Wenzhou Haoxing Machinery Equipment Manufacturing Co., Ltd. Yang Jianying Zip code 325025

【Abstract】Objective: To explore the innovative design concept of high-speed intelligent pipeline low-temperature colloid mill. Scientific and reasonable computerized operation and low-temperature control cooling system verification method to ensure the GMP compliance of various intelligent equipment and information systems. The colloid mill manufacturing industry provides industrial automation and information technology with an effective compliance approach. Methods: Through the interpretation of the innovative design features of the new low-temperature colloid mill and the interpretation of the requirements of computerized systems in GMP regulations and guidelines at home and abroad, combined with the common defects of colloid mill in data integrity and computer system, Basic requirements and ideas for computerized system verification. RESULTS AND CONCLUSION: In combination with the current domestic low-temperature colloid mill system, the cold source forms a closed-circuit circulation system, which makes the energy fully utilized and the application status and regulatory requirements of the computerized system of the industry, as long as the basic computer can be used reasonably. The system verification method can meet the compliance requirements.

[Keywords] high-speed pipeline design; low-temperature colloid mill system verification; computerized system; GMP compliance; fineness

0 Preface 

At present, most of China's colloid mills are small and medium-sized enterprises, with less than a dozen companies. Even in comparison with other domestic machinery industries, there is a big gap in equipment and technology. Before 2000, in major projects such as large-scale pharmaceutical, food, petrochemical, catalyst and synthetic fat pipelines, the supporting colloid mills mainly relied on imports. Only Iridium Technology can independently research and develop high-end products. Therefore, the research and development of the fluid containing particles in the ultra-micro or nano-scale shear dispersion grinding grinding is the inevitability of the localization of imported equipment. The level of industrial automation and informatization in China's pharmaceutical industry is still relatively weak compared to other fields, and the particularity of the pharmaceutical industry is one of the important factors. The pharmaceutical industry produces medicines, and medicines as a special commodity in the entire life cycle of the drug, from research and development, clinical, production, distribution, management, etc., must comply with the corresponding quality management practices (known as GxP), strict Regulatory regulation has made it difficult to effectively promote some new, innovative technology in the pharmaceutical industry.

With the introduction of the “Made in China 2025” strategic plan issued by the Chinese government in 2015, the transformation and upgrading of the manufacturing industry toward the intelligent direction, that is, intelligent manufacturing will be the main direction of in-depth integration of informationization and industrialization [1]. Therefore, in recent years, intelligent equipment and analytical instruments, automation and information systems have developed rapidly in the pharmaceutical industry, and the related computerized systems have become increasingly prominent in terms of regulatory compliance. Although the State Food and Drug Administration has issued an announcement after 2015, the implementation of the GMP appendix "Computerized System" [2] since December 1, 2015 provides a reliable regulatory basis and the pharmaceutical manufacturing enterprise is in a computerized system. There is also a great need for application and verification. However, compared with developed countries in Europe and America, China's relevant laws and regulations are still not perfect, and they are implemented at the specific implementation level. There are still inconsistencies in the understanding of regulations and unclear verification methods. Therefore, it is necessary to combine the current new domestic and international regulatory requirements and development trends, and propose a scientific and reasonable computerized system verification method to ensure that the domestic pharmaceutical industry is widely used in the national economy and people's livelihood under the premise of compliance. field. Due to the need to adapt to the requirements of various working conditions, there is a broad prospect for the rapid development of high-speed intelligent low-temperature colloid mill manufacturing.

1 Compliance requirements for computerized systems

At present, the current domestic regulations applicable to computerized systems are the 2010 edition of the GMP appendix "Computerized Systems". The first article clearly defines the scope and definition: "This appendix applies to computerized systems used in the quality management of pharmaceutical production. A computerized system consists of a series of hardware and software to meet specific functions [2]. At the same time, it also stipulates the verification of computerized systems, software classification, authority management, change management, and data integrity.

In particular, as more and more data fraud problems have been discovered in global drug surveillance inspections in recent years, data integrity has become an important issue in the pharmaceutical industry. Since 2015, national drug regulatory agencies and international The organization has introduced regulations and guidelines related to data integrity. For computerized systems, data integrity is reflected in electronic data, which is easier to find than paper records. With the application of various computerized systems in the pharmaceutical industry, electronic data problems are concentrated. China has also released the "Drug Data Management Specification (Draft for Comment)" on January 5, 2018, which clearly stipulates that data management is part of the drug quality management system and should run through the entire data life cycle [3]. The specification also sets very specific and explicit requirements for electronic data and computerized systems.

Compared with domestic, the application of foreign computerized systems in the pharmaceutical industry started earlier. In addition to regulatory requirements, there are many related guidance documents, which are very specific in automation system verification, software verification, and data integrity. The definition and guidance of China's pharmaceutical industry can be combined with domestic regulatory requirements to develop a reasonable computerized system verification method to meet regulatory requirements.

