*Disinfection*: Process by which surface bioburden is reduced to a safe level or eliminated.
*Clean room*: A room designed, maintained and controlled to prevent particle and microbiological contamination of drug products. Such a room is assigned and reproducibly meets an appropriate air cleanliness classification.
*Dynamic pass box:* Dynamic Pass Box help to prevent the air flow from one area to another while transferring the material from lower cleanliness area to higher cleanliness area or vice versa. One door of the pass box opens at a time and both the doors cannot be opened simultaneously. There is an interlocking system in the pass boxes. Dynamic pass box works like a laminar air flow unit (HEPA filter).
*Aseptic Processing:* Aseptic processing is the processing of drug components (drug products, containers, excipients, etc.) in a manner that precludes microbial contamination of final sealed product.
*Aseptic area*: Area where by, the product is sterilized separately then filled and packaged using sterilized containers and closures in critical processing zones.
*Repacking*: Repacking refers to conversion of a packed product available in finished goods store to a different pack based on specific requirement from customer / subsidiary / contract giver without changing the primary pack.
*Disinfection*: Process by which surface bio burden is reduced to a safe level or eliminated.
*Qualified personnel:* Individuals who have appropriate education, training and experience to perform their duties.
*Clean area:* An area with defined particle and microbiological cleanliness standards.
*Aseptic Processing:* Aseptic processing is the process by which a sterile (aseptic) product is packaged in a sterile container in a way that maintains sterility.
*Critical Surface:* Surfaces that may come in contact with or directly affect a sterilized product or its container-closures. Critical surfaces are rendered sterile prior to the start of manufacturing operation, and sterility is maintained throughout processing.
*Pressure Differential:* Pressure differentials used to maintain airflow in direction from higher cleanliness to adjacent less clean areas.
*CIP:* Clean in Place is defined as techniques that allow cleaning of equipment without dismantling or manual cleaning with minimal operator involvement.
*SIP*: Sanitize in Place is generally referred to technique used for sanitization or sterilization i.e. reduction or complete removal of micro-organism after CIP clean.
*Deactivation:* Deactivation is a process of making an active pharmaceutical agent inactive by dilution with solvent (e.g. water etc.) or by use of chemical (e.g. sodium hypochlorite etc.)
*Decontamination:* Decontamination is a process by which micro-organisms removed, inactivated or destroyed in order render an object safe.
*Integrity Testing*: A fundamental requirement of critical process filtration applications that verifies the absence of leaks and defects.
*Capsule Filter*: Compact, self-contained filter assembly.
*Cartridge Filter*: Filter element encased in housing. Generally, the filter elements are disposal while the housing units are multi-use.
*Sterilizing Grade Filter*: A filter intended for terminal processing of sterile liquids that has been tested under worst case actual processing conditions for the ability to retain a minimum challenge of 107 cells of Brevundimonas diminuta per cm sq. of filter area.
*Bubble point*: The measured differential gas pressure which a wetting liquid (e.g., water, alcohol, product) is pushed out of the largest pores of a wetted porous membrane and a steady stream of gas bubbles or bulk gas flow is detected.
*Bubble point test:* A test to indicate the maximum pore size of a filter. The differential gas pressure at which a liquid (usually water) is pushed out of the largest pores and a steady stream of gas bubbles is detected from a previously wetted filter under specific test conditions. Used to test filter integrity with specific, validated, pressure values, wetting liquids and temperatures for specific pore-size (and type of) filters.
*Water intrusion test/ HydroCorr test* : The HydroCorr test is based on the fact that water is repelled by the pores Hydrophobic filters by surface tension and capillary forces. The HydroCorr test is a highly sensitive, non-alcohol, water flow integrity test for hydrophobic membrane filters. The minimum pressure required to force liquid into the largest pores is called the water intrusion pressure.
*Water, solvent or product wet integrity*: Integrity test limits stated within the filter manufacturer’s documentation are based on wetting the filter matrix with water, solvent or product of defined quality at ambient temperature.
*Post filtration integrity testing:* More often, post filtration integrity testing is performed using the product as final wetting agent.
Differential pressure. The pressure difference between the two adjacent rooms is called as differential pressure and it is calculated by finding out the difference in room pressures between two rooms. The limits are based on the classification of the rooms.
Relative Humidity: The ratio of amount of water vapor actually present in the air to the greatest amount possible at the same temperature.
*Grade A*: A local zone for high risk operations.
*Grade B*: For aseptic preparation and filling, this is the background environment for the Grade A zone.
*Grade C:* Clean areas for carryout less critical stages in the manufacture of sterile products.
*Clean area*: An area with defined particle and microbiological cleanliness standards.
*Drug product*: A finished dosage form, for e.g. tablet, capsule, solution, parenteral, etc. that contains an active drug ingredient generally but not necessarily in association with inactive ingredients.
*Return*: A drug product that has left the control of the manufacturer and returned back from the market to the manufacturer or distributor, which may or may not present a quality defect.
*Salvaged Drug Product* : Drug product that has been subjected to improper storage conditions including extremes in temperature, humidity, smoke, fumes, pressure, age, or radiation due to natural disasters, fires, accidents, or equipment failures and subsequently returned to the marketplace. Drug salvaging is not permitted.
*Aseptic Manufacturing Area*: The classified part of a facility that includes the aseptic processing room and ancillary clean rooms. For purposes of this document, this term is synonymous with “aseptic processing facility” as used in the segregated segment context.
*Aseptic Processing Facility:* A building or segregated segment of it containing clean rooms in which air supply, materials, and equipment are regulated to control microbial and particle contamination.
*Aseptic Processing Room*: A processing room in which one or more aseptic activities or processes is/are performed.
*Aseptic Processing Simulation (APS)*: A means for establishing the capability of an aseptic process as performed using a growth medium.
Note: Aseptic processing simulations are understood to be synonymous with media fills, process simulations, simulated product fills, broth trials, broth fills, etc.
*Asepsis*: A state of control attained by using an aseptic work area and performing activities in a manner that precludes microbiological contamination of the exposed sterile product.
