Starting from the requirements of GMP and pharmaceutical technology for the selection of equipment materials, we focus on the selection of commonly used stainless steel in pharmaceutical equipment, and explain it in combination. At the same time, the principle of selection of non-metallic materials is briefly described.
Although China's pharmaceutical equipment products have been developed for many years, its application has been quite mature, but the equipment management and procurement personnel of pharmaceutical companies are still in a fuzzy state of choice for pharmaceutical equipment materials, especially the choice of metal materials is more confusing. It is believed that the selection of 316L material is in line with GMP. This wrong concept has a certain precipitation in China and abroad. Although the author has written such articles, people have changed this, but some people in the industry are still indulging in this. This is a misinterpretation of GMP, which is also contrary to the GMP inclusion.
1. GMP requirements for pharmaceutical equipment materials (1) GMP (98 edition) 1 Article 32 states: “The surface of equipment directly in contact with pharmaceuticals should be smooth, flat, easy to clean or disinfect, corrosion-resistant, and not chemically altered with pharmaceuticals. Or adsorbing drugs.†Article 34 states: “...the materials used in tanks and pipelines shall be non-toxic and corrosion-resistant.... The vents of water tanks for injection shall be fitted with a hydrophobic sterilizing filter that does not shed fibers.â€
(2) GMP (Public Version 98) Appendix 2* Section 3 Article 7 states: “The clean room (area) should use sanitary tools that are free from falling off, easy to clean, and easy to disinfect...†Section 2 of the second section considers: "The equipment, containers, pipes, valves, pumps, etc. that come into contact with the liquid should be made of high-quality corrosion-resistant materials.... Filtering equipment must not absorb the liquid components and release foreign matter. It is forbidden to use asbestos-containing filter equipment."
Looking at paragraph 211.65(a) of cGMP3 in the United States, it believes that: "The surface of the equipment should not react when it comes into contact with components, intermediate materials or drugs. It does not absorb or adsorb, so as not to change the safety and identification characteristics of the drug. Content (or potency), quality or purity beyond the statutory or other established requirements."
It can be said that the relevant provisions of the GMP-related documents have not seen the mandatory provisions for the selection of pharmaceutical equipment. GMP has only specified the directional requirements for the selection of pharmaceutical equipment, and no specific regulations have been made. Although, in the domestic authoritative monograph of the "Guidelines for the Validation of Pharmaceutical Production" 4, some statements have been made on the selection of equipment and piping in some production processes. For example, the material for injection water is 316L, which is targeted, not The material that comes into direct contact with the material of the pharmaceutical equipment is described by 316L. Moreover, the preface of this book clearly states that “it is a guiding tool for verification work, and there is no legal verification requirement.†Note: GMP only provides directional regulations for the selection of pharmaceutical equipment.
2, pharmaceutical process materials requirements for pharmaceutical equipment People pay attention to pharmaceutical equipment materials should be "easy to clean or disinfect, corrosion-resistant, do not chemically change or adsorb drugs", do not forget another material selection principle, this is Effective control of insoluble particulates.
In the medicine, the particles are roughly dust particles, metal or other particles. The presence of the particles directly affects the quality of the medicine and endangers people's lives. A large number of clinical data indicate that if the drug is contaminated by 7-2 μm dust particles, especially intravenous drugs, it can cause pyrogen reaction, pulmonary arteritis, microthrombus or foreign body granuloma, which can cause serious death. Therefore, in 1985, the Chinese Pharmacopoeia first limited the insoluble particles of infusion. It is stipulated that no more than 50 particles greater than or equal to 10 μm per milliliter, and no more than five particles greater than or equal to 25 μm.
At the same time, it is also clearly stated in the literature 4 that the contamination of aseptic and insoluble particulates is the two main characteristics distinguishing sterile raw materials from non-sterile bulk drugs, and is also one of the important projects in the production process and control.
Control of contamination of insoluble particulates In the production of sterile raw materials, an indicator that is difficult to control, the insoluble particles of each sterile product must be within a certain range, that is, insoluble particles of more than 10 μm and less than 25 μm are controlled at 300 / Below g, the insoluble particles larger than 25 μm are controlled at 30/g or less 4 .
The listed sources of insoluble particulates have four aspects in the manufacturing process, namely utility systems, operating systems, process material systems, and equipment or appliance systems. The key to the control of insoluble particles in the equipment or appliance system is closely related to the material selection. When some materials are in high-speed contact on the surface of the material, a certain amount of metal particles are generated based on the low surface hardness of the material. For example, the surface hardness of the 316L stainless steel is relatively soft. High-speed motion and surface contact with relatively soft materials inevitably produce metal particles. In order to ensure the amount of insoluble particulate contamination, it is necessary to strictly control all relevant links, especially the selection of materials is particularly important.
3. Discussion on the selection of commonly used stainless steel materials in pharmaceutical equipment In the metal materials, austenitic stainless steel is a pharmaceutical equipment product using zui as a wide range of materials, common varieties are 316L (00Cr17Ni14Mo2), 316 (0Cr17Ni12Mo2), 304L (00Cr19Ni11) 304 (0Cr19Ni9) and 1Cr18Ni9Ti (commonly known as 18-8), their common feature is corrosion resistance and good heat resistance. The commonality of these austenitic stainless steels is corrosion resistance, and their "corrosion resistance" is relative, which refers to the characteristics of high chemical stability under certain external conditions and certain corrosive media. However, when such austenitic stainless steel is used in some media, it will cause intergranular corrosion, pitting corrosion and the like, especially in Cl-containing media, which is usually prone to corrosion, usually using ultra-low carbon or Low carbon solution (ie 316L or 304L). However, ultra-low carbon is not the fundamental way to address such corrosion and is related to other factors.
