This guidance document describes the current basic concepts on sterility assurance and procedures for manufacturing and controlling sterile pharmaceutical products in order to advise manufacturers of sterile pharmaceutical products and regulatory personnel responsible for pharmaceutical inspections on sterility assurance.
This guidance is intended to be applied in the aseptic processing of parenteral drugs; however, its basic concepts may also be useful when manufacturing ophthalmic solutions and other sterile pharmaceutical products. The concepts and descriptions contained in this guidance may be superseded by other processes or procedures of manufacture that are justifiably comparable or more stringent (except for the Ministerial Ordinance, “Regulations for Manufacturing Control and Quality Control of Medicinal Products and Quasi-Medicinal Products” [“GMP regulations,” Ordinance No. 179, 2004], and other regulatory requirements, notifications, and issues), as long as the quality of pharmaceutical products can be ensured.
3. Quality System
The quality system for aseptic manufacturing of sterile pharmaceutical products is structured to satisfy the requirements for the establishment, documentation, implementation, and maintenance of an efficient and adequate quality control system in compliance with Sections 1 (General Rules) and 3 (Manufacturing Control and Quality Control of Sterile Pharmaceutical Products) of Chapter 2 of the current GMP regulations.
3.1 General Requirements
1. General
The written quality system should comprise an organizational structure and description of Guidance on the Manufacture of Sterile Pharmaceutical Products by Aseptic Processing operational procedures, manufacturing processes, resources used, and activities necessary to ensure compliance with the requirements for aseptic processing of sterile pharmaceutical products stipulated in this guidance document. All quality control-related activities to be undertaken, including sterility assurance-related activities, should be identified and documented in detail. Manufacturers of pharmaceutical products under aseptic conditions are also required to establish and implement an adequate quality system by setting up quality control standards suitable for the prevention of microbial product contamination during processing. This quality system should include an investigation system for identifying deficiencies in sterilization procedures and assessing abnormalities or deviations in control parameters from the standards, as well as a verification system for ensuring the acceptability of corrective and preventive measures taken and whether or not the outcome of these measures was achieved.
2. Scope of application
This guidance is applicable to the quality system governing all processes in sterile pharmaceutical product manufacturing at facilities where pharmaceutical products are manufactured under aseptic conditions. In practice, the scope of application includes environmental control, control of laboratory testing of sterile pharmaceutical products, quality control of aseptic processing, validation, and systematized control of manufacturing processes and product quality such as documentation and change control.
3. Document control
The following documents should be prepared, used for fulfilling requirements stipulated in each provision of this document, and archived to ensure the sterility of sterilized pharmaceutical products: documents on initial, periodic and change validation; standard operating procedures (SOPs); area maps with cleanliness levels; movement diagrams of raw materials, personnel, intermediate products, and finished products; equipment and instrument layout charts; instructions; records of data; deviation control records; change control records; out-of-specification (OOS) test results; calibration records; environmental monitoring records; log books; and computer system data (e.g. records stored on electronic media).
4. Risk management
The concept and procedures for risk management should be included in the quality system, and contamination preventive measures should be implemented to minimize risks of contaminating pharmaceutical products with microorganisms, endotoxins, and foreign matters. The risk management system should be based on risk assessment procedures for analyzing and evaluating factors affecting product sterility and contamination with endotoxins and foreign matters as well as based on verification of risk control procedures for demonstrating the Guidance on the Manufacture of Sterile Pharmaceutical Products by Aseptic Processing reliability and validity of risk avoidance procedures.
5. Qualification of aseptic processing environment
Environmental parameters of the aseptic processing area should be identified and verified for qualification. Based on qualification assessment results, a program for HVAC system maintenance and environmental monitoring should be established and implemented.
6. Qualification of aseptic processing equipment and facilities
Equipment and instruments used for the manufacture of sterile pharmaceutical products in the aseptic processing area as well as other equipment and facilities that may affect aseptic processing should be evaluated for qualification. Based on qualification assessment results, a program for maintaining the equipment and facilities should be established.
7. Prospective validation and periodic review of process control
Process validation that simulates all processes and activities related to sterilization of pharmaceutical products should be conducted. Such processes and activities are required to achieve commercial sterility of pharmaceutical products based on scientific evidence-based designs and operations. A process control program should also be established and validated.
8. Periodic revalidation
Periodic revalidation should include a process simulation program and periodic valuation of sterilization processes that may affect the sterility of pharmaceutical products.
9. Time limitation for aseptic manufacturing operations
Manufacturing processes of sterile pharmaceutical products from the preparation of drug solution to filtration and sterilization should be conducted as quickly as possible. The maximum allowable time from filtration, storage, and filling to sealing should be established by taking into account the product composition, manufacturing processes, and storage conditions as well as risks inherent to these processes.
10. Cleaning and disinfection of facilities and equipment
A program for cleaning and disinfecting facilities and equipment should be established taking into account the potential development of drug-resistant microorganisms. The program should contain procedures for screening and classifying bacterial isolates in each manufacturing environment.
11. Pest control
An appropriate pest control program should be directed to aseptic manufacturing facilities to prevent contamination of sterile pharmaceutical products with insects and other vermin.
12. Flow of raw materials
Flow diagrams of raw materials, parts, and other articles necessary for processing products Guidance on the Manufacture of Sterile Pharmaceutical Products by Aseptic Processing into the aseptic processing area should be established and, as the situation may require, appropriate disinfection and sterilization procedures should be implemented. Appropriate measures should be takento prevent microbial invasion into the working area during the transfer of raw materials and other materials.
13. Gowning and flow of personnel
Appropriate procedures should be practiced to prevent microbial invasion into the aseptic processing area during the entry or exit of personnel. Gowning procedures and flow of personnel should be standardized.
14. Change control
Changes in standard procedures should be confirmed to have no negative impact on the sterility of pharmaceutical products based on scientific evidence. Changes implemented should be evaluated by applicable qualification and validation procedures, and, wherever possible, control parameters should be established to control risks inherent to such changes based on risk assessment results.
15. Calibration
A calibration program including calibration frequency and accuracy requirements should be established and implemented to calibrate analytical equipment used in quality testing and measuring, inspection, and control devices used in the manufacturing process.
.JPG)
![Difference between Stability[Shelf life] Specification and Release Specification](https://4.bp.blogspot.com/-O3EpVMWcoKw/WxY6-6I4--I/AAAAAAAAB2s/KzC0FqUQtkMdw7VzT6oOR_8vbZO6EJc-ACK4BGAYYCw/w680/nth.png)
0 Comments