*Bioburden*: The total number of microorganisms associated with a specific item.
*Barrier*: A physical partition that affords aseptic processing area (ISO 5) protection by separating it from the surrounding area.
*Clean Area:* An area with defined particle and microbiological cleanliness standards.
*Clean room*: A room designed, maintained, and controlled to prevent particle and microbiological contamination of drug products. Such a room is assigned and reproducibly meets an appropriate air cleanliness classification.
*Component*: Any ingredient intended for use in the manufacture of a drug product, including those that may not appear in the final drug product.
*Colony Forming Unit (CFU)*: A microbiological term that describes the formation of a single macroscopic colony after the introduction of one or more microorganisms to microbiological growth media. One colony forming unit is expressed as 1 CFU.
*Critical Area*: An area designed to maintain sterility of sterile materials. Sterilized product, containers, closures, and equipment may be exposed in critical areas.
*Clean Zone*: See Clean Area.
*Critical surfaces:* Surfaces that may come into contact with or directly affect a sterilized product or its containers or closures. Critical surfaces are rendered sterile prior to the start of the manufacturing operation, and sterility is maintained throughout processing.
*Decontamination*: A process that reduces viable Bioburden.
*Disinfection*: Process by which surface Bioburden is reduced to a safe level or eliminated. Some disinfection agents are effective only against vegetative microbes, while others possess additional capability to effectively kill bacterial and fungal spores.
*Dynamic:* Conditions relating to clean area classification under conditions of normal production.
*Environmental Flora (isolates):* Microorganisms associated with a processing environment.
*Gowning Qualification:* A program that establishes, both initially and on a periodic basis, the capability of an individual to do the complete sterile gown in an aseptic manner.
*Growth Promotion Test:* Test performed to demonstrate that media will support microbial growth.
*Integral unit*: The unit which is intact and can retain the sterility of the product. The units with cosmetic defect are also considered as integral units.
*Intervention*: An aseptic manipulation or activity performed by personnel that occurs within the critical area.
*Inherent interventions (Routine Interventions):* An intervention that is an integral part of the aseptic process and is required for set-up or routine operations and / or monitoring, e.g., aseptic assembly, container replenishment, environmental sampling, etc. Inherent interventions are required by batch record, procedure, or work instruction for the proper conduct of the aseptic process.
*Corrective interventions (Non-Routine Interventions):* An intervention that is performed to correct or adjust an aseptic process during its execution. Examples include such activities as: clearing component misfeed, adjusting sensors, and replacing equipment components.
*Isolator:* A decontaminated unit, supplied with Class 100 (ISO 5) or higher air quality that provides uncompromised, continuous isolation of its interior from the external environment (e.g., surrounding clean room air and personnel).
*Laminar flow*: An airflow moving in a single direction and in parallel layers at constant velocity from the beginning to the end of a straight-line vector.
*Non-integral unit:* The unit in which the integrity is compromised due to mechanical defects (breakage, cracks, etc.) and inappropriate closing of barrier system (e.g. Stoppering defect, etc.).
*Sterile Product:* For the purposes of this guidance, sterile product refers to one or more of the elements exposed to aseptic conditions and ultimately making up the sterile finished drug product. These elements include the containers, closures, and components of the finished drug product.
*Unidirectional flow*: An airflow moving in a single direction, in robust and uniform manner, and at sufficient speed to reproducibly sweep particles away from the critical processing or testing area.
*Worst Case:* A set of conditions encompassing upper and lower processing limits and circumstances, including those within standard operating procedures, that pose the greatest chance of process or product failure (when compared to ideal conditions). In the context of aseptic process simulations, worst case is considered to be the combination of events and circumstances that could expose a drug product to the greatest chance of microbial contamination.
*Active Fill duration:* Duration required to process a batch which includes routine shift changes & breaks (excluding extended stoppages).
*Non-filling time (Extended stoppages):* The exceptional durations (excluding shift changes/breaks) where filling activity is stopped due to machine down times.
*Qualified personnel:* Individuals who have appropriate education, training and experience to perform their duties.
*Standard Operating Procedure*: A document used to describe the activity /task in a step–by–step or in a chronological order. It defines what is being managed and how it is controlled.
*Audit:* Audit is systematic process of objectively obtaining and evaluating of a person, system, process, product or facility.
*Auditor:* A qualified specialist who provides specific knowledge or expertise related to the Pharmaceutical Manufacturing Quality System and/ or specific processes and activity.
*Auditee*: A management person responsible to coordinate the audit activities, arrange for personnel and material to be made available and communicate required information to the auditor during the review.
*Unplanned Audit*: Audits performed which are not planned as part of the Annual internal audit in aseptic area program. These audits are scheduled on an “as needed” basis to evaluate activities and use of procedures in place in the department/ focused area.
*Aseptic Processing*: In aseptic processing- drug product, container and closure are subject to sterilization separately and then brought together.
*Aseptic Technique*: Aseptic Technique is manipulation of sterile products to prevent contamination.
*Observation:* A Non-conformance or deficiency or scope for improvement to GMP/ GLP noted during Audit.
*Critical Observation:* Conditions, practices or processes that adversely affect product quality and/ or the safety of patients and/or the purity, efficacy of product and data integrity.
*Major Observation:* conditions, practices or processes that might adversely affect product quality and/ or the safety of patients and/ or the quality and integrity of data. (OR) observation which could potentially cause adverse consequences to the patient if left un- addressed could be considered indicative of poor control could be considered major deviation by regulatory authorities.
*Minor Observation:* conditions, practices or processes that would not be expected to adversely affect product quality and/ or the safety of patients and/or the quality and integrity of data. (OR) other observation that does not present any risk to the user or product but required action although activities can proceed.
*Nonconformance:* failure to meet the compliance to any approved procedure/ protocol/ system etc. in shall be treated as Nonconformance.
*Deficiency:* Incompleteness or inadequacy of any approved practice/ procedure/ protocol/ system etc. in the meeting regulatory and cGMP requirements.
*Subject Matter Expert (SME):* An individual with a specific area of knowledge applicable to an audit.
