to an OSD plant that manufactures medicinal products such as

tablets, capsules and powders to be taken orally.

performance qualification (PQ)

PQ is the documented verification that the process and/or the total process

related to the system performs as intended throughout all anticipated operating ranges.

point extraction

Air extraction to remove dust with the extraction point located as close as

possible to the source of the dust.

pressure cascade

A process whereby air flows from one area, which is maintained at a higher

pressure, to another area at a lower pressure.

qualification

Qualification is the planning, carrying out and recording of tests on equipment and a system, which forms part of the validated process, to demonstrate that it will perform as intended.

relative humidity

The ratio of the actual water vapour pressure of the air to the saturated water vapour pressure of the air at the same temperature expressed as a percentage. More simply put, it is the ratio of the mass of moisture in the air, relative to the mass at 100% moisture saturation, at a given temperature.

standard operating procedure (SOP)

An authorized written procedure, giving instructions for performing operations, not necessarily specific to a given product or material, but of a more general nature (e.g. operation of equipment, 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.

turbulent flow

Turbulent flow, or non-unidirectional airflow, is air distribution that is introduced into the controlled space and then mixes with room air by means of

induction.

unidirectional airflow (UDAF)

Unidirectional airflow is a rectified airflow over the entire cross-sectional area of a clean zone with a steady velocity and approximately parallel streamlines(see also turbulent flow). (Modern standards no longer refer to laminar flow, but have adopted the term unidirectional airflow.)

validation

The documented act of proving that any procedure, process, equipment, material, activity or system actually leads to the expected results.

validation master plan (VMP)

VMP is a high-level document which establishes an umbrella validation plan for

the entire project, and is used as guidance by the project team for resource and technical planning (also referred to as master qualification plan).

commingling

The blending of carry-over material from one grade of an excipient with another, usually due to a continuous process.

drug masterfile1

Detailed information concerning a specific facility, process or product submitted to the drug regulatory authority, intended for incorporation into the application for marketing authorization.

model product

A product which simulates a group of similar products.

mother liquor

A concentrated solution from which the product is obtained by evaporation,

freezing, and/or crystallization.

pharmaceutical excipients

Substances, other than the active ingredient, which have been appropriately

evaluated for safety and are included in a drug delivery system to:

— aid in the processing of the drug delivery system during its manufacture;

— protect, support or enhance stability, bioavailability, or patient

acceptability;

— assist in product identification; or

— enhance any other attribute of the overall safety and effectiveness of the drug during storage or use.

1 This term appears to be specific to United States regulations.

Some Important Definitions

Quality Assurance1

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 Control

Quality control covers 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.

active pharmaceutical ingredient (API)

Any substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form and that, when so used, becomes an active ingredient of that pharmaceutical dosage form. 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.

airlock

An enclosed space with two or more doors, which is interposed between two or more rooms, e.g. of differing classes of cleanliness, for the purpose of controlling the airflow between those rooms when they need to be entered. An airlock is designed for use either by people or for goods and/or equipment.

authorized person

The person recognized by the national regulatory authority as having the responsibility for ensuring that each batch of finished product has been manufactured, tested and approved for release in compliance with the laws and regulations in force in that country.

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.

batch records

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. bulk produc tAny product that has completed all processing stages up to, but not including, final packaging. Calibration 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.

clean area

An area with defined environmental control of particulate and microbial contamination, constructed and used in such a way as to reduce the introduction, generation, and retention of contaminants within the area.

consignment (or delivery)

The quantity of a pharmaceutical(s), made by one manufacturer and supplied at one time in response to a particular request or order. A consignment may comprise one or more packages or containers and may include material belonging to more than one batch.

contamination

The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or on to a starting material or intermediate during production, sampling, packaging or repackaging, storage or transport.

critical operation

An operation in the manufacturing process that may cause variation in the quality of the pharmaceutical product.

cross-contamination

Contamination of a starting material, intermediate product or finished product with another starting material or product during production.

finished product

A finished dosage form that has undergone all stages of manufacture, including packaging in its final container and labelling.

in-process control

Checks performed during production in order to monitor and, if necessary, to adjust the process to ensure that the product conforms to its specifications. The control of the environment or equipment may also be regarded as a part of inprocess control.

intermediate product

Partly processed product that must undergo further manufacturing steps before it becomes a bulk product.

large-volume parenterals

Sterile solutions intended for parenteral application with a volume of 100 ml or more in one container of the finished dosage form.

manufacture

All operations of purchase of materials and products, production, quality control, release, storage and distribution of pharmaceutical products, and the related controls.

manufacturer

A company that carries out operations such as production, packaging, repackaging, labelling and relabelling of pharmaceuticals.

marketing authorization (product licence, registration certificate)

A legal document issued by the competent drug regulatory authority that establishes the detailed composition and formulation of the product and the pharmacopoeial or other recognized specifications of its ingredients and of the final product itself, and includes details of packaging, labelling and shelf-life

master formula

A document or set of documents specifying the starting materials with their quantities and the packaging materials, together with a description of the procedures and precautions required to produce a specified quantity of a finished product as well as the processing instructions, including the in-process controls.

master record

A document or set of documents that serve as a basis for the batch documentation (blank batch record).

packaging

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.

packaging material

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.

pharmaceutical product

Any material or product intended for human or veterinary use presented in its finished dosage form or as a starting material for use in such a dosage form, that is subject to control by pharmaceutical legislation in the exporting state and/or the importing state.

production

All operations involved in the preparation of a pharmaceutical product, from receipt of materials, through processing, packaging and repackaging, labeling and relabelling, to completion of the finished product.

qualification

Action of proving that any premises, systems and items of equipment work correctly and actually lead to the expected results. The meaning of the word “validation” is sometimes extended to incorporate the concept of qualification.

quarantine

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.

reconciliation

A comparison between the theoretical quantity and the actual quantity.

recovery

The introduction of all or part of previous batches (or of redistilled solvents and similar products) of the required quality into another batch at a defined stage of manufacture. It includes the removal of impurities from waste to obtain a pure substance or the recovery of used materials for a separate use.

reprocessing

Subjecting all or part of a batch or lot of an in-process drug, bulk process intermediate (final biological bulk intermediate) or bulk product of a single batch/ lot to a previous step in the validated manufacturing process due to failure to meet predetermined specifications. Reprocessing procedures are foreseen as occasionally necessary for biological drugs and, in such cases, are validated and pre-approved as part of the marketing authorization.

reworking

Subjecting an in-process or bulk process intermediate (final biological bulk intermediate) or final product of a single batch to an alternate manufacturing process due to a failure to meet predetermined specifications. Reworking is an unexpected occurrence and is not pre-approved as part of the marketing authorization.