It is pointed out that the ultra-low carbon austenitic stainless steel is easy to produce three problems in pharmaceutical equipment: (1) even when the Cl- content in the medium exceeds a certain value, even ultra-low carbon austenitic stainless steel will corrode; (2) When the content of Cl- in the medium is small, the ultra-low carbon austenitic stainless steel will corrode due to improper processing and treatment; (3) The ultra-low carbon austenitic stainless steel has a comprehensive mechanical index due to the decrease of C content. It is also relatively low, especially the surface hardness is correspondingly low, and insoluble particles are easily generated during high speed and material operation.
Therefore, people should note that 316L is not stainless steel that is not corroded, nor is it made of metal particles. Don't think that 316L is GMP.
3.1. Corrosion of austenitic stainless steel and prevention of common corrosion of austenitic stainless steels are intergranular corrosion and pitting corrosion. The corrosion mechanism 5: one is intergranular corrosion. When the austenitic stainless steel is manufactured and welded, the sensitized temperature region at the heating temperature and the heating rate, the supersaturated carbon in the material first precipitates at the grain boundary and combines with the chromium to form chromium carbide. The diffusion rate in the body is higher than that in the chromium. The chromium is not enough to supplement the chromium lost by the formation of chromium carbide. The result is that the chromium content of the grain boundary decreases with the continuous precipitation of chromium carbide, forming a so-called chromium-depleted zone. The electrode potential is lowered. When contacted with a corrosive medium containing Cl-, it causes corrosion of the microbattery. Although the corrosion is only on the surface of the grain, it quickly penetrates into the interior to form intergranular corrosion; the second is pitting. When the material is in contact with a corrosive medium containing Cl-, the Cl- invades the passivation film at the defect of the material passivation film, such as inclusions, chromium-depleted regions, grain boundaries, weld heat affected regions or dislocations. The metal ions combine to form a strong acid salt to dissolve the passivation film, and Cl- causes the film to be devoid of destruction, forming a "passivation-activation" microbattery, causing pitting corrosion, and corrosive current causes perforation of the material.
Factors affecting the corrosion of austenitic stainless steel: (1) medium chloride ion.
The Cl- content should be controlled at a certain value (check the corresponding material corrosion manual for details), and the ultra-low carbon austenitic stainless steel should be used with caution when the Cl- content exceeds the value. In the national standard "Steel Pressure Vessel" (GB150-98), the chloride ion content of water in the water pressure test of stainless steel container shall not exceed 25ppm (1ppm is one millionth), so it can be seen that the water pressure test The requirements for chloride ions are so harsh 6 that it is not necessary to talk about pharmaceutical equipment products. (2) Factors affecting intergranular corrosion7. When the temperature is outside the sensitized zone, carbon atoms are unlikely to cause chromium depletion at the grain boundaries. Only when the temperature is heated in the sensitization zone, the temperature gradient will cause a chromium-depleted zone. In addition, it is also related to its carbon content. The more carbon content, the more the amount of diffusion, the more the amount of carbide formation, so that the intergranular corrosion tends to penetrate into the grain boundary to increase the depth, causing intergranular corrosion. (3) Factors affecting pitting 7. It has been proved in literature that if the amount of chromium is increased, pitting will not occur. However, the amount of chromium does not contribute to the intergranular resistance to chromium deficiency. Increasing the amount of molybdenum greatly improves the pitting resistance, which is related to the formation of a MoOCl2 protective film by Cl-, thereby preventing Cl- penetrating the passivation film.
Measures to prevent corrosion of austenitic stainless steel: (1) reduce the carbon content of stainless steel, low carbon stainless steel or ultra-low carbon stainless steel can avoid or reduce the precipitation of chromium carbides in the intergranular, thereby reducing or avoiding intergranular corrosion; (2) Solution treatment, in which all of the carbides are dissolved in the austenite under the action of high temperature, thereby eliminating the tendency of intergranular corrosion. Generally, when austenitic stainless steel is purchased, it can be selected by solution treatment; (3) like 316 type Mo-containing stainless steel can form a protective film to effectively prevent pitting; (4) When welding materials, automatic argon arc welding is preferred. If it is impossible to use manual argon arc welding, low current and rapid cooling, and water cooling, etc., reduce the heat affected zone. Thereby reducing or avoiding intergranular corrosion and pitting; (5) pickling passivation treatment. The material needs to be polished after welding, and the inner wall is pickled and passivated to make the inner surface of the material have a dense passivation film, which can delay or avoid the pitting phenomenon caused by Cl-penetration into the passivation film; (6) Structural design. Reduce welds or staggered welds. Use materials for high temperatures to reduce the thermal expansion structure, thereby reducing heat effects or areas of stress concentration, thereby reducing these two types of corrosion tendencies.
3.2. Discussion on Insoluble Particles of Austenitic Stainless Steel In the case of manufacturers and users of pharmaceutical equipment, people are eager to choose materials while avoiding a very important principle, that is, controlling insoluble particles. Selection of materials. Looking at pharmaceutical equipment products, some parts will be in direct contact with the drug at high speed to cause wear, and a small amount of metal particles generated by abrasion will be incorporated into the drug.