*Corrective Action*: A measure taken to correct an identified compliance or performance observation.
*Preventive Action:* A measure taken to prevent the re-occurrence of an identified compliance or performance deviation.
*Audit assignment*: Audit assignment address depth and reason for inspection (routine audit, for cause, quality trend data).
*Cytotoxic Drugs:* Cytotoxic drugs are therapeutic agents intended for, but not limited to, the treatment of cancer. These drugs are known to be highly toxic to cells, mainly through their action on cell reproduction.
*Cytotoxic drugs:* Cytotoxic drugs (antineoplastic) describe a group of
medicines that contain chemicals which are toxic to cells, preventing them
replication or growth, and so are used to treat cancer.
*Sample*: A portion of material/product collected according to a defined sampling procedure, sufficient to carry out the test as per testing procedure
*Random Sample*: Samples which are collected at different locations/ time during product processing having an equal probability of representing the complete batch.
*Control sample/Reserve sample*: Samples which are representative of each lot or batch of drug product shall be retained and stored under conditions consistent with product labelling. The reserve sample shall be stored in the same immediate container-closure system in which the drug product is marketed or in one that has essentially the same characteristics. The reserve sample consists of at least twice the quantity necessary to perform all the required tests, except those for sterility and pyrogens.
*Representative sample:* Sample of product obtained according to a sampling procedure designed to ensure that the different parts of a batch or the different properties of non-uniform materials are proportionately represented.
*Sampling plan:* Description of the location, number of units and/or quantity of material that should be collected and require tests.
*Sampling Procedure*: 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/SOP.
*Process Validation:* Collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. Process validation involves a series of activities taking place over the Lifecycle of the product and process.
*Process Design*: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up / optimization activities.
*Process Qualification:* During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial Manufacturing. In place of Process Qualification, process validation terms like “Prospective Validation or Concurrent validation may be used, as appropriate. Refer definitions of Prospective and Concurrent validations, as below.
*Continued Process Verification:* Ongoing assurance is gained during routine production that the process remains in a state of control following the successful process qualification.
*Process Revalidation:* The validation exercise to ensure that any changes/improvements introduced into the process or its environment does not adversely affect the product quality attributes.
*Prospective Validation:* PV conducted prior to the distribution (for commercial use) of either a new product or a product made under a modified production process, where the modifications are significant and may affect the product’s characteristics for new products.
*Critical Process Parameter (CPP)*: A Process Parameter that has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.
*Ongoing Process Verification*: Documented evidence that the process remains in a state of control during commercial manufacture.
*State of Control"*: A Condition in which the set of controls consistently provides assurance of continued process performance and product quality.
*Critical Quality Attribute (CQA):* A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality
*Quality Target Product Profile (TPP)*: A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product..
*Process Capability*: Is the ability of a process to manufacture product that meets predefined requirements.
*Stable Process: Statistical Process Control (SPC)*: Consistent and Predictable. It does not exhibit special cause variation. The variation present is due to only common cause variations.
*Unstable Process: Out of Statistical Process Control (SPC)*: Not Consistent or Predictable. It exhibits special cause variation.
*Common Cause Variations* - Common causes are the process inputs and conditions that contribute to the regular, everyday variation in a process. They are part of the process and contribute to output variation because they themselves vary. Each common cause contributes a small part of the total variation. By looking at a process over time, we know how much variation to expect from common causes. The process is stable, or predictable, when all the variation is due to common causes.
*Special Cause Variations* - Special causes are factors that are not always present in a process but that appear because of some particular circumstance. Special causes are not usually present. They may come and go sporadically; may be temporary or long-term. A special cause is something special or specific that has a pronounced effect on the process. The process is unstable, or unpredictable, when special causes contribute to the variation.
*Critical Material Attribute (CMA)*: A material attribute (e.g., particle size, morphology, excipient grade) that has an effect on one or more CQAs.
*Control Strategy*: A planned set of controls, derived from current product and process understanding that assures process performance and product quality (ICH Q10). Every product manufacturing process has an associated control strategy. A control strategy can include, but is not limited to, the following:*
i) Controls on critical materials (including raw materials, starting materials, intermediates, reagents, primary packaging materials for the drug substance, etc.) and CMAs.
ii) Controls implicit in the design of the manufacturing process (e.g., sequence of purification steps [biotechnological/biological drug substances], or order of addition of reagents [chemical entities]).
iii) In-process controls (including in-process tests and CPPs).
*Measurable Statistics (MS):* Statistical data derived through testing or observation intended to provide information relevant to process monitoring. (Such as process capability statistics).
*Contingency Samples:* Samples withdrawn in addition to the number of samples required for single routine analysis. These samples are supposed to be used for additional testing required during OOS/OOT Investigation, if any.
*Clean Room*: - A room in which the concentration of airborne particles is controlled to meet a specified airborne particulate cleanliness class. In addition, the concentration of microorganisms in the environment is monitored; each cleanliness class defined is also assigned a microbial level for air, surface, and personnel gear.
Environmental monitoring program: Documented program implemented via standard operation procedures that describes in detail the methods and acceptance criteria for monitoring particulates and microorganisms in controlled environments (air, surface, personnel gear). The program includes sampling sites/location, frequency of sampling and investigation and corrective actions.
*Controlled Environment*: - Any area in an aseptic process system for which airborne particulate and microorganism levels are controlled to specific levels, appropriate to the activities conducted within that environment.
*Alert level*: - An Alert level in microbiological environmental monitoring is that level of microorganisms that shows a potential drift from normal operating conditions. Exceeding the Alert level is not necessarily grounds for definitive corrective action, but it should at least prompt a documented follow-up investigation.
*Action level*: - An Action level in microbiological environmental monitoring is that level of microorganisms that when exceeded requires immediate follow-up and, if necessary, corrective action.
*Static monitoring:* Microbiological monitoring during the at rest condition of the clean room where the installation is complete with equipment installed and operating in a manner agreed upon, but with no personnel present.
*Dynamic monitoring:* Microbiological monitoring during the operational condition of the clean room where the installation is functioning in the specified manner, with the specified number of personnel present and working in the manner agreed upon.
