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The process layout of the API production workshop is crucial to the normal production and product quality of the workshop. The article analyzes the characteristics, layout principles and factors affecting the layout of API workshops, and focuses on the dimensions, number of layers, layer height and material flow forms of API workshops that are widely used at present.
Part 1 Introduction
China is a major producer of APIs, with a total output of one million tons. With the increasing pressure of production costs and environmental protection costs in Europe and the United States, as well as the improvement of the process technology, production quality and pharmaceutical market registration and certification capabilities of Chinese raw material drug manufacturers, a large number of raw material drug companies have accelerated their transfer to China. The production of Chinese raw material drug industry The scale keeps increasing. In the API industry, the process layout of the API workshop is crucial to the normal production and quality of the workshop. Reasonable process layout can realize advanced process and equipment, and create a good environment for workshop production, operation, equipment installation and maintenance, safety, sanitation, and environmental protection.
Part 2 – Main Features Of API Workshop
(1) The reaction process is complicated, the operation procedures are various, and some reaction conditions are harsh. For example, there will be side reactions and intermediate products in the reaction process, and some reactions need to be carried out under high temperature and high pressure conditions.
(2) A large amount of flammable and explosive organic solvents, acids, alkalis, and toxic substances are used, and the workshop has high requirements for fire protection, explosion protection, and corrosion protection. Commonly used solvents in raw material drug workshops are methanol, toluene, ethanol, hydrochloric acid, and liquid caustic soda.
(3) The number and types of equipment are large, and the types and quantities of pipelines are large; the API workshop involves reaction kettles (glass-lined, stainless steel), storage tanks, solid-liquid separation (centrifuges, filters), drying (double cone vacuum drying, Spray drying), condenser (spiral plate, spiral winding, tube), vacuum pump (oil-free vertical, Roots vacuum pump), transfer pump and other equipment.
(4) It is necessary to fully consider the dangerous process and the process layout using special materials (such as the need for separate rooms, independent ventilation, etc.).
(5) Try to use the potential energy to consider the transportation of materials (high-level tank, solid feeding), so as to save energy and shorten the pipeline.
(5) The post of fine-baking package (refinement, drying, packaging) of raw material medicine should follow the requirements of GMP (production in clean area and explosion venting of fine-baking package, etc.).
Part 3 Layout Principles Of API Workshop
(1) The layout of the workshop is based on the premise of meeting the requirements of process production, based on the process flow, from the perspective of facilitating production operation and production management, rationally carry out functional area division and equipment layout design.
(2) The layout of the workshop should meet the requirements of safety, environmental protection and occupational hygiene. Specifically, in the first principle, it is necessary to conform to the layout of the process flow, echo vertically and horizontally, ensure the continuity of the horizontal and vertical directions, shorten the material transportation route as much as possible, and save energy; the same equipment or similar equipment, similar in nature and Closely connected equipment is relatively concentrated to facilitate centralized management and unified operation; the vertical layout of equipment must not only fully consider the passage of personnel operating desks, but also consider the operating space required for equipment maintenance and material transportation.
Part 4 Factors Affecting the Layout of API Workshops
The production of raw materials should be controlled according to GMP requirements from the time when the starting materials of raw materials are introduced into the process. The main factors affecting the layout of the API workshop include the selection and layout of process equipment, ventilation and exhaust systems, production process control systems, occupational health and safety, and piping systems.
(1) Selection And Layout Of Process Equipment.
The layout of the equipment should meet the continuity of the horizontal and vertical directions; make full use of the potential difference to make the materials flow automatically, avoid too much material going back and forth between the floors; arrange the equipment as neatly as possible, and leave enough space for operation and maintenance; it needs to meet GMP requirements, etc. In addition, some special requirements of raw material drug workshops must be met. The type selection of the reactor should be based on the characteristics of the material and the reaction characteristics, etc., to reduce the use of glass-lined general-purpose reactors; the heat exchanger for acidic materials should be made of alloy materials; integrated equipment for washing, separation, and drying should be used as much as possible; closed solid feeders should be used, involving Highly toxic, flammable and explosive materials in contact with water use a glove box with an isolator; a fully automatic packaging line is used. The layout plan of the workshop uses potential energy to consider the transportation of materials.
(2) Ventilation And Exhaust System.
The necessity of ventilation and exhaust system design for chemical raw material medicine workshop: the demand for safe production in the workshop; the need for fire and explosion protection in the workshop; the need for the working environment of workshop workers. Therefore, reasonable, safe and comprehensive ventilation and exhaust design must be carried out in the raw material drug synthesis workshop. According to the requirements of the specification, the Class A workshop must be fully exhausted.