2 computerized system verification method

The general computerized system verification method mainly refers to the fifth edition of GAMP published by the International Pharmaceutical Engineering Association (ISPE). GAMP is the “Good Automation Manufactory Practice” [4], which is also internationally recognized. A general guide to computerized system validation.

The laboratory-related computerized system verification can refer to the Validation of Computerised Systems "Guidelines for the Validation of Computerized Systems" revised by the European Medicines Quality Administration (EDQM) in August 2018. It mainly includes the Excel calculation worksheet verification commonly used in laboratories. And verification methods for complex systems such as the Laboratory Information Management System (LIMS) [5]. Software verification can be found in the US Food and Drug Administration (FDA) General Principles of Software Validation; Final Guidance for Industry and FDA Staff General Software Validation Guide [6].

3 low temperature colloid mill system verification

The innovative design of high-speed intelligent pipeline colloid mill developed by Iridium Technology has many aspects of innovation, and the user can configure the computer S/D automatic remote control by himself. According to the requirements, the cold source such as the coolant can be set to be in contact with the grinding medium, only as an indirect. Cooling medium, achieving ultra-low temperature pulverization, material explosion-proof, anti-oxidation, non-polluting materials comply with GMP standards and other comprehensive effects, while the pulverized materials remain in their original state. The whole colloid mill grinding system and the filter, compensation device, transmission device, intelligent temperature control and other mechanical components are the new intelligent colloid mill unit, which can be mechanized under closed conditions by simply connecting the feed and discharge or return pipelines online. The degree of automation is high, and the high-speed pipeline colloid mill is a new type of dispersing, homogenizing, mixing, high-shear ultra-fine grinding and so on. Widely used in titanium dioxide, white carbon black, silicone oil, carbon black, chemical additives: defoamers, foaming agents, catalysts, matting agents, adhesives, pigments, flame retardant materials, coating pastes, emulsified oil, asphalt, coal Pulp, graphene, nanomaterials and other food, chemical, pharmaceutical, daily chemical, biological engineering, water treatment, minerals, new energy and other industries.

The low-temperature colloid mill is the fourth-generation new colloid mill. The system uses the refrigeration source as the indirect medium and has no contact with the medium. The pulverized material passes through the cooling state at low temperature and enters the mechanical grinder chamber through the colloid grinding wheel (stator). And the rotor) relatively high-speed rotation, material and blade, toothed disc, material and material reciprocal impact, collision, shearing, mixing, mixing, emulsification, homogenization, grinding, friction and other comprehensive effects, to achieve ultra-fine particles The ideal effect.

The ingenious structural design of the low-temperature colloid mill avoids contamination of materials and temperature rise during grinding and pulverization. Since the rotation speed of the grinding wheel is relatively low, the heat generated by the friction is greatly reduced; the coolant takes the heat away from the cooling chamber and the material is taken out by the crushing chamber. Therefore, at normal temperature, the medium temperature will decrease with the treatment time, and the adjustment range of the low temperature colloid mill and the refrigeration device can be set at 0-25 ° C, 25-45 ° C and other grades. It can meet the needs of most users. For special users with high requirements for low temperature, this series can load the water cooling system processing capacity without increasing the occupied area to achieve better low temperature effect.

In the process of material pulverization, the low-temperature colloid mill system forms a closed-circuit circulation system, which makes full use of energy and saves energy: during grinding and pulverization, the treated materials (solid-liquid mixture) are maintained for a long time under the regulation of cold source temperature. Continuous operation at a low temperature of 0-25 degrees for 24 hours. According to the characteristic temperature of the material, the temperature can be adjusted during the grinding and pulverizing process of the low temperature colloid mill. The pulverization temperature is selected, the energy consumption is reduced, and the pulverization fineness can reach 10- 700 mesh, even reaching the micron μ and other fineness, different from the low temperature pulverizer using liquid nitrogen cold source to the medium for direct freezing, the advantage of this equipment: the use of cooling liquid and other cold sources are not in contact with the grinding medium, only as an indirect cooling medium , to achieve ultra-low temperature pulverization, material explosion-proof, anti-oxidation and non-polluting materials and other comprehensive effects, while the pulverized materials remain in their original state.

3.1 Protection system with filter and multi-directional displacement compensation device makes the performance of the grinding pump more stable and safer.

3.2 High-speed pipeline low-temperature colloid mill assembly The sealing of the contact surface adopts O-type static seal, especially the improvement of the component of the discharge port connecting the sealing surface makes the mechanical seal of the machine bear the pressure and the sealing strength.