*Aseptic*: Technically, the absence of microorganisms, but in aseptic processing this refers to methods and operations that minimize microbial contamination in environments where sterilized product and components are filled and/or assembled.
*Trend analysis*: A review performed either routinely or in response to an alert or action condition. This review provides analysis of specific environmental monitoring data.
*Risk Assessment analysis*: Analysis of the identification of contamination potentials in controlled environments that establish priorities in terms of severity and frequency and that will develop methods and procedures that will eliminate, reduce, minimize or mitigate their potential for microbial contamination of the product/container/closure system.
*Sampling plan*: A documented plan that describes the procedures and methods for sampling a controlled environment; identifies the sampling sites/locations, the sampling frequency, number of samples, describes the method of analysis and how to interpret the results.
*Turbidity:* It is a measure of the degree to which the microbiological clear medium or broth loses its transparency due to the presence of suspended particulates or microbial growth i.e. the cloudiness or lack of transparency of the medium.
Qualified Personnel – Personnel who are qualified for a particular technique/test with their qualification status valid. They responsible for routine activities and to undertake qualification and re-qualification activities.
*Aseptic Manufacturing Area:* The classified part of a facility that includes the
aseptic processing room and ancillary clean rooms. For purposes of this
document, this term is synonymous with “aseptic processing facility” as used in
the segregated segment context.
*Aseptic Processing Facility:* A building or segregated segment of it containing
clean rooms in which air supply, materials, and equipment are regulated to
control microbial and particle contamination.
*Aseptic Processing Room*: A processing room in which one or more aseptic
activities or processes is/are performed.
*Aseptic Processing Simulation (APS*): A means for establishing the capability
of an aseptic process as performed using a growth medium. Note: Aseptic
processing simulations are understood to be synonymous with media fills,
process simulations, simulated product fills, broth trials, broth fills, etc.
*Asepsis:* A state of control attained by using an aseptic work area and
performing activities in a manner that precludes microbiological contamination
of the exposed sterile product.
*Bioburden*: The total number of microorganisms associated with a specific
item.
*Barrier*: A physical partition that affords aseptic processing area (ISO 5)
protection by separating it from the surrounding area.
*Clean Area:* An area with defined particle and microbiological cleanliness
standards.
*Clean room*: A room designed, maintained, and controlled to prevent particle
and microbiological contamination of drug products. Such a room is assigned
and reproducibly meets an appropriate air cleanliness classification.
*Component*: Any ingredient intended for use in the manufacture of a drug
product, including those that may not appear in the final drug product.
*Colony Forming Unit (CFU)*: A microbiological term that describes the
formation of a single macroscopic colony after the introduction of one or more
microorganisms to microbiological growth media. One colony forming unit is
expressed as 1 CFU.
*Critical Area*: An area designed to maintain sterility of sterile materials.
Sterilized product, containers, closures, and equipment may be exposed in
critical areas.
*Clean Zone*: See Clean Area.
*Critical surfaces:* Surfaces that may come into contact with or directly affect a
sterilized product or its containers or closures. Critical surfaces are rendered
sterile prior to the start of the manufacturing operation, and sterility is
maintained throughout processing.
*Decontamination*: A process that reduces viable Bioburden.
*Disinfection*: Process by which surface Bioburden is reduced to a safe level or
eliminated. Some disinfection agents are effective only against vegetative
microbes, while others possess additional capability to effectively kill bacterial
and fungal spores.
*Dynamic*: Conditions relating to clean area classification under conditions of
normal production.
*Environmental Flora (isolates):* Microorganisms associated with a processing
environment.
*Gowning Qualification:* A program that establishes, both initially and on a
periodic basis, the capability of an individual to do the complete sterile gown in
an aseptic manner.
*Growth Promotion Test:* Test performed to demonstrate that media will support
microbial growth.
*Integral unit*: The unit which is intact and can retain the sterility of the product.
The units with cosmetic defect are also considered as integral units.
*Intervention*: An aseptic manipulation or activity performed by personnel that
occurs within the critical area.
*Inherent interventions (Routine Interventions):* An intervention that is an
integral part of the aseptic process and is required for set-up or routine
operations and / or monitoring, e.g., aseptic assembly, container
replenishment, environmental sampling, etc. Inherent interventions are
required by batch record, procedure, or work instruction for the proper conduct
of the aseptic process.
*Corrective interventions (Non-Routine Interventions):* An intervention that is
performed to correct or adjust an aseptic process during its execution.
Examples include such activities as: clearing component misfeed, adjusting
sensors, and replacing equipment components.
*Isolator*: A decontaminated unit, supplied with Class 100 (ISO 5) or higher air
quality that provides uncompromised, continuous isolation of its interior from
the external environment (e.g., surrounding clean room air and personnel).
*Laminar flow*: An airflow moving in a single direction and in parallel layers at
constant velocity from the beginning to the end of a straight line vector.
*Non-integral unit*: The unit in which the integrity is compromised due to
mechanical defects (breakage, cracks, etc.) and inappropriate closing of barrier
system (e.g. Stoppering defect, etc.).
*Sterile Product*: For the purposes of this guidance, sterile product refers to one
or more of the elements exposed to aseptic conditions and ultimately making
up the sterile finished drug product. These elements include the containers,
closures, and components of the finished drug product.
*Unidirectional flow*: An airflow moving in a single direction, in robust and
uniform manner, and at sufficient speed to reproducibly sweep particles away
from the critical processing or testing area.
*Worst Case*: A set of conditions encompassing upper and lower processing
limits and circumstances, including those within standard operating
procedures, that pose the greatest chance of process or product failure (when
compared to ideal conditions). In the context of aseptic process simulations,
worst case is considered to be the combination of events and circumstances
that could expose a drug product to the greatest chance of microbial
contamination.
*Active Fill duration:* Duration required to process a batch which includes routine
shift changes & breaks (excluding extended stoppages).
*Non-filling time* *(Extended stoppages):* The exceptional durations (excluding
shift changes/breaks) where filling activity is stopped due to machine down
times.
