Although the pharmaceutical industry has implemented GMP for many years and its application has also been quite mature, but some equipment management and procurement personnel of pharmaceutical business are still confused about the choice of materials for pharmaceutical equipment, especially for the choice of metal materials. Generally, they agreed that the choice of 316L stainless steel material is in line with the GMP requirements, for example, when we received the Blister Machine URS from customer, it should be emphasized that parts contacted with drug must be 316L, regardless of the specific environment in which it is used. In fact, this is a misinterpretation of GMP.
1. GMP Requirements for Pharmaceutical Equipment Materials
According to China’s GMP regulations: “the surface of the equipment contacted with the drug directly should be smooth, easy to clean or disinfect, corrosion-resistant, no chemical changes with the drug and no adsorption of drugs;”
According to cGMP regulations in US: “the surface of the equipment should not react with the intermediate material or medicament, no sorption, no adsorption, without altering the safety of the drug, changing identifying-characteristics, content, quality or purity, making it beyond the statutory or other established requirements.”
That is, we do not see the mandatory provisions of the selection of pharmaceutical equipment in all document related to GMP, GMP only made orientation rules of the selection of pharmaceutical equipment without specific provisions.
2. Pharmaceutical Technology’s Requirements for Pharmaceutical Equipment
When concerning about the fact that pharmaceutical equipment materials should be “easy to clean or disinfection, corrosion resistance, and no chemical changes with drugs or adsorption of drugs,” do not forget the principle of another selection, which is the effective control of insoluble particles at the same time.
The particles in the drug include dust particles, metal or other particles; the existence of particles would affect the quality of drugs, endangering people’s lives and safety directly. A large number of clinical data show that if the drug is contaminated by 7-2μm dust particles, especially for intravenous medication, it can lead to pyrogen reaction, pulmonary arteritis, microthrombosis or foreign body granuloma, etc., or even it will cause death. Therefore, the Chinese Pharmacopoeia made clear interpretation for limitation about the infusion of insoluble particles in 1985 for the first time, that is, particles per milliliter that is greater than or equal to 10μm shall not exceed 50, particles that are greater than or equal to 25μm shall not exceed five.
Meanwhile, the literature also clearly states: sterile and insoluble particles of pollution are two main differences between sterile bulk drugs and non-sterile raw materials; also they are one of the most important projects in the production process and control. Control of the contamination of insoluble particles is one of the most difficult controls in the production of sterile raw materials. The insoluble particles of each sterile product must be controlled within a certain range, that is, the insoluble fine particles more than 10μm and less than 25μm should be controlled within 300 / g or less, and the insoluble fine particles more than 25μm should be controlled to 30 / g or less4.
The source of the listed insoluble particles has four aspects in the production process, namely the utility system, the operating system, the process material system, and the equipment or appliance system. Equipment or equipment system insoluble particles control and material selection is closely related, when part of the material and the surface of the machine contact with each other with high-speed, certain amount of metal particles would be produced due to low hardness of surface, for example, 316L stainless steel is soft relatively in surface hardness, the contact between high-speed movement of materials and soft surface of the parts will produce metal particles. In order to ensure the amount of insoluble particulate contamination, various related processes must be controlled strictly, especially for the selection of materials.
3. Discussion on the Selection of Stainless Steel Used in Pharmaceutical Equipment
In the metal materials, austenitic stainless steel is the most widely used material for pharmaceutical equipment products. The common varieties are 316L (00Cr17Ni14Mo2), 316 (0Cr17Ni12Mo2), 304L (00Cr19Ni11), 304 (0Cr19Ni9) and 1Cr18Ni9Ti and their common characteristics are 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 high chemical stability characteristics under certain external conditions and certain corrosive medium. However, such austenitic stainless steel in the case of certain media use, it will produce intergranular corrosion, pitting or other types of corrosion, especially in the Cl-containing it is very easy to produce corrosion, usually ultra-low carbon or low-carbon method are used to solve the problem (i.e. select 316L or 304L). However, ultra-low carbon is not the fundamental way to solve such corrosion, but related to other factors.
It should be noted that the ultra low carbon austenitic stainless steel in the pharmaceutical equipment products would present three issues as follows: (1) when the Cl - content in medium exceeds a certain value, even if the ultra - low carbon austenitic stainless steel will be corroded; (2) when the Cl - content in medium is of a small amount, ultra - low carbon austenitic stainless steel will be corroded due to improper processing and processing; (3) due to the reduction of the amount of C, the comprehensive mechanical indicators of ultra-low carbon austenitic stainless steel are relatively low, especially when the surface hardness is low, it is easy to produce insoluble particles with such high-speed in material operation.
Therefore, it should be noted that 316L is neither non-corrosive stainless steel, nor the material without metal particles, do not think that the election of the 316L must be consistent with the GMP.
3.1. The corrosion of austenitic stainless steel and method of corrosion protection
The common corrosion of austenitic stainless steel is intergranular corrosion and pitting. The corrosion mechanism5 are as follow. The first is intergranular corrosion. When the austenitic stainless steel is in the manufacture and welding and when the heating temperature and heating rate are in a sensitized temperature area, the supersaturated carbon in the material will be separated out in the grain boundary, which will be combined with chromium to form chromium carbide. Then the so-called chromium deficiency area is formed, which will lead to the decrease of electrode potential. When it contacts with Cl- and other corrosive media, the micro-battery corrosion will be caused. Although the corrosion is only in the grain surface, it will quickly go into the internal part to form intergranular corrosion. The second is pitting. When the material contacts with the corrosive media such as Cl-, Cl- will combine with metal ions after invasion in the defective areas of the material, such as inclusions, chromium deficiency area, grain boundaries, affected heat zones by welding, etc., and finally lead to pitting.