For example, the pulverization of the universal pulverizer mainly involves the impact pulverization and the shear squeezing movement of the particles and the collision target. For the pulverization of the small particles, the main function of the pulverization process in the universal pulverizer is the impact pulverization of the particles and the collision target. (The inner ring gear, the outer ring gear, the outer ring impact ring) and the shear extrusion pulverization, and the collision pulverization between the particles is not obvious. On the other hand, the material particles are strongly sheared at the gap formed by the moving ring gear and the fixed ring gear, and are also a major factor in material pulverization. The process produces a certain amount of wear, which is confirmed by the wear scar diagram of the ring gear tooth surface in Document 8. There are also experiments in which the particles from the side of the ring gear are squeezed and rubbed to form a deeper wear scar. It can be seen that the particles between the fixed and moving ring gears are severely pulverized by the shearing force. It is precisely because of the severe frictional shearing action between the particles and the target plate that the parts in direct contact with the material are seriously worn, thereby causing the phenomenon of insoluble impurities and metal particles in the pulverization process. In particular, the existing universal grinder and the direct contact parts of the materials are austenitic stainless steel (some are more than 316L), the surface hardness of the material is lower than other metals, and the moving ring of the universal grinder is 3000~4000rpm. Under the smash, it is easy to produce metal particles, which can be verified by the loss of weighing method. The production of sterile bulk drugs has certain requirements for the control of insoluble impurities and metal particles. GMP requires that production equipment can ensure product reliability and can not tolerate uncertainty. The author's intention is not that the sterile raw materials can not be used in the universal crusher, but depending on the conditions of different working conditions.
Another example is that a metal pump similar to a filled positive displacement pump can cause such problems. Some manufacturers have taken a paradoxical path. The material must be 316L. When the hardness is not matched, the surface will be used. Carburizing to increase hardness. As everyone knows, this carbon has changed from the original austenitic lattice to other crystal lattices, and it has lost its original intention of choosing austenitic steel for corrosion protection.
Problems like this are everywhere. It is terrible that manufacturers and users have not paid enough attention to this. Therefore, the author hereby appeals to peers to deal with it scientifically.
4. Application, material selection and processing of austenitic stainless steel 4.1 Basic treatment principle The basic principles of austenitic stainless steel selection: (1) parts that are in direct contact with liquid materials (that is, where there is Cl-precipitation), especially It is the pipeline for water for injection. Ultra-low carbon austenitic stainless steel such as 316L should be used. (2) For parts that are in direct contact with solid materials (that is, where there is no Cl-precipitation), general austenitic stainless steel can be selected. (3) When there is a conflict between the control of the anti-corrosion and the insoluble particles, the main control object should be taken first, and then other aspects should be managed properly, and the selection should be considered comprehensively. When the stainless steel does not meet the above requirements, it can be preferred among other materials. (4) The choice of austenitic stainless steel is the beginning of anti-corrosion, and it is not necessary to assume that everything will be fine or GMP-compliant, and more importantly, ensure that processing and passivation treatments are reliably handled.
4.2. Discussion on the selection of austenitic stainless steel materials The austenitic stainless steel materials selected for pharmaceutical equipment products often include plates, pipes, bar stocks and castings and forgings. The processing methods include cold work welding and machining. In the design of pharmaceutical equipment, different products have different design requirements, such as corrosion resistance, strength, stiffness, hardness (wear resistance) or machinability. For austenitic stainless steels, corrosion resistance, strength, stiffness and machinability are characteristic, and they cannot cope with the special requirements of hardness (wear resistance). Thus, pharmaceutical equipment is a comprehensive selection of materials based on process and application.
(1) The selection of austenitic stainless steel materials for pharmaceutical equipment should not only be made in low-carbon or ultra-low-carbon, but also fully consider other relevant factors in order to truly comply with GMP. In a sense, reasonable consideration of other relevant factors plays an important role in preventing corrosion of stainless steel. I have done this kind of experiment. In the production of sterile liquid storage tank (outer jacket, CaCl2 in the jacket), one cylinder material is selected as 316L, and the other is selected as 1Cr18Ni9Ti, which is considered in the manufacture of 1Cr18Ni9Ti. As for other related factors (guarantee from the structure, welding process, post-processing, etc.), the result is that only one 316L tank has been corroded for 3 to 4 months, while the other 1Cr18Ni9Ti tank has not been used for nearly two years. Corrosion 9 occurs. This shows that 316L austenitic stainless steel can not meet the GMP, but also gives us a reasonable choice of stainless steel.
(2) People often pay attention to the fact that the surface roughness of the polished product is as small as possible, and the step of pickling and passivation is neglected, which is also the key to ensuring corrosion resistance of the product. Because the inner wall of the product is pickled and passivated, the inner surface of the material has a dense passivation film, which can delay or avoid the pitting phenomenon caused by Cl-penetration of the passivation film. Sometimes it is not possible to pickle passivation when it is not possible to pickle passivation. Regarding polishing, the good method of Zui is manual mechanical polishing, and then electro-polishing. The advantages of this method are as follows: 1) the powder during mechanical polishing can be removed together with the metal surface layer; 2) the surface is smooth and the surface area is greatly reduced, so that 3) If there are pits or welding defects, after electropolishing, it can be repaired at a glance; 4) Electropolishing can form a very good passivation film on the surface, which greatly improves the corrosion resistance. ; 5) Eliminate the residual stress generated by mechanical polishing.
For example, the pipeline for injection water is used for long-term heat preservation and steam sterilization. When the domestic manufacturer installs the pipeline, due to the selection of the polishing tube, the automatic argon arc welding is considered, and the smear after the welding is not forgotten. Process.
