Sterile Pharmaceutical Products
The production of sterile preparations should be carried out in clean areas, entry to which should be through airlocks for personnel and for equipment and materials. Clean areas should be maintained to an appropriate standard of cleanliness and supplied with air that has passed through filters of the required efficiency.
The various operations of component preparation (such as those involving containers and closures), product preparation, filling, and sterilization should be carried out in separate areas within the clean area.
These areas are classified into four grades.
Manufacturing operations are divided here into two categories:
- First, those where the product is terminally sterilized.
- Second, those which are conducted aseptically at some or all stages.
What is the Action level ?
Established criteria of microbial or airborne particle level that, when exceeded, should trigger an appropriate investigation and corrective actions based on the investigation.
What is Alert level ?
Established criteria of microbial or airborne particle level (and microbial species, if necessary) providing early warning of potential drift from normal conditions which are not necessarily grounds for definitive corrective action but require follow-up investigation
what is Aseptic processing ?
A method of producing a sterile product in which sterile bulk drug or sterile raw materials are compounded and assembled with sterile packaging components in a controlled environment, in which the entry or supply of air, materials, equipment, and personnel are regulated to control microbial and particulate contamination to an acceptable level (Grade A or B)
What is Bioburden ?
The population of viable microorganisms on or in raw materials, products, and labeling/packaging materials is determined before sterilization.
what is Biological indicator (BI) ?
A microbiological test system providing defined resistance to a specified sterilization process under defined conditions, which is used as an indicator of sterilization cycle efficacy.
What is Calibration ?
A set of operations that establish, under specified conditions, the relationship between values indicated by a measuring instrument or system, or values represented by a material measure or reference material, and the corresponding values measured under specified conditions. Predetermined limits for the acceptance of measurement results should be established.
What is Chemical indicator (CI) ?
Test system that reveals fluctuation(s) in one or more predefined process variables based on a chemical or physical change resulting from exposure to a sterilization process.
What is Clean area ?
An area maintained and controlled to prevent contamination with foreign matters and microbes from pharmaceutical products in accordance with defined particle and microbiological cleanliness standards. For the purpose of this document, this term is synonymous with the manufacturing area for aseptic products
What is Cleaning ?
Removal of contaminants with water/cleaning agents from an item to the extent necessary for further processing or for the intended use.
What is Cleanliness level
A quality that indicates the contamination control conditions of a monitored item. The level is classified into Grades A, B, C, and D according to the number of particles larger than 0.5 µm per m3 in the air.
What is Critical area ?
A designated processing area where sterilized containers, raw materials, intermediate compounds, or the surface of equipment that come into contact with sterilized products may be exposed to the environment. This area is also referred to as the “critical processing area.” The quality of air should be Grade A or higher than Grade C depending on the sterilization conditions to be applied.
What is Critical parameter ?
A product quality parameter which is essential for the control of the applied sterility process, and which requires monitoring
What is Disinfection ?
A process by which surface bioburden is reduced to a safe level or eliminated
What is D value ?
A value indicating the extinction rate of microorganisms killed under defined conditions. The D value is defined as the time or radiation dose required to inactivate 90% of a population (one-tenth of the starting value) of the test microorganism understated exposure conditions
What is z value?
Temperature change that results in a ten-fold change of the D value
What is F0 value?
The number of equivalent minutes of steam sterilization at a temperature of 121.1°C delivered to a container or unit of product, calculated using a z value of 10K
What is Endotoxin ?
: Lipopolysaccharide contained within the outer membrane of Gram-negative bacteria that may lead to pyrogenic reactions and other biological activities in humans
What is Overkill sterilization ?
A sterilization process providing a sterility assurance level (SAL) of less than 10-6 , regardless of the bioburden count in the product being sterilized or the resistance of objective microorganisms to the sterilization. The process generally provides at least a 12-log reduction of indicator microorganism having a minimum D value of 1.0 minute
What is Sterile?
Free from viable microorganisms
What s Sterility assurance level (SAL) ?
Probability of viable microorganisms being present on a product unit after exposure to the proper sterilization process, normally expressed as 10-n
What is Sterilization?
A process that destroys or eliminates all viable microbes to render a product free from viable microorganisms
What is Sterilization cycle?
A series of sterilization processes to be performed within a closed sterile chamber, consisting of dehumidification; conditioning; and the injection, product exposure, and removal of sterilizing agent
What is Sterilizing agent ?
A combination of physical and/or chemical substances capable of sterilizing a pharmaceutical product under specified conditions
What is Terminal sterilization ?
A process whereby a product is sterilized in its final container or packaging, which permits the measurement and evaluation of quantifiable microbial lethality. In principle, the SAL should be less than 10-6.
What is the Environmental monitoring program?
The planning, organization, and implementation of actions for all subjects to maintain the cleanliness of manufacturing areas and contact surfaces within these areas at a designated level. The intent of the program is to facilitate the manufacture of aseptic pharmaceutical products at a high-quality level by foreseeing the deterioration of the environment in manufacturing areas, preventing or eliminating potential risk factors affecting the quality of products, and implementing appropriate measures for cleanliness control
What is High efficiency particulate (HEPA) air filter ?
Filters with a minimum efficiency of 99.97% for 0.3 µm particle size, as determined by test
What is Loading pattern ?
Specified configurations on fixed chamber parts and the number, type, location, and orientation of products presented for sterilization within the sterilization chamber
What is Operating cycle ?
A complete combination of manufacturing processes run sequentially in the order determined by automatic control equipment
What is Process challenge device (PCD) ?
An item used to assess the performance of a sterilization process, as exemplified by the confirmation of heat penetration with steam, by placing a biological indicator (BI) or chemical indicator (CI) inside the item for which steam penetration is difficult to achieve
What is Standard operating procedures (SOPs) ?
Authorized written procedures providing instructions for performing operations not necessarily specific to a given product or material but of a more general nature (e.g. equipment operation, maintenance, and cleaning; validation; cleaning of premises and environmental control; and sampling and inspection)
What is Specifications ?
A list or statement of authorized particulars, specifying detailed requirements
What is Parametric release ?
Declaration that a product is sterile based on records, demonstrating that the process parameters are delivered within specified tolerances
What is Validation ?
A documented act of confirming that the structure and equipment of the factory; the procedure, process, and methods of manufacturing; and quality control do in fact lead to expected results
What is Design qualification (DQ) ?
Documented verification that the proposed designs of the facilities, equipment, or systems is suitable for the intended uses
What is Installation Qualification (IQ) ?
Documented verification that all premises, supporting utilities or equipment are correctly installed and operate in accordance with the manufacturer’s recommended specifications.
What is Operational Qualification (OQ) ?
Documented verification that installed or improved equipment, systems, or premises operate within predetermined limits when used in accordance with operational procedures
What is Performance qualification (PQ) ?
Documented verification that the premises, systems, or equipment operates consistently with each other and provides reproducible results within the defined specifications and parameters for prolonged periods of time
What is Quality System ?
A system identifying the organizational structure, responsibilities, procedures, processes, and resources for implementing quality management
What is Saturated steam ?
Water vapor in a state of equilibrium between condensation and evaporation.
What is Direct support area ?
A background or adjacent area directly supporting the critical area. The Air cleanliness level of the direct support area should be Grade B (when the critical area is controlled as Grade A) or Grade C
What is Indirect support area ?
An area where containers, raw materials, and products before sterilization are exposed to the environment and where materials and equipment for aseptic processing are cleaned