*Clean room*: A room designed, maintained and controlled to prevent particle and microbiological contamination of drug products. Such a room is assigned and reproducibly meets an appropriate air cleanliness classification.
*Dynamic pass box:* Dynamic Pass Box help to prevent the air flow from one area to another while transferring the material from lower cleanliness area to higher cleanliness area or vice versa. One door of the pass box opens at a time and both the doors cannot be opened simultaneously. There is an interlocking system in the pass boxes. Dynamic pass box works like a laminar air flow unit (HEPA filter).
*Aseptic Processing:* Aseptic processing is the processing of drug components (drug products, containers, excipients, etc.) in a manner that precludes microbial contamination of final sealed product.
*Aseptic area*: Area where by, the product is sterilized separately then filled and packaged using sterilized containers and closures in critical processing zones.
*Repacking*: Repacking refers to conversion of a packed product available in finished goods store to a different pack based on specific requirement from customer / subsidiary / contract giver without changing the primary pack.
*Disinfection*: Process by which surface bio burden is reduced to a safe level or eliminated.
*Qualified personnel:* Individuals who have appropriate education, training and experience to perform their duties.
*Clean area:* An area with defined particle and microbiological cleanliness standards.
*Aseptic Processing:* Aseptic processing is the process by which a sterile (aseptic) product is packaged in a sterile container in a way that maintains sterility.
*Critical Surface:* Surfaces that may come in contact with or directly affect a sterilized product or its container-closures. Critical surfaces are rendered sterile prior to the start of manufacturing operation, and sterility is maintained throughout processing.
*Pressure Differential:* Pressure differentials used to maintain airflow in direction from higher cleanliness to adjacent less clean areas.
*CIP:* Clean in Place is defined as techniques that allow cleaning of equipment without dismantling or manual cleaning with minimal operator involvement.
*SIP*: Sanitize in Place is generally referred to technique used for sanitization or sterilization i.e. reduction or complete removal of micro-organism after CIP clean.
*Deactivation:* Deactivation is a process of making an active pharmaceutical agent inactive by dilution with solvent (e.g. water etc.) or by use of chemical (e.g. sodium hypochlorite etc.)
*Decontamination:* Decontamination is a process by which micro-organisms removed, inactivated or destroyed in order render an object safe.
*Integrity Testing*: A fundamental requirement of critical process filtration applications that verifies the absence of leaks and defects.
*Capsule Filter*: Compact, self-contained filter assembly.
*Cartridge Filter*: Filter element encased in housing. Generally, the filter elements are disposal while the housing units are multi-use.
*Sterilizing Grade Filter*: A filter intended for terminal processing of sterile liquids that has been tested under worst case actual processing conditions for the ability to retain a minimum challenge of 107 cells of Brevundimonas diminuta per cm sq. of filter area.
*Bubble point*: The measured differential gas pressure which a wetting liquid (e.g., water, alcohol, product) is pushed out of the largest pores of a wetted porous membrane and a steady stream of gas bubbles or bulk gas flow is detected.
*Bubble point test:* A test to indicate the maximum pore size of a filter. The differential gas pressure at which a liquid (usually water) is pushed out of the largest pores and a steady stream of gas bubbles is detected from a previously wetted filter under specific test conditions. Used to test filter integrity with specific, validated, pressure values, wetting liquids and temperatures for specific pore-size (and type of) filters.
*Water intrusion test/ HydroCorr test* : The HydroCorr test is based on the fact that water is repelled by the pores Hydrophobic filters by surface tension and capillary forces. The HydroCorr test is a highly sensitive, non-alcohol, water flow integrity test for hydrophobic membrane filters. The minimum pressure required to force liquid into the largest pores is called the water intrusion pressure.
*Water, solvent or product wet integrity*: Integrity test limits stated within the filter manufacturer’s documentation are based on wetting the filter matrix with water, solvent or product of defined quality at ambient temperature.
*Post filtration integrity testing:* More often, post filtration integrity testing is performed using the product as final wetting agent.
Differential pressure. The pressure difference between the two adjacent rooms is called as differential pressure and it is calculated by finding out the difference in room pressures between two rooms. The limits are based on the classification of the rooms.
Relative Humidity: The ratio of amount of water vapor actually present in the air to the greatest amount possible at the same temperature.
*Grade A*: A local zone for high risk operations.
*Grade B*: For aseptic preparation and filling, this is the background environment for the Grade A zone.
*Grade C:* Clean areas for carryout less critical stages in the manufacture of sterile products.
*Clean area*: An area with defined particle and microbiological cleanliness standards.
*Drug product*: A finished dosage form, for e.g. tablet, capsule, solution, parenteral, etc. that contains an active drug ingredient generally but not necessarily in association with inactive ingredients.
*Return*: A drug product that has left the control of the manufacturer and returned back from the market to the manufacturer or distributor, which may or may not present a quality defect.
*Salvaged Drug Product* : Drug product that has been subjected to improper storage conditions including extremes in temperature, humidity, smoke, fumes, pressure, age, or radiation due to natural disasters, fires, accidents, or equipment failures and subsequently returned to the marketplace. Drug salvaging is not permitted.
*Aseptic Manufacturing Area*: The classified part of a facility that includes the aseptic processing room and ancillary clean rooms. For purposes of this document, this term is synonymous with “aseptic processing facility” as used in the segregated segment context.
*Aseptic Processing Facility:* A building or segregated segment of it containing clean rooms in which air supply, materials, and equipment are regulated to control microbial and particle contamination.
*Aseptic Processing Room*: A processing room in which one or more aseptic activities or processes is/are performed.
*Aseptic Processing Simulation (APS)*: A means for establishing the capability of an aseptic process as performed using a growth medium.
Note: Aseptic processing simulations are understood to be synonymous with media fills, process simulations, simulated product fills, broth trials, broth fills, etc.
*Asepsis*: A state of control attained by using an aseptic work area and performing activities in a manner that precludes microbiological contamination of the exposed sterile product.
*Bioburden*: The total number of microorganisms associated with a specific item.
