English
Spanish
French
German
Arabic
Hindi
Korean
Russian
Dutch
Part 1 Introduction
Sterile drugs can be divided into terminally sterilized products and non-terminal sterilized products according to different production processes. The latter needs to be produced using aseptic production processes because the semi-finished products cannot use any form of terminal sterilization process to remove microorganisms.
The routine non-terminal sterilized small-capacity injection subpackage workshop process is as follows: Raw and auxiliary materials are respectively processed through thickening, filtering, diluting, sterilizing and filtering, etc., waiting for subpackaging; packaging materials (vials or ampoules) that pass the inspection are managed into bottles , bottle washing, and bottle drying (sterilization) to the filling room, and the filling operation is carried out under A-level laminar flow protection; The A-level laminar flow enters and exits the freeze dryer to ensure product quality. After freeze-drying, it is fully plugged and capped. After the capping process is completed, the entire packaging process is completed. For small-volume water injection products, there is no need to freeze-dry after filling, and the capping or sealing operation is directly performed to complete the entire packaging process.
The filling process is the core process of the sub-packaging workshop. At present, the washing, drying and filling lines are mostly used for washing bottles. After being sterilized in a tunnel oven, they are automatically filled under A-level laminar flow. The entire production and transmission process is in a closed environment. To reduce pollution and ensure product quality. The subpackaging workshop is one of the important production workshops of many pharmaceutical companies. Scientific and reasonable workshop design is the basic premise to avoid production quality risks and an important guarantee for the production of qualified products.
Part 2 Relevant Requirements Of The 2010 Version Of GMP For The Production Environment Of Non-Terminal Sterilized Products
The 2010 version of GMP requires the cleanliness level of the production environment for non-terminal sterilized products as follows:
(1) Level A in the context of level B: the operation and transshipment of products in an incompletely sealed state, such as product filling (or potting), sub-packaging, plugging, capping, etc.; sterilization and filtration cannot be performed before filling Preparation of liquid medicine or product; assembly of packaging materials directly in contact with medicine, assembly of equipment after sterilization, transportation and storage in an incompletely sealed state; crushing, screening, mixing, and subpackaging of sterile raw materials.
(2) Grade B: Transshipment of products in an incompletely sealed state in fully sealed containers; packaging materials and appliances that directly contact drugs are transshipped and stored in airtight containers after sterilization.
(3) Grade C: Preparation of medicinal liquid or product that can be sterilized and filtered before filling; product filtration.
(4) Class D: final cleaning, assembly or packaging, and sterilization of packaging materials and appliances that directly contact pharmaceuticals.
In the non-terminal sterilization production process, liquid products that can be sterilized and filtered are usually sterile filtered to remove microorganisms, and packaging materials, etc. are sterilized and then filled, sealed or semi-stopped respectively. For non-terminal sterilized products, since the products will not be further sterilized after packaging, the entire production process and operating environment conditions must be strictly controlled to ensure that the products are not contaminated by microorganisms.
Part 3 Key Points Of Process Layout Design For Non-Terminal Sterilized Product Subpackaging Workshop
3.1 Design Of The Core Area Of Aseptic Production
The core area of the non-terminal sterilized small-capacity injection subpackaging workshop mainly includes: product filling area, area where the product or container is exposed in the sterile area, delivery of the container after sterilization, assembly area, etc., the design of the core area The following aspects should be noted:
3.1.1 Control Of Pollution Sources
The pollution sources in the production core area of the packaging workshop mainly come from process equipment, instruments entering the sterile area, personnel and their operating processes, etc. The main types of pollution sources are divided into dust particle pollution and microbial pollution. Personnel, as one of the largest sources of pollution, need to enter the sterile environment after wearing sterile clothing and air locks; the core area should be set up separately to separate the entry and exit passages for personnel; factors such as personnel production, cleaning methods, and daily maintenance should be fully considered , carry out appropriate space design, and also consider the protection of operators and the environment; set up access control systems and other measures to restrict the entry and exit of personnel in non-filling areas, and ensure the control of pollution risks in core production areas in terms of hardware.
3.1.2 Control Of Airflow Direction And Pressure Difference
The 2010 version of GMP requires that the air cleanliness level of the core area of aseptic production be grade A, the background level be grade B, and the air velocity of the one-way flow of grade A must be within the range of 0.36-0.54 m/s. A good airflow direction helps to meet the temperature, humidity and cleanliness requirements of the environment, ensuring effective purification capabilities. Due to the large amount of air supply and return air in the filling area, sufficient return air area should be left in the design, and the locations of air supply and return air outlets should be arranged reasonably. Appropriate pressure gradients should be maintained between different functional rooms of the same cleanliness level in the clean area, and pressure differential control should be performed on adjacent clean rooms to ensure reasonable air flow organization and a sterile production environment.
3.2 Design Of The Capping Operation Area
The traditional capping operation usually produces aluminum scrap and some inactive metal particles, which may cause the risk of polluting the product and the environment. The design of the capping area should ensure that the capping process will not pollute the environment and products. First, through improving the process The equipment reduces risks, and the second is to optimize the design of the capping area.