(3) The selection of the main parts and materials of the universal grinder mentioned above, the author's point of view should be based on different situations to make reasonable choices, and have a choice in the control of corrosion and insoluble particles. The main considerations are two points: First, the hardness of the pulverized material, generally the Mohs hardness of Chinese and Western medicinal materials is 1-2. When the Mohs hardness of the pulverized material is close to 1, 18-8 steel can be selected; when the Mohs hardness of the pulverized material is close to 1-2, stainless steel surface hardness treatment or other materials such as 9Cr18Mo can be used; when the pulverized material Mohs When the hardness is close to or greater than 2, consideration should be given to changing the form of jet pulverization. Second, under the strict control of insoluble particulates, the manufacturer should actively communicate with the user and make a design confirmation (DQ) report based on the URS selection of materials for direct contact with the material. The DQ is based on the wear test to determine Whether the particles generated in the pulverizing material operation are within this process index.
(4) It is rare to hear the use of 316L when selecting the punch and die for the tablet press, and the design of the punch and die of the tablet press requires a surface HRC ≥ 45, which is comprehensively tested at home and abroad. The selection of rods and dies is selected in steels such as Cr12MoV, Cr12, 9Cr18Mo, W18Cr4VCo5, ​​5CrW2Si and CW6Mo5Cr4V3. This is based on the direct connection of the punch and die of the tablet press. The material is powder, ie there is no corrosion medium such as Cl-. The generation of conditions. If the 316L is used for the ram, the ram will be "lost" and blocked when it is used, causing the chip weight to exceed the standard and fail to operate normally. This example shows that sometimes the material selection is not necessarily austenitic stainless steel. When considering anti-corrosion and hardness, the advantages and disadvantages should be weighed. This may be a reference for the comprehensive selection of the above-mentioned universal crusher.
(5) In the production of powder injection, the metering screw of the filling machine is used as a powder. It is used for a long time without corrosive medium such as Cl- (only sterilization, except for short-time and quick drying). The material is 316L or 1Cr18Ni9Ti. ? From the perspective of material strength, stiffness and machinability, 1Cr18Ni9Ti is better than 316L. From the point of view of machining, 316L is difficult to turn (easy to stick), especially for the processing of slender screws, it is difficult to ensure the roughness of the surface of the screw, and to ensure the shape and shape tolerance, in addition, using 316L The screw is flexible and produces different axial degrees. The author used the screw of 1Cr18Ni9Ti to replace the foreign 316L screw for the screw of the imported packaging machine for more than ten years, and no corrosion occurred.
(6) The reversing rotary valve of the paste filling machine should have good matching between the female rotor and the male rotor cone under the premise of ensuring that the seal does not leak. When the two are repeatedly intermittently rotating, they should have A certain hardness difference, austenitic stainless steel is generally selected, but the remaining problem is how to solve the difference between the two hardness? Foreign products can increase the hardness of austenitic stainless steel by cold work hardening process, but it cannot be solved domestically. Some manufacturers use heat treatment methods or hard chrome layer coating methods, the former will produce corrosion and the paste will change color, and the latter will fall off after use and produce insoluble particles. At this time, the male material can only be selected from non-metallic materials under the existing conditions.
(7) The selection of the internal cavity of the tunnel oven and the 100-level laminar flow oven (except the steam sterilization box), the pharmaceutical factory often asks the manufacturer for the requirement of 316L. According to the author's opinion, it seems to be a little higher, because its function is to evaporate water. Or heat sterilization, will not be used in long-term corrosion medium conditions such as Cl-, the probability of producing austenitic stainless steel two corrosion is extremely low, so the choice of 304 material is sufficient.
5, the choice of non-metallic materials for pharmaceutical equipment Pharmaceutical equipment products in addition to metal materials, there are certain non-metallic materials, which are roughly plastic, rubber, ceramics and other materials, as well as insulation and filter materials. In the selection, it is generally necessary to meet this criterion: no toxicity and corrosion resistance, the specific performance is the use of no shedding, reaction with the drug, no sorption, adsorption, and does not change the safety, identification, content of the drug (or potency), quality or purity beyond legal or other established requirements.
5.1 Selection of plastic materials Under the premise of meeting the above criteria, it is also necessary to pay attention to the non-deformation during disinfection (sterilization). The purchase material warranty must have at least food grade guarantee. The plastic materials commonly used in pharmaceutical equipment products are: (1) oil nylon (caprolactam, cast nylon added with oil), nylon (NY, commonly used nylon 1010, etc.), polypropylene (PP, especially reinforcing or composite) Other sanitary engineering plastics such as acrylonitrile-butadiene-styrene (ABS) and polyoxymethylene (POM) are generally used in cases where they are not in direct contact with the drug (sometimes also used in direct contact with solid preparations and powders). ), external contact with the medicine package as a conveying part. (2) Materials such as polytetrafluoroethylene (PTFE) can also be used in direct contact with pharmaceuticals.
5.2. Selection of rubber materials Under the premise of satisfying the above criteria, attention should also be paid to disinfection (sterilization) (ie, no deformation). At least the sanitary material (or medical) warranty should be provided for the purchase material warranty. Silicone rubber is often used. It can be used in direct contact with drugs.
5.3. Selection of filter materials Under the premise of meeting the above criteria, it is also necessary to pay attention to the fact that the materials are not detached from fibers, do not adsorb liquid components and release foreign bodies, and it is forbidden to use asbestos-containing filter equipment.
6. Conclusions The selection of materials for pharmaceutical equipment can be summarized as follows: (1) The selection of pharmaceutical equipment is comprehensive, both from the perspective of preventing corrosion, and also taking into account the requirements of insoluble particulate control; (2) GMP only proposes pharmaceuticals The requirements for equipment selection, in accordance with the GMP principles, must also take into account the specific requirements and special points of the corresponding process, but also to rationally use materials for different use conditions; (3) in the rational selection of materials, but also comprehensive consideration of manufacturing and other Link.