*Barrier*: A physical partition that affords aseptic processing area (ISO 5) protection by separating it from the surrounding area.
*Clean Area:* An area with defined particle and microbiological cleanliness standards.
*Clean room*: A room designed, maintained, and controlled to prevent particle and microbiological contamination of drug products. Such a room is assigned and reproducibly meets an appropriate air cleanliness classification.
*Component*: Any ingredient intended for use in the manufacture of a drug product, including those that may not appear in the final drug product.
*Colony Forming Unit (CFU)*: A microbiological term that describes the formation of a single macroscopic colony after the introduction of one or more microorganisms to microbiological growth media. One colony forming unit is expressed as 1 CFU.
*Critical Area*: An area designed to maintain sterility of sterile materials. Sterilized product, containers, closures, and equipment may be exposed in critical areas.
*Clean Zone*: See Clean Area.
*Critical surfaces:* Surfaces that may come into contact with or directly affect a sterilized product or its containers or closures. Critical surfaces are rendered sterile prior to the start of the manufacturing operation, and sterility is maintained throughout processing.
*Decontamination*: A process that reduces viable Bioburden.
*Disinfection*: Process by which surface Bioburden is reduced to a safe level or eliminated. Some disinfection agents are effective only against vegetative microbes, while others possess additional capability to effectively kill bacterial and fungal spores.
*Dynamic:* Conditions relating to clean area classification under conditions of normal production.
*Environmental Flora (isolates):* Microorganisms associated with a processing environment.
*Gowning Qualification:* A program that establishes, both initially and on a periodic basis, the capability of an individual to do the complete sterile gown in an aseptic manner.
*Growth Promotion Test:* Test performed to demonstrate that media will support microbial growth.
*Integral unit*: The unit which is intact and can retain the sterility of the product. The units with cosmetic defect are also considered as integral units.
*Intervention*: An aseptic manipulation or activity performed by personnel that occurs within the critical area.
*Inherent interventions (Routine Interventions):* An intervention that is an integral part of the aseptic process and is required for set-up or routine operations and / or monitoring, e.g., aseptic assembly, container replenishment, environmental sampling, etc. Inherent interventions are required by batch record, procedure, or work instruction for the proper conduct of the aseptic process.
*Corrective interventions (Non-Routine Interventions):* An intervention that is performed to correct or adjust an aseptic process during its execution. Examples include such activities as: clearing component misfeed, adjusting sensors, and replacing equipment components.
*Isolator:* A decontaminated unit, supplied with Class 100 (ISO 5) or higher air quality that provides uncompromised, continuous isolation of its interior from the external environment (e.g., surrounding clean room air and personnel).
*Laminar flow*: An airflow moving in a single direction and in parallel layers at constant velocity from the beginning to the end of a straight-line vector.
*Non-integral unit:* The unit in which the integrity is compromised due to mechanical defects (breakage, cracks, etc.) and inappropriate closing of barrier system (e.g. Stoppering defect, etc.).
*Sterile Product:* For the purposes of this guidance, sterile product refers to one or more of the elements exposed to aseptic conditions and ultimately making up the sterile finished drug product. These elements include the containers, closures, and components of the finished drug product.
*Unidirectional flow*: An airflow moving in a single direction, in robust and uniform manner, and at sufficient speed to reproducibly sweep particles away from the critical processing or testing area.
*Worst Case:* A set of conditions encompassing upper and lower processing limits and circumstances, including those within standard operating procedures, that pose the greatest chance of process or product failure (when compared to ideal conditions). In the context of aseptic process simulations, worst case is considered to be the combination of events and circumstances that could expose a drug product to the greatest chance of microbial contamination.
*Active Fill duration:* Duration required to process a batch which includes routine shift changes & breaks (excluding extended stoppages).
*Non-filling time (Extended stoppages):* The exceptional durations (excluding shift changes/breaks) where filling activity is stopped due to machine down times.
*Qualified personnel:* Individuals who have appropriate education, training and experience to perform their duties.
*Standard Operating Procedure*: A document used to describe the activity /task in a step–by–step or in a chronological order. It defines what is being managed and how it is controlled.
*Audit:* Audit is systematic process of objectively obtaining and evaluating of a person, system, process, product or facility.
*Auditor:* A qualified specialist who provides specific knowledge or expertise related to the Pharmaceutical Manufacturing Quality System and/ or specific processes and activity.
*Auditee*: A management person responsible to coordinate the audit activities, arrange for personnel and material to be made available and communicate required information to the auditor during the review.
*Unplanned Audit*: Audits performed which are not planned as part of the Annual internal audit in aseptic area program. These audits are scheduled on an “as needed” basis to evaluate activities and use of procedures in place in the department/ focused area.
*Aseptic Processing*: In aseptic processing- drug product, container and closure are subject to sterilization separately and then brought together.
*Aseptic Technique*: Aseptic Technique is manipulation of sterile products to prevent contamination.
*Observation:* A Non-conformance or deficiency or scope for improvement to GMP/ GLP noted during Audit.
*Critical Observation:* Conditions, practices or processes that adversely affect product quality and/ or the safety of patients and/or the purity, efficacy of product and data integrity.
*Major Observation:* conditions, practices or processes that might adversely affect product quality and/ or the safety of patients and/ or the quality and integrity of data. (OR) observation which could potentially cause adverse consequences to the patient if left un- addressed could be considered indicative of poor control could be considered major deviation by regulatory authorities.
*Minor Observation:* conditions, practices or processes that would not be expected to adversely affect product quality and/ or the safety of patients and/or the quality and integrity of data. (OR) other observation that does not present any risk to the user or product but required action although activities can proceed.
*Nonconformance:* failure to meet the compliance to any approved procedure/ protocol/ system etc. in shall be treated as Nonconformance.
*Deficiency:* Incompleteness or inadequacy of any approved practice/ procedure/ protocol/ system etc. in the meeting regulatory and cGMP requirements.
*Subject Matter Expert (SME):* An individual with a specific area of knowledge applicable to an audit.
*Corrective Action*: A measure taken to correct an identified compliance or performance observation.