Methods to prevent corrosion of austenitic stainless steel: (1) Reducing the carbon content of stainless steel. Low-carbon stainless steel or ultra-low carbon stainless steel is available to reduce or avoid intergranular corrosion. (2) Solution treatment. Let the carbonization are all dissolved in austenite under high temperature to eliminate the tendency of intergranular corrosion. When purchasing austenitic stainless steel, the products of undergoing solution treatment can be generally chosen. (3) The 316 type of Mo-containing stainless steel can form a protective film to effectively prevent pitting. (4)The automatic argon arc welding is preferred and the manual argon arc welding can be chosen if it doesn’t work when welding. Low current and rapid cooling, as well as water cooling can be used to reduce the affected heat area. Thereby intergranular corrosion and pitting can be reduced or avoided. (5) Pickling passivation treatment. Materials after welding need to be polished and pickling passivation treatment needs to be done in the inner wall, so the inner surface of the material will have a layer of dense passivation film which can delay or avoid Cl- penetrating into passivation film to avoid pitting. It is often considered that the lower is the surface roughness value of stainless steel after polishing; the better is the stainless steel. But the treatment of pickling passivation is neglected. After pickling passivation treatment, a layer of dense passivation film will be formed, that can delay or avoid Cl- penetrating into passivation film to avoid pitting. About the polishing, the best way is manual mechanical polishing, plus electrolytic polishing. The advantages of this method are: 1) Powder and metal surface produced by mechanical polishing can be removed by electrolytic polishing; 2) It can make a smooth surface and better cleaning effect better; 3) Any pits or welding defects are clear at a glance and can be repaired after electrolytic polishing; 4) A very good passivation film can be formed in the stainless steel surface after electrolytic polishing to greatly improve the corrosion resistance; 5) Eliminating the residual internal stress produced by mechanical polishing; 6) Improving the structural design to reduce the weld joint. For the materials used under high temperature, we should try to reduce the thermal expansion structure, the thermal impact or stress concentration area to reduce the tendency of these two types of corrosion.
3.2. Insoluble particles of austenitic stainless steel
In the manufacture of pharmaceutical equipment, people are keen to prevent corrosion, but another important issue is often overlooked, that is, controlling the insoluble particles. Some parts of the pharmaceutical equipment will have direct contact with drugs when it is in high-speed operation, which leads to abrasion. A small amount of metal particles produced by abrasion will be involved in the drug.
For example, in the crushing process of the universal crusher, the materials can directly contact with mechanical parts. The abrasion of mechanical parts after collision, extrusion, and cutting are serious and insoluble impurities and metal particles pollution is made during the crushing process.
4. Application, Selection and Processing of Austenitic Stainless Steel
4.1. The basic principles of treatment
The basic principles of choosing austenitic stainless steel are: (1) When the parts directly contact with the liquid material, especially the pipeline for injection of water, 316L type of ultra-low carbon austenitic stainless steel should be chosen; (2) When the parts directly contact with the solid material, general austenitic stainless steel should be chosen; (3) When there is a conflict of controlling anti-corrosion and insoluble particles, the austenitic stainless steel should be chosen according to the main control object. Then try to properly handle other aspects. When the stainless steel does not meet the above requirements, it can be preferred in other materials; (4) It doesn’t mean the austenitic stainless steel is in line with GMP when it is chosen. Processing and passivation treatment as well as other methods should be adopted to further improve its quality.
4.2. Material selection of austenitic stainless steel
The materials of austenitic stainless steel used in products of pharmaceutical equipment often include board, pipe, bar as well as casting and forging. The processing methods are cold welding, machining and so on. In the process of pharmaceutical equipment design, different products have different design requirements, such as corrosion resistance, strength, stiffness, hardness and so on. For the austenitic stainless steel, its corrosion resistance, strength, stiffness and machinability has its inherent characteristics, so it is not suitable in these parts that have high demand of hardness and wear resistance, such as the punch & die of the Tablet Press Machine, which directly contact with drugs when working. However, 316L type of austenitic stainless steel is generally not used for this. The surface hardness of designing punch & die of the Tablet Press Machine should reach HRC ≥ 45 and the current material selection of them are Cr12MoV, Cr12, 9Cr18Mo, W18Cr4VCo5, 5CrW2Si and CW6Mo5Cr4V3, etc., because the punch & die of the Tablet Press Machine usually directly connected with powder materials, that is, no Cl- and other corrosive media. If the material of punch is chosen with 316L which has no enough hardness, it will lead to deviation go beyond the standard and rust of the edges and corners of punch after short using. Taking the feeder of Blister Machine as an example, generally only the material of hopper is adopted with 316L, while the materials of other parts are often aluminum, plexiglass, silicone, etc. It means that the materials which directly contact with drugs are sometimes not necessarily selected with austenitic stainless steel. In considering the corrosion protection and hardness, we should weigh the pros and cons to choose the materials according to the comprehensive factors such as process and application.
5. The Selection of Non-metallic Materials for Pharmaceutical Equipment
In addition to metal materials, there are a large number of non-metallic materials for pharmaceutical equipment such as plastic, rubber, ceramics and other materials. For example, the material of Blister Machine’s feeder often uses silica gel, plexiglass, etc. There is a layer of Teflon on the surface of Blister Machine forming heating plate to prevent from sticking other materials. In the selection, it generally needs to meet this criterion, non-toxic and corrosion-resistant, no shedding when using, no reaction when contacting with drugs, no adsorption, and no change of the drug security and so on.