Although China's pharmaceutical equipment products have been developed for many years, its application has been quite mature, but the equipment management and procurement personnel of pharmaceutical companies are still in a fuzzy state of choice for pharmaceutical equipment materials, especially the choice of metal materials is more confusing. It is believed that the selection of 316L material is in line with GMP. This wrong concept has a certain precipitation in China and abroad. Although the author has written such articles, people have changed this, but some people in the industry are still indulging in this. This is a misinterpretation of GMP, which is also contrary to the GMP inclusion.
1. GMP requirements for pharmaceutical equipment materials (1) GMP (98 edition) 1 Article 32 states: “The surface of equipment directly in contact with pharmaceuticals should be smooth, flat, easy to clean or disinfect, corrosion-resistant, and not chemically altered with pharmaceuticals. Or adsorbing drugs.†Article 34 states: “...the materials used in tanks and pipelines shall be non-toxic and corrosion-resistant.... The vents of water tanks for injection shall be fitted with a hydrophobic sterilizing filter that does not shed fibers.â€
(2) GMP (Public Version 98) Appendix 2* Section 3 Article 7 states: “The clean room (area) should use sanitary tools that are free from falling off, easy to clean, and easy to disinfect...†Section 2 of the second section considers: "The equipment, containers, pipes, valves, pumps, etc. that come into contact with the liquid should be made of high-quality corrosion-resistant materials.... Filtering equipment must not absorb the liquid components and release foreign matter. It is forbidden to use asbestos-containing filter equipment."
Looking at paragraph 211.65(a) of cGMP3 in the United States, it believes that: "The surface of the equipment should not react when it comes into contact with components, intermediate materials or drugs. It does not absorb or adsorb, so as not to change the safety and identification characteristics of the drug. Content (or potency), quality or purity beyond the statutory or other established requirements."
It can be said that the relevant provisions of the GMP-related documents have not seen the mandatory provisions for the selection of pharmaceutical equipment. GMP has only specified the directional requirements for the selection of pharmaceutical equipment, and no specific regulations have been made. Although, in the domestic authoritative monograph of the "Guidelines for the Validation of Pharmaceutical Production" 4, some statements have been made on the selection of equipment and piping in some production processes. For example, the material for injection water is 316L, which is targeted, not The material that comes into direct contact with the material of the pharmaceutical equipment is described by 316L. Moreover, the preface of this book clearly states that “it is a guiding tool for verification work, and there is no legal verification requirement.†Note: GMP only provides directional regulations for the selection of pharmaceutical equipment.
2, pharmaceutical process materials requirements for pharmaceutical equipment People pay attention to pharmaceutical equipment materials should be "easy to clean or disinfect, corrosion-resistant, do not chemically change or adsorb drugs", do not forget another material selection principle, this is Effective control of insoluble particulates.
In the medicine, the particles are roughly dust particles, metal or other particles. The presence of the particles directly affects the quality of the medicine and endangers people's lives. A large number of clinical data indicate that if the drug is contaminated by 7-2 μm dust particles, especially intravenous drugs, it can cause pyrogen reaction, pulmonary arteritis, microthrombus or foreign body granuloma, which can cause serious death. Therefore, in 1985, the Chinese Pharmacopoeia first limited the insoluble particles of infusion. It is stipulated that no more than 50 particles greater than or equal to 10 μm per milliliter, and no more than five particles greater than or equal to 25 μm.
At the same time, it is also clearly stated in the literature 4 that the contamination of aseptic and insoluble particulates is the two main characteristics distinguishing sterile raw materials from non-sterile bulk drugs, and is also one of the important projects in the production process and control.
Control of contamination of insoluble particulates In the production of sterile raw materials, an indicator that is difficult to control, the insoluble particles of each sterile product must be within a certain range, that is, insoluble particles of more than 10 μm and less than 25 μm are controlled at 300 / Below g, the insoluble particles larger than 25 μm are controlled at 30/g or less 4 .
The listed sources of insoluble particulates have four aspects in the manufacturing process, namely utility systems, operating systems, process material systems, and equipment or appliance systems. The key to the control of insoluble particles in the equipment or appliance system is closely related to the material selection. When some materials are in high-speed contact on the surface of the material, a certain amount of metal particles are generated based on the low surface hardness of the material. For example, the surface hardness of the 316L stainless steel is relatively soft. High-speed motion and surface contact with relatively soft materials inevitably produce metal particles. In order to ensure the amount of insoluble particulate contamination, it is necessary to strictly control all relevant links, especially the selection of materials is particularly important.
3. Discussion on the selection of commonly used stainless steel materials in pharmaceutical equipment In the metal materials, austenitic stainless steel is a pharmaceutical equipment product using zui as a wide range of materials, common varieties are 316L (00Cr17Ni14Mo2), 316 (0Cr17Ni12Mo2), 304L (00Cr19Ni11) 304 (0Cr19Ni9) and 1Cr18Ni9Ti (commonly known as 18-8), their common feature is corrosion resistance and good heat resistance. The commonality of these austenitic stainless steels is corrosion resistance, and their "corrosion resistance" is relative, which refers to the characteristics of high chemical stability under certain external conditions and certain corrosive media. However, when such austenitic stainless steel is used in some media, it will cause intergranular corrosion, pitting corrosion and the like, especially in Cl-containing media, which is usually prone to corrosion, usually using ultra-low carbon or Low carbon solution (ie 316L or 304L). However, ultra-low carbon is not the fundamental way to address such corrosion and is related to other factors.