*Preventive Action:* A measure taken to prevent the re-occurrence of an identified compliance or performance deviation.
*Audit assignment*: Audit assignment address depth and reason for inspection (routine audit, for cause, quality trend data).
*Cytotoxic Drugs:* Cytotoxic drugs are therapeutic agents intended for, but not limited to, the treatment of cancer. These drugs are known to be highly toxic to cells, mainly through their action on cell reproduction.
*Cytotoxic drugs:* Cytotoxic drugs (antineoplastic) describe a group of
medicines that contain chemicals which are toxic to cells, preventing them
replication or growth, and so are used to treat cancer.
*Sample*: A portion of material/product collected according to a defined sampling procedure, sufficient to carry out the test as per testing procedure
*Random Sample*: Samples which are collected at different locations/ time during product processing having an equal probability of representing the complete batch.
*Control sample/Reserve sample*: Samples which are representative of each lot or batch of drug product shall be retained and stored under conditions consistent with product labelling. The reserve sample shall be stored in the same immediate container-closure system in which the drug product is marketed or in one that has essentially the same characteristics. The reserve sample consists of at least twice the quantity necessary to perform all the required tests, except those for sterility and pyrogens.
*Representative sample:* Sample of product obtained according to a sampling procedure designed to ensure that the different parts of a batch or the different properties of non-uniform materials are proportionately represented.
*Sampling plan:* Description of the location, number of units and/or quantity of material that should be collected and require tests.
*Sampling Procedure*: 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/SOP.
*Process Validation:* Collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. Process validation involves a series of activities taking place over the Lifecycle of the product and process.
*Process Design*: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up / optimization activities.
*Process Qualification:* During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial Manufacturing. In place of Process Qualification, process validation terms like “Prospective Validation or Concurrent validation may be used, as appropriate. Refer definitions of Prospective and Concurrent validations, as below.
*Continued Process Verification:* Ongoing assurance is gained during routine production that the process remains in a state of control following the successful process qualification.
*Process Revalidation:* The validation exercise to ensure that any changes/improvements introduced into the process or its environment does not adversely affect the product quality attributes.
*Prospective Validation:* PV conducted prior to the distribution (for commercial use) of either a new product or a product made under a modified production process, where the modifications are significant and may affect the product’s characteristics for new products.
*Critical Process Parameter (CPP)*: A Process Parameter that has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.
*Ongoing Process Verification*: Documented evidence that the process remains in a state of control during commercial manufacture.
*State of Control"*: A Condition in which the set of controls consistently provides assurance of continued process performance and product quality.
*Critical Quality Attribute (CQA):* A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality
*Quality Target Product Profile (TPP)*: A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product..
*Process Capability*: Is the ability of a process to manufacture product that meets predefined requirements.
*Stable Process: Statistical Process Control (SPC)*: Consistent and Predictable. It does not exhibit special cause variation. The variation present is due to only common cause variations.
*Unstable Process: Out of Statistical Process Control (SPC)*: Not Consistent or Predictable. It exhibits special cause variation.
*Common Cause Variations* - Common causes are the process inputs and conditions that contribute to the regular, everyday variation in a process. They are part of the process and contribute to output variation because they themselves vary. Each common cause contributes a small part of the total variation. By looking at a process over time, we know how much variation to expect from common causes. The process is stable, or predictable, when all the variation is due to common causes.
*Special Cause Variations* - Special causes are factors that are not always present in a process but that appear because of some particular circumstance. Special causes are not usually present. They may come and go sporadically; may be temporary or long-term. A special cause is something special or specific that has a pronounced effect on the process. The process is unstable, or unpredictable, when special causes contribute to the variation.
*Critical Material Attribute (CMA)*: A material attribute (e.g., particle size, morphology, excipient grade) that has an effect on one or more CQAs.
*Control Strategy*: A planned set of controls, derived from current product and process understanding that assures process performance and product quality (ICH Q10). Every product manufacturing process has an associated control strategy. A control strategy can include, but is not limited to, the following:*
i) Controls on critical materials (including raw materials, starting materials, intermediates, reagents, primary packaging materials for the drug substance, etc.) and CMAs.
ii) Controls implicit in the design of the manufacturing process (e.g., sequence of purification steps [biotechnological/biological drug substances], or order of addition of reagents [chemical entities]).
iii) In-process controls (including in-process tests and CPPs).
*Measurable Statistics (MS):* Statistical data derived through testing or observation intended to provide information relevant to process monitoring. (Such as process capability statistics).
*Contingency Samples:* Samples withdrawn in addition to the number of samples required for single routine analysis. These samples are supposed to be used for additional testing required during OOS/OOT Investigation, if any.
*Clean Room*: - A room in which the concentration of airborne particles is controlled to meet a specified airborne particulate cleanliness class. In addition, the concentration of microorganisms in the environment is monitored; each cleanliness class defined is also assigned a microbial level for air, surface, and personnel gear.
Environmental monitoring program: Documented program implemented via standard operation procedures that describes in detail the methods and acceptance criteria for monitoring particulates and microorganisms in controlled environments (air, surface, personnel gear). The program includes sampling sites/location, frequency of sampling and investigation and corrective actions.
*Controlled Environment*: - Any area in an aseptic process system for which airborne particulate and microorganism levels are controlled to specific levels, appropriate to the activities conducted within that environment.
*Alert level*: - An Alert level in microbiological environmental monitoring is that level of microorganisms that shows a potential drift from normal operating conditions. Exceeding the Alert level is not necessarily grounds for definitive corrective action, but it should at least prompt a documented follow-up investigation.
*Action level*: - An Action level in microbiological environmental monitoring is that level of microorganisms that when exceeded requires immediate follow-up and, if necessary, corrective action.
*Static monitoring:* Microbiological monitoring during the at rest condition of the clean room where the installation is complete with equipment installed and operating in a manner agreed upon, but with no personnel present.
*Dynamic monitoring:* Microbiological monitoring during the operational condition of the clean room where the installation is functioning in the specified manner, with the specified number of personnel present and working in the manner agreed upon.
