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Five Concerns for Aseptic Manufacturing Process Control

2022-06-06

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Marya

Sterile medicines generally refer to medicines without the presence of living microorganisms. Sterile, no pyrogen or bacterial endotoxin, no insoluble particles, high purity. Sterility quality assurance for sterile pharmaceutical products focuses on controlling the prevention of microbial, particulate and pyrogen contamination.

The EU GMP Sterility Appendix mentions that quality risk management should be fully implemented in the production of sterile drugs. The principle of aseptic production process is that the principle of aseptic control should be adhered to throughout the process, and should be carried out from the time the raw materials for production enter the production area. Do a good job of disinfection and pretreatment in the process of material transfer. From the new sterile appendix, we can see that supervision is paying more and more attention to the safety and stability of the use of sterile drugs. Preventing contamination in the production process is the key to achieve sterility and the  most important part of the pharmaceutical process.
                            
Sterile medicines generally refer to medicines without the presence of living microorganisms. Sterile, no pyrogen or bacterial endotoxin, no insoluble particles, high purity. Sterility quality assurance for sterile pharmaceutical products focuses on controlling the prevention of microbial, particulate and pyrogen contamination. It involves plant, equipment, process, and key operations to ensure the continuous and stable production of qualified drugs, minimize risks in the drug production process, and prevent contamination, cross-contamination, confusion and errors.
 

The following is the author's personal understanding of the aseptic production process, for the reference of colleagues, please criticize and correct the shortcomings:

Concern 1: Sterilization and Filtration Process

Regarding the sterilization filtration process, a common and unreasonable practice is that after the liquid medicine reaches the buffer tank of the filling machine after two-stage sterilization filtration, the breathing port of the high level tank of the liquid medicine is not equipped with a respirator or the respirator has not been tested for integrity. Lack of effective control.

Such a design may result in microorganisms contamination of the elevated tank. For the sterilization filtration process, it includes two aspects: the purpose and the result, that is, the purpose of a certain step of the filtration process is to sterilize, and according to the process requirements, the fluid after filtration, such as products, feed liquids, buffer solutions or microorganisms in the air , should be completely removed and blocked, the filtered feed liquid should be free of live microorganisms, then such filtration is sterilization filtration, and the filter used must also be a sterilization grade filter. The installation position of the filter, the relevant information of the filter, the method of the filter integrity test, the integrity test and record before and after filtration, the replacement, disinfection or sterilization of the filter, and the treatment after the filter is found to be faulty. to be concerned about.

For another example, a 0.22μm or 0.45μm filter is generally used before final sterilization in the production of large infusions. Although its purpose is to sterilize, it does not require the filtered material to be completely sterile, but only requires that after filtration, the microbial load of the feed liquid is less than a certain value, such as 10cfu/100ml, and there is no heat-resistant bacteria, so this step of filtration is not sterilization filtration, but "bioburden reduction filtration" to be precise.


Concern 2: Production equipment management

►Whether the compressed air quality and the purity of the inert gas in direct contact with the drug during production have been confirmed, and whether it meets the requirements of aseptic production;

►Whether the management of sterilizer and freeze-drying equipment (dry heat, moist heat) is in place, whether the temperature probe or controller is calibrated, and whether the temperature probe is damaged and repaired in time;

►Whether the freeze-drying equipment has an automatic recording device;

►Whether the automatic records of (dry heat, moist heat) sterilizers and freeze-drying equipment are archived;

►Using a linkage production line, or a single machine for potting...

►Inadequate management of production-related equipment may introduce pollution risks.


Concern 3: The cleaning and disinfection of post-production equipment

►After each batch of production is finished and cleaned, the cleaning effect of this time should be confirmed;

►The longest production time of key processes in aseptic production (cleaning time after the end of production, longest storage time after equipment cleaning to production) should be verified and used to guide production;

►Cleaning, disinfection or sterilization of key operating areas and production equipment, the SOP for cleaning and disinfection should be detailed, specific and operable; for CIP cleaning, the operating parameters should be specific, the cleaning parameters should be verified. The characteristics of the product are used to design cleaning parameters, and the cleaning process usually contains multiple steps;

►Each step in the process has a function and a set of parameters that are controlled within defined limits to ensure the effective removal of dirt (and cleaning agents). The details of the cleaning process may vary from species to species and from process to process. Key parameters should be able to be fixed, such as time, temperature, pressure, flow rate, etc.


Focus 4: The water system

There are common defects in domestic enterprises, and the design of the water system is unreasonable. I have seen the pipes in the mezzanine are inverted "几". It does not meet the requirements of gravity full emptying. Once the system is out of operation, there will be stagnant water, so the risk of microbial contamination will be great.

Some water points are connected to the pipeline after the valve, and some equipment water points are added with a pneumatic valve controlled by the equipment after the original water point. In the same situation, the tank level gauge is installed at the bottom of the tank. When emptying, the water at the level gauge cannot be emptied.

In this way, the "3D" requirements we require will not be met. This is conducive to the growth and reproduction of microorganisms. In addition, the installation position of the temperature detection point of the water for injection circulation system is unreasonable, and it cannot reflect whether the system really maintains a circulation above 70 °C, and the bacterial endotoxin at the key use points of the water for injection is not monitored.


Focus 5: Aseptic Production Process Management

►Appropriate technical or management measures should be adopted in the production process to avoid contamination and cross-contamination;

►The production operations of different products in the clean area should be strictly distinguished, and all materials, main production equipment and rooms used should have status signs;

►The total number of people entering the clean area should be controlled, and the sanitary conditions of personnel and clean work clothes should be monitored;

►Materials and tools entering the clean area must undergo corresponding purification treatment, including surface disinfection, ultraviolet lamp irradiation, and vaporized hydrogen peroxide (VHP) transfer. The treatment method should be verified and should meet the requirements for use in the clean area;

►The tools and utensils that have been cleaned and sterilized should have a valid period of use; the cleaning tools of non-terminally sterilized products should be processed or sterile before being introduced into the aseptic operation area, and should be sent out in time after use;

►Disinfectants used in aseptic production areas should be sterile filtered or reach aseptic state by other means, and the validity period should be specified, and the cleaning agents and disinfectants used should not affect the quality of products;

►The product to be sterilized and the sterilized product should be clearly distinguished, and there should be measures to prevent confusion.


Finally, the batch production records should be timely, true and complete, and should be able to reflect the key process parameters of the production process control and the main production operation process, so that the production process of the product can be traced;

The original sterilization record or curve should be attached to the batch record;

The production process should meet the approved production process requirements, and organize production in strict accordance with the approved process parameters.