It is pointed out that the ultra-low carbon austenitic stainless steel is easy to produce three problems in pharmaceutical equipment: (1) even when the Cl- content in the medium exceeds a certain value, even ultra-low carbon austenitic stainless steel will corrode; (2) When the content of Cl- in the medium is small, the ultra-low carbon austenitic stainless steel will corrode due to improper processing and treatment; (3) The ultra-low carbon austenitic stainless steel has a comprehensive mechanical index due to the decrease of C content. It is also relatively low, especially the surface hardness is correspondingly low, and insoluble particles are easily generated during high speed and material operation.
Therefore, people should note that 316L is not stainless steel that is not corroded, nor is it made of metal particles. Don't think that 316L is GMP.
3.1. Corrosion of austenitic stainless steel and prevention of common corrosion of austenitic stainless steels are intergranular corrosion and pitting corrosion. The corrosion mechanism 5: one is intergranular corrosion. When the austenitic stainless steel is manufactured and welded, the sensitized temperature region at the heating temperature and the heating rate, the supersaturated carbon in the material first precipitates at the grain boundary and combines with the chromium to form chromium carbide. The diffusion rate in the body is higher than that in the chromium. The chromium is not enough to supplement the chromium lost by the formation of chromium carbide. The result is that the chromium content of the grain boundary decreases with the continuous precipitation of chromium carbide, forming a so-called chromium-depleted zone. The electrode potential is lowered. When contacted with a corrosive medium containing Cl-, it causes corrosion of the microbattery. Although the corrosion is only on the surface of the grain, it quickly penetrates into the interior to form intergranular corrosion; the second is pitting. When the material is in contact with a corrosive medium containing Cl-, the Cl- invades the passivation film at the defect of the material passivation film, such as inclusions, chromium-depleted regions, grain boundaries, weld heat affected regions or dislocations. The metal ions combine to form a strong acid salt to dissolve the passivation film, and Cl- causes the film to be devoid of destruction, forming a "passivation-activation" microbattery, causing pitting corrosion, and corrosive current causes perforation of the material.
Factors affecting the corrosion of austenitic stainless steel: (1) medium chloride ion.
The Cl- content should be controlled at a certain value (check the corresponding material corrosion manual for details), and the ultra-low carbon austenitic stainless steel should be used with caution when the Cl- content exceeds the value. In the national standard "Steel Pressure Vessel" (GB150-98), the chloride ion content of water in the water pressure test of stainless steel container shall not exceed 25ppm (1ppm is one millionth), so it can be seen that the water pressure test The requirements for chloride ions are so harsh 6 that it is not necessary to talk about pharmaceutical equipment products. (2) Factors affecting intergranular corrosion7. When the temperature is outside the sensitized zone, carbon atoms are unlikely to cause chromium depletion at the grain boundaries. Only when the temperature is heated in the sensitization zone, the temperature gradient will cause a chromium-depleted zone. In addition, it is also related to its carbon content. The more carbon content, the more the amount of diffusion, the more the amount of carbide formation, so that the intergranular corrosion tends to penetrate into the grain boundary to increase the depth, causing intergranular corrosion. (3) Factors affecting pitting 7. It has been proved in literature that if the amount of chromium is increased, pitting will not occur. However, the amount of chromium does not contribute to the intergranular resistance to chromium deficiency. Increasing the amount of molybdenum greatly improves the pitting resistance, which is related to the formation of a MoOCl2 protective film by Cl-, thereby preventing Cl- penetrating the passivation film.
Measures to prevent corrosion of austenitic stainless steel: (1) reduce the carbon content of stainless steel, low carbon stainless steel or ultra-low carbon stainless steel can avoid or reduce the precipitation of chromium carbides in the intergranular, thereby reducing or avoiding intergranular corrosion; (2) Solution treatment, in which all of the carbides are dissolved in the austenite under the action of high temperature, thereby eliminating the tendency of intergranular corrosion. Generally, when austenitic stainless steel is purchased, it can be selected by solution treatment; (3) like 316 type Mo-containing stainless steel can form a protective film to effectively prevent pitting; (4) When welding materials, automatic argon arc welding is preferred. If it is impossible to use manual argon arc welding, low current and rapid cooling, and water cooling, etc., reduce the heat affected zone. Thereby reducing or avoiding intergranular corrosion and pitting; (5) pickling passivation treatment. The material needs to be polished after welding, and the inner wall is pickled and passivated to make the inner surface of the material have a dense passivation film, which can delay or avoid the pitting phenomenon caused by Cl-penetration into the passivation film; (6) Structural design. Reduce welds or staggered welds. Use materials for high temperatures to reduce the thermal expansion structure, thereby reducing heat effects or areas of stress concentration, thereby reducing these two types of corrosion tendencies.
3.2. Discussion on Insoluble Particles of Austenitic Stainless Steel In the case of manufacturers and users of pharmaceutical equipment, people are eager to choose materials while avoiding a very important principle, that is, controlling insoluble particles. Selection of materials. Looking at pharmaceutical equipment products, some parts will be in direct contact with the drug at high speed to cause wear, and a small amount of metal particles generated by abrasion will be incorporated into the drug.