The 2010 version of GMP stipulates that capping should be carried out in a level A environment under the background of level B; according to factors such as the tightness of the corked product, the design of capping equipment, and the characteristics of aluminum caps, the capping operation can be selected in level C Or in a grade A air supply environment under a grade D background.
According to the requirements, capping should use aseptic aluminum caps as an aseptic process, that is, the capping operation should be carried out in a B+A environment to ensure the sterility of the air before capping; or it should be carried out outside the sterile area as a clean process, and At the same time, it ensures that the vials are under A-level air protection from filling to capping to reduce the risk of pollution.
In addition, the following points should be paid attention to: the capping operation area should be separated from the filling operation area, and a separate capping operation room should be set up; the capping operation area should be provided with independent personnel access channels; Independent exhaust device, relatively negative pressure, to ensure that the capping operation will not have adverse effects on other areas of the clean area.
3.3 Adoption Of Closed Operating System
Since manual operation will cause many risks and uncertainties, it has become a development trend to use washing, filling and sealing equipment, restricted access isolation system and isolation operator to realize closed and automated production. The 2010 version of GMP proposes that operations with high contamination risks should be completed in isolated operators. With the help of the isolation barrier system, the operator and the product are separated, on the one hand, the sterility guarantee of the product production process is improved, and on the other hand, the protection of the operator is realized.
The transfer of freeze-dried semi-finished products should consider adopting an automatic loading and unloading system. The system is usually divided into three types: fixed, mobile and mixed. The use of this system can fully realize the automatic operation of the core area and reduce the A-level area. The intervention of the operator reduces the probability of drug contamination and better guarantees the sterility requirements.
3.4 Design In Other Aspects
As a high-risk area and a production area with high energy consumption, the sub-packaging area should minimize the B-level and A-level areas on the premise of meeting the requirements of production operations and daily maintenance; the liquid distribution tank should be as close as possible to the filling equipment so that the The pipeline is the shortest; reasonably set the changing path for personnel to meet the requirements of the specification, and should not be too complicated; rationally design the logistics channel to prevent product/material crossover; set up waste outlets separately to prevent clean material and waste gas material from crossing.
Part 4 Comparative Application Analysis Of The Layout Mode Of Subpackaging Workshops For Non-Terminal Sterilized Products
4.1 U-shaped Layout
The subpackaging workshop for freeze-dried powder injection products is mainly composed of four production units: washing and drying, filling, freeze-drying, and capping. The cleanliness level of each production unit is different, and each production area is relatively independent. It is arranged in a U shape, centered on filling and freeze-drying, and the filling and freeze-drying room is arranged on the side of the material gallery of the workshop, which is convenient for large equipment installation and viewing. Filling freeze-drying room, extinguishing room and other areas are set in the center of the workshop, which meets the requirements of GMP for the location of clean partitions.
The U-shaped layout of the freeze-drying workshop is becoming more and more common. The advantages of this layout are:
(1) The washing, drying and filling equipment are arranged in an L shape. First, the area of the clean area is relatively reduced. Second, it is convenient for equipment maintenance. It is not necessary to enter the high-level clean area during equipment maintenance, which effectively reduces the risk of pollution;
(2) It can better meet the needs of personnel to visit advanced and automated production equipment;
(3) It is suitable for modular design. One module is an independent freeze-drying workshop, which is suitable for the production of multiple varieties of products. Multiple production modules can be copied in one factory building according to capacity requirements;
(4) The main flow and the main logistics corridor are set separately, the main flow enters and exits from the south side, and the main logistics enters and exits from the north side to avoid the intersection of people and things.
4.2 I-Shaped Layout Mode
4.2.1 I-Shaped Layout Of Freeze-Dried Powder Injection Workshop
The I-shaped layout of the freeze-drying workshop is shown in Figure 2. This layout mode elongates the entire production line and increases the use area of the clean area to a certain extent; the logistics flow is divided into north and south sides, and the flow of personnel is mainly from the west. Side entry and exit, crossing of people and logistics can be avoided; the whole module is irregular in shape, which wastes production area and is not conducive to the duplication of multiple modules on the same floor.
4.2.2 I-Shape Layout Of Water Injection Workshop
In contrast, the small-capacity water needle injection dispensing workshop is more suitable for this layout. The I-shaped model has a compact layout, saves space, minimizes the area of the clean area, and saves workshop operating costs; personnel entrances are concentrated on the north side, and materials The corridor is set on the west side, the inner packaging material enters from the northwest side, and the products exit from the southwest side. There is no intersection between people and things as a whole; the linkage equipment for washing, drying and filling is linear, and the room is close to the corridor, which is convenient for visiting; this layout is suitable for the same floor. Arrange 2 independent production modules.
Part 5 Conclusion
Non-terminal sterilized products have high requirements on the aseptic production process and the level of sterility assurance of environmental control. Subpackaging is a high-risk operation. The design of the subpackaging workshop should be strictly in accordance with the requirements of the specifications to minimize the risk of product contamination. Based on the previous project design experience and the 2010 version of GMP requirements, this article expresses some views on the design of non-terminal sterilized product subpackaging workshops, and discusses them with you.