3.3 Selection of sanitary grade high quality materials SUS304, SUS316L, etc., to achieve localization of product materials, improve the service life of the main part of the product using stainless steel; stator and rotor and material contact parts are made of hard alloy material by special process, its hardness can be reached Brinell hardness of about HB600, with wear resistance, corrosion resistance, difficult to change, high precision.

3.4 The jacketed cooling water circulation system is adopted to reduce the temperature of the water-washed water-cooled combined mechanical sealing device (the 昊星科技-grade water-punching mechanical seal device-patent number CN201020608706.3, etc.), which overcomes the lack of liquid material or idling of the machine. The shortcomings of running friction and wear, high sealing precision, reduce the friction of the moving and static grinding body, form a flow field with stable flow pressure, improve the grinding uniformity of the dynamic and static grinding body, and make the powder dispersion fineness less than 2UM, which enhances the stability. And sealing, to achieve zero leakage, and only need to turn on the cooling water to the water-cooling mechanical seal when starting the machine, it has the cooling spindle operating temperature and prolongs the mechanical life.

4 automated software grading

Software hierarchical management is also a key link in computerized system verification, which needs to be determined in conjunction with the results of risk assessment. The software grading method is usually based on GAMP 5 and is divided into infrastructure software (category 1), non-configurable software (category 3), configurable software (category 4), and custom software (category 5) [4]. However, in some complex systems actually used by enterprises, such as SCADA (Data Acquisition and Monitoring Control System) or MES (Manufacturing Execution System), there is a possibility of combining COTS (commercial ready-made products) software and custom code.

Enterprises usually classify the entire system software. If it is classified as Category 3 or 4, it may cause some key functions that affect GxP to be unverified. If it is set to 5, it may greatly increase the complexity and difficulty of the verification work. It poses certain risks to patient safety and product quality. Therefore, it is necessary to ensure that appropriate personnel assistance is provided to perform a hierarchical evaluation of the various functional modules of a complex computerized system to ensure that key functions affecting GxP are verified.

4 high-speed pipeline innovative design

4.1 The inlet and outlet of the equipment are all connected by pipeline. The material is directly multi-automatic integrated continuous production by ultra-fine particle crushing, dispersing, emulsifying, depolymerizing, homogenizing, mixing, grinding and conveying. process.

4.2 The movable washer is arranged behind the adjustment disc and in front of the stator to replace the traditional plane and bearing sliding action, reduce the adjustment tolerance of the adjustment disc, and in the absence of lubricating oil, the adjustment of the adjustment disc is dexterous, the structure is simple, the precision is high, and the stability is good. .

4.3 Power transmission: The high-speed rotation of the machine will produce mechanical centrifugal force output pressure (head) can be used as the power of the pump, with the function of conveying materials at the same time, and save energy, high line speed 30-50r / S Running.

4.4 In-situ cleaning device, in the case of no need to open or disassemble the machine and pipe connection, the cleaning liquid is directly cleaned in place by the interface of the in-situ cleaning device, which is convenient, fast and flexible to ensure GMP.

4.5 In the pipeline operation, the stator and rotor that can be adjusted at any time adopt the design of the spacing between high-precision bevel gears. At the same time, the machine adopts the positioning plate positioning structure to make the spacing between the stator and the rotor adjust smoothly, easy to operate and fast. In place.

5 Low temperature colloid mill structure classification

5.1 Feeding port cover opening method: the cover can be semi-open, manhole and flange closed;

5.2 Low temperature colloid mill and high shear dispersing emulsifier (gap type) emulsifier make the material dispersion emulsified and mixed to make it sufficient;

5.3 Low temperature colloid mill and single or multiple cycles of material circulation piping through control valves

5.4 Low-temperature colloid mill and mixer stirrer combined with low-speed stirring and high-speed dispersion to make the material more evenly dispersed

5.5 Low-temperature colloid mill and tank caps from the tank body: divided into single layers or sandwiches (can be designed according to specific requirements and processes)

5.6 Low-temperature colloid mill and emulsifier homogenizer, pipeline grinder (grinding pump) and electronic control cabinet are equipped with automatic equipment.

6 Fineness curve at 5-25 °C

 

7 low temperature colloid mill technical parameters

Model Processing capacity m3/h Motor power kw to r/min Import and export mm Temperature range °C

JM-FBF80-2Z 0.1-0.5 3/4 2950 32/25 5-15

JM-FBF100-2Z 1-2 5.5 2950 50/25 5-15

JM-FBF120-2Z 1-3 5.5/7.5 2900 50/25 5-15

JM-FBF140A-2Z 1-4 7.5 2900 65/32 5-20

JM-FBF140B-2Z 2-5 11/15 2900 65/32 5-20

JM-FBF180A-2Z 2-6 7.5 2900 80/40 5-25

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