At present, the widely used ventilation and exhaust system adopts the comprehensive supply of comfortable air and comprehensive exhaust: adopting this method can effectively adjust the temperature of the workshop, and the environment of the entire workshop is comfortable, easy to operate and easy to manage. However, the machine is larger and requires a larger floor space. In addition, there are many devices, high energy consumption and high cost.
Considering that some equipment or rooms may have a high gas concentration, local exhaust ventilation is required to meet the safety, environmental protection, and occupational health requirements of the workshop.
(3) Production Process Control System.
The production of raw materials is a relatively complicated process, and the requirements for equipment are increasing day by day. Existing production equipment often has some defects, and it is necessary to carry out automatic control design in the process design of the workshop to better achieve the level of workshop automation. In addition, because there may be dangerous process behaviors in the drug synthesis workshop, it is necessary to control the parameters and reaction substances in the process of process synthesis reaction. For example, in terms of temperature control in the reaction workshop, there are many designs related to temperature, temperature design units, etc. This can better meet intermittent temperature control and some constant temperature reaction requirements. Only by effectively controlling the internal units can it be connected with the temperature measuring instruments inside the reaction workshop to accurately and directly handle the abnormal temperature inside the reaction workshop. The raw material drug workshop should have a high degree of automatic control capability. The main parameters involved in the process include temperature, pressure, liquid level, flow rate, oxygen content, pH value, combustible gas, toxic gas, and equipment operating status. Perform online modification of display, record, adjustment, accumulation, control, interlock, alarm, printing, and setting parameters; shutdown operations can be performed on on-site operating rotating equipment. There are automatic adjustments for important process parameters, mainly single-parameter adjustments, and over-limit alarms or interlocks are used for process parameters that may cause danger to ensure safe production.
(4) Pipeline layout. The pipeline layout of the raw material drug workshop should first meet the requirements of the production process and meet the production requirements; it is easy to operate and manage, and can ensure installation and production; it is easy to install, overhaul and operate and manage; it is required to be neat and beautiful, and save materials and investment as much as possible. The distance between the overhead pipeline and the ground should be convenient for operation and inspection in addition to meeting the technological requirements. The layout of pipelines should take into account the layout of non-process pipelines such as cables, lighting, instruments, heating and ventilation.
Part 5 API Workshop Layout
The shape of raw material drug workshops is mostly rectangular. Considering the pressure relief of the workshop explosion hazard, the aspect ratio is mostly between 3 and 4, and the workshop length should not be too long. Subsidence creates cracks. Reactors are usually arranged on the north and south sides of the API workshop, with an aisle in the middle, and three spans are set up in the north and south directions, with spans of 7.0m, 4.0m, and 7.0m respectively. If the volume of the reactor is small, the span can be appropriately reduced.
In order to save land resources and save energy, reduce the level transfer of materials in the workshop, and increase the utilization rate of the workshop, the number of floors in the raw material drug workshop is currently set to 4 floors. If the reactor solvent in the workshop is small, the setting can be 5~ Level 6. Raw material drug workshop The floor height of the raw material drug workshop needs to be determined according to the height of the equipment used in the workshop. When the bottom discharge centrifuge is used and the volume of the crystallization kettle is large, the layer height can be set at 6.0-6.5m. 2. The height of the third layer can be 5.5-6m to ensure that the materials in the upper layer of reactor flow to the next layer of reactor; Control the total building height of the workshop within 24m.
According to the flow mode of materials, the layout of API workshop can be divided into vertical flow and flat flow; according to the number of floors in the workshop, it can be divided into multi-layer and single-layer. At present, it is widely used, the layout is relatively reasonable, and the layout with a high degree of space utilization is multi-layer vertical flow. The feeding layer is arranged on the uppermost layer. The solid material with a large amount of feeding is carried out by a large bag feeder and the crane is used for feeding, and the solid material with a small amount of feeding is carried out by a small bag feeder. The use of interlayer feeding can effectively prevent dust from spilling and avoiding the harm caused by dust to operators. The main reaction area is arranged in the middle layer, including the reactor, condenser, high-level tank, supporting air bag (public works), etc., and part of the centrifugal section. Reactors with dangerous processes or special materials that need to be isolated from other reaction areas (separate compartments) should be arranged in the corner of the workshop as much as possible. The lowest layer is equipped with equipment such as centrifugation, drying and receiving storage tanks.
Part 6 Conclusion
In the process design of the raw material drug workshop, it is necessary to combine the process characteristics, and under the premise of meeting the safety, environmental protection and other relevant specifications, flexibly design from the aspects of production airtightness, ventilation and exhaust systems, and automatic control to minimize chemical odors , to avoid adverse effects on operators and the environment, and truly achieve clean production of API production.