For example, the pulverization of the universal pulverizer mainly involves the impact pulverization and the shear squeezing movement of the particles and the collision target. For the pulverization of the small particles, the main function of the pulverization process in the universal pulverizer is the impact pulverization of the particles and the collision target. (The inner ring gear, the outer ring gear, the outer ring impact ring) and the shear extrusion pulverization, and the collision pulverization between the particles is not obvious. On the other hand, the material particles are strongly sheared at the gap formed by the moving ring gear and the fixed ring gear, and are also a major factor in material pulverization. The process produces a certain amount of wear, which is confirmed by the wear scar diagram of the ring gear tooth surface in Document 8. There are also experiments in which the particles from the side of the ring gear are squeezed and rubbed to form a deeper wear scar. It can be seen that the particles between the fixed and moving ring gears are severely pulverized by the shearing force. It is precisely because of the severe frictional shearing action between the particles and the target plate that the parts in direct contact with the material are seriously worn, thereby causing the phenomenon of insoluble impurities and metal particles in the pulverization process. In particular, the existing universal grinder and the direct contact parts of the materials are austenitic stainless steel (some are more than 316L), the surface hardness of the material is lower than other metals, and the moving ring of the universal grinder is 3000~4000rpm. Under the smash, it is easy to produce metal particles, which can be verified by the loss of weighing method. The production of sterile bulk drugs has certain requirements for the control of insoluble impurities and metal particles. GMP requires that production equipment can ensure product reliability and can not tolerate uncertainty. The author's intention is not that the sterile raw materials can not be used in the universal crusher, but depending on the conditions of different working conditions.
Another example is that a metal pump similar to a filled positive displacement pump can cause such problems. Some manufacturers have taken a paradoxical path. The material must be 316L. When the hardness is not matched, the surface will be used. Carburizing to increase hardness. As everyone knows, this carbon has changed from the original austenitic lattice to other crystal lattices, and it has lost its original intention of choosing austenitic steel for corrosion protection.
Problems like this are everywhere. It is terrible that manufacturers and users have not paid enough attention to this. Therefore, the author hereby appeals to peers to deal with it scientifically.
4. Application, material selection and processing of austenitic stainless steel 4.1 Basic treatment principle The basic principles of austenitic stainless steel selection: (1) parts that are in direct contact with liquid materials (that is, where there is Cl-precipitation), especially It is the pipeline for water for injection. Ultra-low carbon austenitic stainless steel such as 316L should be used. (2) For parts that are in direct contact with solid materials (that is, where there is no Cl-precipitation), general austenitic stainless steel can be selected. (3) When there is a conflict between the control of the anti-corrosion and the insoluble particles, the main control object should be taken first, and then other aspects should be managed properly, and the selection should be considered comprehensively. When the stainless steel does not meet the above requirements, it can be preferred among other materials. (4) The choice of austenitic stainless steel is the beginning of anti-corrosion, and it is not necessary to assume that everything will be fine or GMP-compliant, and more importantly, ensure that processing and passivation treatments are reliably handled.
4.2. Discussion on the selection of austenitic stainless steel materials The austenitic stainless steel materials selected for pharmaceutical equipment products often include plates, pipes, bar stocks and castings and forgings. The processing methods include cold work welding and machining. In the design of pharmaceutical equipment, different products have different design requirements, such as corrosion resistance, strength, stiffness, hardness (wear resistance) or machinability. For austenitic stainless steels, corrosion resistance, strength, stiffness and machinability are characteristic, and they cannot cope with the special requirements of hardness (wear resistance). Thus, pharmaceutical equipment is a comprehensive selection of materials based on process and application.
(1) The selection of austenitic stainless steel materials for pharmaceutical equipment should not only be made in low-carbon or ultra-low-carbon, but also fully consider other relevant factors in order to truly comply with GMP. In a sense, reasonable consideration of other relevant factors plays an important role in preventing corrosion of stainless steel. I have done this kind of experiment. In the production of sterile liquid storage tank (outer jacket, CaCl2 in the jacket), one cylinder material is selected as 316L, and the other is selected as 1Cr18Ni9Ti, which is considered in the manufacture of 1Cr18Ni9Ti. As for other related factors (guarantee from the structure, welding process, post-processing, etc.), the result is that only one 316L tank has been corroded for 3 to 4 months, while the other 1Cr18Ni9Ti tank has not been used for nearly two years. Corrosion 9 occurs. This shows that 316L austenitic stainless steel can not meet the GMP, but also gives us a reasonable choice of stainless steel.
(2) People often pay attention to the fact that the surface roughness of the polished product is as small as possible, and the step of pickling and passivation is neglected, which is also the key to ensuring corrosion resistance of the product. Because the inner wall of the product is pickled and passivated, the inner surface of the material has a dense passivation film, which can delay or avoid the pitting phenomenon caused by Cl-penetration of the passivation film. Sometimes it is not possible to pickle passivation when it is not possible to pickle passivation. Regarding polishing, the good method of Zui is manual mechanical polishing, and then electro-polishing. The advantages of this method are as follows: 1) the powder during mechanical polishing can be removed together with the metal surface layer; 2) the surface is smooth and the surface area is greatly reduced, so that 3) If there are pits or welding defects, after electropolishing, it can be repaired at a glance; 4) Electropolishing can form a very good passivation film on the surface, which greatly improves the corrosion resistance. ; 5) Eliminate the residual stress generated by mechanical polishing.
For example, the pipeline for injection water is used for long-term heat preservation and steam sterilization. When the domestic manufacturer installs the pipeline, due to the selection of the polishing tube, the automatic argon arc welding is considered, and the smear after the welding is not forgotten. Process.