*Aseptic*: Technically, the absence of microorganisms, but in aseptic processing this refers to methods and operations that minimize microbial contamination in environments where sterilized product and components are filled and/or assembled.
*Trend analysis*: A review performed either routinely or in response to an alert or action condition. This review provides analysis of specific environmental monitoring data.
*Risk Assessment analysis*: Analysis of the identification of contamination potentials in controlled environments that establish priorities in terms of severity and frequency and that will develop methods and procedures that will eliminate, reduce, minimize or mitigate their potential for microbial contamination of the product/container/closure system.
*Sampling plan*: A documented plan that describes the procedures and methods for sampling a controlled environment; identifies the sampling sites/locations, the sampling frequency, number of samples, describes the method of analysis and how to interpret the results.
*Turbidity:* It is a measure of the degree to which the microbiological clear medium or broth loses its transparency due to the presence of suspended particulates or microbial growth i.e. the cloudiness or lack of transparency of the medium.
Qualified Personnel – Personnel who are qualified for a particular technique/test with their qualification status valid. They responsible for routine activities and to undertake qualification and re-qualification activities.
*Aseptic Manufacturing Area:* The classified part of a facility that includes the
aseptic processing room and ancillary clean rooms. For purposes of this
document, this term is synonymous with “aseptic processing facility” as used in
the segregated segment context.
*Aseptic Processing Facility:* A building or segregated segment of it containing
clean rooms in which air supply, materials, and equipment are regulated to
control microbial and particle contamination.
*Aseptic Processing Room*: A processing room in which one or more aseptic
activities or processes is/are performed.
*Aseptic Processing Simulation (APS*): A means for establishing the capability
of an aseptic process as performed using a growth medium. Note: Aseptic
processing simulations are understood to be synonymous with media fills,
process simulations, simulated product fills, broth trials, broth fills, etc.
*Asepsis:* A state of control attained by using an aseptic work area and
performing activities in a manner that precludes microbiological contamination
of the exposed sterile product.
*Bioburden*: The total number of microorganisms associated with a specific
item.
*Barrier*: A physical partition that affords aseptic processing area (ISO 5)
protection by separating it from the surrounding area.
*Clean Area:* An area with defined particle and microbiological cleanliness
standards.
*Clean room*: A room designed, maintained, and controlled to prevent particle
and microbiological contamination of drug products. Such a room is assigned
and reproducibly meets an appropriate air cleanliness classification.
*Component*: Any ingredient intended for use in the manufacture of a drug
product, including those that may not appear in the final drug product.
*Colony Forming Unit (CFU)*: A microbiological term that describes the
formation of a single macroscopic colony after the introduction of one or more
microorganisms to microbiological growth media. One colony forming unit is
expressed as 1 CFU.
*Critical Area*: An area designed to maintain sterility of sterile materials.
Sterilized product, containers, closures, and equipment may be exposed in
critical areas.
*Clean Zone*: See Clean Area.
*Critical surfaces:* Surfaces that may come into contact with or directly affect a
sterilized product or its containers or closures. Critical surfaces are rendered
sterile prior to the start of the manufacturing operation, and sterility is
maintained throughout processing.
*Decontamination*: A process that reduces viable Bioburden.
*Disinfection*: Process by which surface Bioburden is reduced to a safe level or
eliminated. Some disinfection agents are effective only against vegetative
microbes, while others possess additional capability to effectively kill bacterial
and fungal spores.
*Dynamic*: Conditions relating to clean area classification under conditions of
normal production.
*Environmental Flora (isolates):* Microorganisms associated with a processing
environment.
*Gowning Qualification:* A program that establishes, both initially and on a
periodic basis, the capability of an individual to do the complete sterile gown in
an aseptic manner.
*Growth Promotion Test:* Test performed to demonstrate that media will support
microbial growth.
*Integral unit*: The unit which is intact and can retain the sterility of the product.
The units with cosmetic defect are also considered as integral units.
*Intervention*: An aseptic manipulation or activity performed by personnel that
occurs within the critical area.
*Inherent interventions (Routine Interventions):* An intervention that is an
integral part of the aseptic process and is required for set-up or routine
operations and / or monitoring, e.g., aseptic assembly, container
replenishment, environmental sampling, etc. Inherent interventions are
required by batch record, procedure, or work instruction for the proper conduct
of the aseptic process.
*Corrective interventions (Non-Routine Interventions):* An intervention that is
performed to correct or adjust an aseptic process during its execution.
Examples include such activities as: clearing component misfeed, adjusting
sensors, and replacing equipment components.
*Isolator*: A decontaminated unit, supplied with Class 100 (ISO 5) or higher air
quality that provides uncompromised, continuous isolation of its interior from
the external environment (e.g., surrounding clean room air and personnel).
*Laminar flow*: An airflow moving in a single direction and in parallel layers at
constant velocity from the beginning to the end of a straight line vector.
*Non-integral unit*: The unit in which the integrity is compromised due to
mechanical defects (breakage, cracks, etc.) and inappropriate closing of barrier
system (e.g. Stoppering defect, etc.).
*Sterile Product*: For the purposes of this guidance, sterile product refers to one
or more of the elements exposed to aseptic conditions and ultimately making
up the sterile finished drug product. These elements include the containers,
closures, and components of the finished drug product.
*Unidirectional flow*: An airflow moving in a single direction, in robust and
uniform manner, and at sufficient speed to reproducibly sweep particles away
from the critical processing or testing area.
*Worst Case*: A set of conditions encompassing upper and lower processing
limits and circumstances, including those within standard operating
procedures, that pose the greatest chance of process or product failure (when
compared to ideal conditions). In the context of aseptic process simulations,
worst case is considered to be the combination of events and circumstances
that could expose a drug product to the greatest chance of microbial
contamination.
*Active Fill duration:* Duration required to process a batch which includes routine
shift changes & breaks (excluding extended stoppages).
*Non-filling time* *(Extended stoppages):* The exceptional durations (excluding
shift changes/breaks) where filling activity is stopped due to machine down
times.
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