This article introduces several sterilization methods for sterile medicinal products: moist heat sterilization, dry heat sterilization, radiation sterilization, ethylene oxide sterilization and sterile filtration, and studies the various sterilization methods of sterilization principles, influencing factors, advantages and disadvantages and products adapted to sterilization, and explores methods for sterilization decisions of sterile medicinal products by selecting decision tree for sterilization methods of solution dosage form products and dry powder products or semi-solid, non-solution dosage forms.
1. Sterilization overview of sterile medicinal products
Sterilization method refers to the use of physical and chemical methods to kill or remove all surviving microbial propagule or spores, so that the sterilized items to achieve sterility. In the production of sterile medicinal products, the prevention of endotoxin contamination and microbial contamination has been the focus of attention of regulatory agencies and manufacturers. Sterilization of sterile medicinal products should be achieved to remove or kill spores and microbial propagules in the drugs so as to ensure the safety of the drug preparation itself, and also to ensure the stability of the drugs and their clinical therapeutic effects. So the adoption of appropriate sterilization methods by these sterile drug manufacturers is of great significance for ensuring drug quality.
2. Introduction to sterilization methods for sterile medicinal products
(1) Moist heat sterilization
Moist heat sterilization refers to the use of high-pressure steam or other thermodynamic sterilization means to kill microorganisms in the articles. Moist heat sterilization is one of the most versatile and effective methods of thermodynamic sterilization, with the characteristics of fast conduction, strong penetration and stronger sterilization ability.
Principle: Moist heat sterilization is the process of denaturing the nucleic acids and proteins of microorganisms by means of humid heat, thereby causing their death. This denaturation refers to the first splitting of the hydrogen bonds in the molecules, followed by the destruction of the internal structure of the nucleic acids and proteins, resulting in the loss of their original functions and the achieving the purpose of sterilization.
Factors affecting the effect of moist heat sterilization include: ① The length of time required for sterilization is related to the number of microorganisms in the initial sterilized material, so according to the first order equation, the number and type of microorganisms in the sterilized material directly affect the sterilization effect. ②In general, microorganisms have the best heat resistance in neutral solution, worse in alkaline solution and worst in acidic solution, so the pH of the sterilization solution is also an influencing factor of the sterilization effect. ③The nature of the sterilized material. If the solution contains nutrients such as amino acids and sugars, the microorganisms will be protected by these nutrients, thus enhancing their heat resistance. ④The penetration of dry and hot air and superheated steam is much worse than that of saturated steam, so the saturation of steam is another influencing factor of sterilization effect, and saturated steam should be used for sterilization as much as possible.
(2) Dry heat sterilization
Dry heat sterilization is a method to kill microorganisms by non-specific oxidation produced by deoxyribonucleases, microorganisms and other biopolymers through high temperature. According to its different ways of using, dry heat sterilization equipment can be divided into continuous and intermittent type. For example, tunnel sterilization oven is continuous, used for the sterilization of vails or ampoules while dry heat sterilization cabinet is intermittent, can be used for the sterilization and removing heat source of equipment components, metal utensils.
The thermodynamic principle of dry heat sterilization is similar to the thermodynamic characteristics of moist heat sterilization, and the killing of microorganisms under certain sterilization conditions also conforms to logarithm principle.
The sterilization of high temperature resistant powder chemicals and some metal equipment, grease and utensils that do not need moisture penetration, and glass and other high temperature resistant items can be considered to use dry heat sterilization, but dry heat sterilization is not suitable for most drugs, plastics and rubber sterilization. Dry heat sterilization can also remove heat source. For example, in the production workshop of sterile drug water needle, some utensils in its B and C level clean area can take dry heat sterilization by using electric heating through double-capacity dry heat sterilization cabinet.
(3) Radiation sterilization
Radiation sterilization is a sterilization method using ionizing radiation to kill microorganisms, and the electromagnetic waves used for sterilization include microwave, ultraviolet, γ-ray, X-rays and so on. At present, radiation sterilization mostly uses γ-ray radiated from 60Co source.
Principle of radiation sterilization process: in a specially designed device, the product is exposed to γ-ray generated by cobalt 60 (60Co) radionuclides, cesium 137 (137Cs) radionuclides, or electron or x-ray beams generated by an electron generator to kill microorganisms.
Radiation sterilization has the following advantages: (1) Room temperature sterilization. small temperature rise during product sterilization, suitable for sterilization of heat-sensitive biological products and drugs. ②Simple process. Once the sterilization parameters are determined, time is the only adjustable factor, which is suitable for industrial mass production, energy saving and no pollution. ③Packaged and then sterilized. The product can be kept sterile for a long time under sealed packaging conditions. ④The penetrating power of radiation is very strong, and its sterilization is complete, and it is not restricted by the packaging and form of the articles. ⑤ There is no radioactive residue, no chemical toxicity and other side effects in the products after irradiation.
(4) Ethylene oxide sterilization
Ethylene oxide sterilization, which is a relatively reliable method of low-temperature sterilization. Ethylene oxide has an unstable three membered ring structure and small molecular properties, which make it high penetrability and chemical activity. The common ethylene oxide sterilization process uses a vacuum course, which generally uses 100% pure ethylene oxide or a mixture of gases containing 40% to 90% ethylene oxide (e.g., mixed with carbon dioxide or nitrogen). When a positive pressure process is used, 8% to 20% ethylene oxide is used in combination with carbon dioxide gas. The product is sterilized in a pressurized chamber filled with sterilizing gas. The standard ethylene oxide sterilization process consists of 3 different stages: pretreatment, sterilization and resolution.
The principle of ethylene oxide sterilization: ethylene oxide is a broad-spectrum sterilant, which can kill various microorganisms such as fungi, spores, viruses and bacteria at room temperature; it can take place alkylation with amino, sulfuric hydroxyl and carboxyl groups on proteins, resulting in the death of microorganisms; it can also inhibit the biological enzyme activity of cholinesterase, choline acetylase, peptide, enzyme and phosphatase; ethylene oxide can also take place alkylation with RNA and DNA, resulting in the inactivation of microorganisms.
(5) Filtration and sterilization
Sterilization filtration is the process of removing microorganisms from fluids through filters, which should not adversely affect product quality. Including liquid and gas sterilization filtration. Sterile pharmaceutical production of liquid sterilization filtration generally uses sterilization filter membrane pore size of not more than 0.22μm, can achieve the effective filtration area per square centimeter in the process conditions to retain 107CFU Pseudomonas defective, which is the general requirements of liquid sterilization filter.
Many final sterilized sterile products use filters to filter the products before filling before final sterilization to control the level of microbial contamination; for sterile products that cannot be final sterilized, such as some sterile water injections, lyophilized powder injections, etc., filter the products by sterilization filtration before filling to achieve sterility level. Consider reducing the risk of sterilization filtration, when one sterilization filter can achieve sterilization filtration effect, add a second (or use more than one) sterilization level filter to guarantee the effect of sterilization filtration, such a setup, usually called "double" or "redundant This is often referred to as a "dual" or "redundant" setup.