(3) The selection of the main parts and materials of the universal grinder mentioned above, the author's point of view should be based on different situations to make reasonable choices, and have a choice in the control of corrosion and insoluble particles. The main considerations are two points: First, the hardness of the pulverized material, generally the Mohs hardness of Chinese and Western medicinal materials is 1-2. When the Mohs hardness of the pulverized material is close to 1, 18-8 steel can be selected; when the Mohs hardness of the pulverized material is close to 1-2, stainless steel surface hardness treatment or other materials such as 9Cr18Mo can be used; when the pulverized material Mohs When the hardness is close to or greater than 2, consideration should be given to changing the form of jet pulverization. Second, under the strict control of insoluble particulates, the manufacturer should actively communicate with the user and make a design confirmation (DQ) report based on the URS selection of materials for direct contact with the material. The DQ is based on the wear test to determine Whether the particles generated in the pulverizing material operation are within this process index.
(4) It is rare to hear the use of 316L when selecting the punch and die for the tablet press, and the design of the punch and die of the tablet press requires a surface HRC ≥ 45, which is comprehensively tested at home and abroad. The selection of rods and dies is selected in steels such as Cr12MoV, Cr12, 9Cr18Mo, W18Cr4VCo5, ​​5CrW2Si and CW6Mo5Cr4V3. This is based on the direct connection of the punch and die of the tablet press. The material is powder, ie there is no corrosion medium such as Cl-. The generation of conditions. If the 316L is used for the ram, the ram will be "lost" and blocked when it is used, causing the chip weight to exceed the standard and fail to operate normally. This example shows that sometimes the material selection is not necessarily austenitic stainless steel. When considering anti-corrosion and hardness, the advantages and disadvantages should be weighed. This may be a reference for the comprehensive selection of the above-mentioned universal crusher.
(5) In the production of powder injection, the metering screw of the filling machine is used as a powder. It is used for a long time without corrosive medium such as Cl- (only sterilization, except for short-time and quick drying). The material is 316L or 1Cr18Ni9Ti. ? From the perspective of material strength, stiffness and machinability, 1Cr18Ni9Ti is better than 316L. From the point of view of machining, 316L is difficult to turn (easy to stick), especially for the processing of slender screws, it is difficult to ensure the roughness of the surface of the screw, and to ensure the shape and shape tolerance, in addition, using 316L The screw is flexible and produces different axial degrees. The author used the screw of 1Cr18Ni9Ti to replace the foreign 316L screw for the screw of the imported packaging machine for more than ten years, and no corrosion occurred.
(6) The reversing rotary valve of the paste filling machine should have good matching between the female rotor and the male rotor cone under the premise of ensuring that the seal does not leak. When the two are repeatedly intermittently rotating, they should have A certain hardness difference, austenitic stainless steel is generally selected, but the remaining problem is how to solve the difference between the two hardness? Foreign products can increase the hardness of austenitic stainless steel by cold work hardening process, but it cannot be solved domestically. Some manufacturers use heat treatment methods or hard chrome layer coating methods, the former will produce corrosion and the paste will change color, and the latter will fall off after use and produce insoluble particles. At this time, the male material can only be selected from non-metallic materials under the existing conditions.
(7) The selection of the internal cavity of the tunnel oven and the 100-level laminar flow oven (except the steam sterilization box), the pharmaceutical factory often asks the manufacturer for the requirement of 316L. According to the author's opinion, it seems to be a little higher, because its function is to evaporate water. Or heat sterilization, will not be used in long-term corrosion medium conditions such as Cl-, the probability of producing austenitic stainless steel two corrosion is extremely low, so the choice of 304 material is sufficient.
5, the choice of non-metallic materials for pharmaceutical equipment Pharmaceutical equipment products in addition to metal materials, there are certain non-metallic materials, which are roughly plastic, rubber, ceramics and other materials, as well as insulation and filter materials. In the selection, it is generally necessary to meet this criterion: no toxicity and corrosion resistance, the specific performance is the use of no shedding, reaction with the drug, no sorption, adsorption, and does not change the safety, identification, content of the drug (or potency), quality or purity beyond legal or other established requirements.
5.1 Selection of plastic materials Under the premise of meeting the above criteria, it is also necessary to pay attention to the non-deformation during disinfection (sterilization). The purchase material warranty must have at least food grade guarantee. The plastic materials commonly used in pharmaceutical equipment products are: (1) oil nylon (caprolactam, cast nylon added with oil), nylon (NY, commonly used nylon 1010, etc.), polypropylene (PP, especially reinforcing or composite) Other sanitary engineering plastics such as acrylonitrile-butadiene-styrene (ABS) and polyoxymethylene (POM) are generally used in cases where they are not in direct contact with the drug (sometimes also used in direct contact with solid preparations and powders). ), external contact with the medicine package as a conveying part. (2) Materials such as polytetrafluoroethylene (PTFE) can also be used in direct contact with pharmaceuticals.
5.2. Selection of rubber materials Under the premise of satisfying the above criteria, attention should also be paid to disinfection (sterilization) (ie, no deformation). At least the sanitary material (or medical) warranty should be provided for the purchase material warranty. Silicone rubber is often used. It can be used in direct contact with drugs.
5.3. Selection of filter materials Under the premise of meeting the above criteria, it is also necessary to pay attention to the fact that the materials are not detached from fibers, do not adsorb liquid components and release foreign bodies, and it is forbidden to use asbestos-containing filter equipment.
6. Conclusions The selection of materials for pharmaceutical equipment can be summarized as follows: (1) The selection of pharmaceutical equipment is comprehensive, both from the perspective of preventing corrosion, and also taking into account the requirements of insoluble particulate control; (2) GMP only proposes pharmaceuticals The requirements for equipment selection, in accordance with the GMP principles, must also take into account the specific requirements and special points of the corresponding process, but also to rationally use materials for different use conditions; (3) in the rational selection of materials, but also comprehensive consideration of manufacturing and other Link.
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