Prevention and control measures for contamination of pharmaceutical equipment in production

There are many factors affecting the quality of pharmaceuticals in pharmaceutical production, and a very important factor is from various pollutions. How to solve the pollution problem is an important aspect to ensure the quality of drugs.

1 Factors affecting the quality of drugs

The quality of the drug is related to the patient's medication safety. To produce high-quality and qualified drugs, there must be three elements: (1) qualified personnel; (2) GMP-compliant software, such as reasonable dosage forms, prescriptions and processes, qualified Raw and auxiliary materials, various specifications and management systems; (3) GMP-compliant hardware, including qualified production environment and production conditions, and meet the required plant and equipment.

2 The meaning of the prevention and control of pollution in production by pharmaceutical equipment

From the above, the production environment, production conditions, and equipment are one aspect that affects the quality of pharmaceuticals. In the production of pharmaceuticals, the pollution of the production environment and production conditions generally includes microorganisms, dust, particles, corrosion, errors and cross-contamination. The prevention and control of pollution in production by pharmaceutical equipment consists of two layers. * The equipment itself does not pollute the drug and does not pollute the environment. The second should have effective means of controlling pollution. To this end, GMP has made a number of guiding regulations for pharmaceutical equipment directly involved in the production of pharmaceuticals. The basic point is to ensure the quality of the drugs, prevent various pollutions that may be caused by the drugs in the production process, and may affect the environment and human health. Hazard and other factors. Therefore, the design of pharmaceutical equipment should comply with GMP requirements, reduce pollution factors, and have good prevention and control of pollution.

3 pharmaceutical equipment is designed to meet GMP requirements

The design, manufacture, technology and performance of pharmaceutical equipment under the specific conditions of pharmaceutical GMP should be based on the general rules of equipment GMP design to promote the establishment and improvement of GMP specifications for pharmaceutical equipment. The specific contents are as follows:

(1) The design of the equipment should meet the requirements of pharmaceutical production and process, be safe, stable, reliable, easy to clean, disinfect or sterilize, facilitate production operation and maintenance, and prevent errors and cross-contamination;

(2) The material selection of the equipment should be strictly controlled. Parts that are in direct contact with the drug should be made of materials that are non-toxic, non-corrosive, do not chemically react with the drug, do not release particles or adsorb the drug;

(3) The inner surface of the equipment and the surface of the working parts that are in direct contact with the drug are not designed with the platform, the groove, and the exposed bolt connection as much as possible. The surface should be smooth, smooth, no dead angle, easy to clean and disinfect;

(4) The equipment should not cause pollution to the environment outside the installation. In view of the different pollution caused by each type of equipment, relevant measures such as dust prevention, leakage prevention, heat insulation and noise prevention should be adopted.

(5) Equipment used in flammable and explosive environments shall be equipped with explosion-proof electrical appliances and equipped with static elimination and safety devices;

(6) The filling or dispensing equipment of the aseptic preparation should be operated in the corresponding clean room, and 100-level laminar flow clean air and positive pressure protection should be used locally;

(7) The design of chemical liquid, water for injection and purification of compressed air pipeline should avoid dead angles and blind tubes. Materials should be non-toxic and corrosion resistant. The inner surface should be electro-polished and easy to clean;

(8) When driving a small amount of foreign matter generated by friction or inevitably using a lubricant, the components should be closed and isolated from the working chamber, and the lubricant used should not cause pollution to drugs, packaging containers, etc.;

(9) The cleaning of aseptic equipment, especially the parts and parts that are in direct contact with the medicine, shall be marked with the date of sterilization and the aseptic effect verification if necessary. Equipment cleaning is equipped with CIP and SIP systems;

(10) Equipment design should meet the requirements of standardization, generalization, serialization and mechatronics. The continuous sealing of the production process and automatic detection are the guarantee for the full implementation of equipment GMP.

4 pharmaceutical equipment to prevent and control pollution in production

The complexity of the pharmaceutical process determines the diversity of equipment functions, while the pros and cons of pharmaceutical equipment are reflected in the ability to meet the requirements of use, compliance with GMP and environmental pollution prevention and control. In the production of pharmaceuticals, pharmaceutical equipment is the key means to ensure the quality of pharmaceuticals. The requirements of imported pumps for Castel Red Wine GMP are mainly aimed at reducing the pollution of pharmaceuticals in the production process and achieving the goal of ensuring the quality of pharmaceuticals. Prevention and control of pollution in terms of appearance structure, material selection and equipment verification.

4.1 functional aspects

4.1.1 purification function

Cleanliness is one of the main points of GMP. To achieve this standard, it is necessary to design a purification function in the processing of pharmaceuticals, where the cleanliness of the room where the drug is exposed does not meet the requirements or the possibility of contamination by man-machines. This form of functionality is not the same for different equipment requirements. The approximate is as follows:

(1) Equipment that uses gas in the process, especially gas and medicine or equipment that is in direct contact with the medicine packaging material, and the gas needs to be subjected to terminal filtration sterilization treatment, such as compressed air of a blister packaging machine;

(2) Washing bottles or other pharmaceutical packaging materials cleaning equipment should take into account the cleanliness of process water, generally using water for injection or purified water, such as washing machine, rubber stopper cleaning equipment;

(3) Equipment for generating dust during production shall be provided with a dust remover or a dust-collecting mechanism, such as a pulverizer, granulator, tablet press, etc.;

(4) In the clean room (area), purify and maintain the relative pressure difference between the functions by purifying the air conditioning system, preventing dust from spreading and preventing cross-contamination.

4.1.2 Isolation function

According to GMP requirements, the preparation process should avoid microbial or particulate pyrogen contamination, and isolation is a good method. Since the production of sterile products should be compounded, filled or dispensed and sealed in a high quality environment, and there are many variable influencing factors in the process, special requirements are imposed on the production of sterile drugs. An important manifestation of this in the design of the preparation equipment is to achieve the sealing of the production process and implement the isolation technology.

Isolation technology in the pharmaceutical industry involves the production of sterile products such as water needles, powder needles, and infusions, as well as the production of medical syringes. In aseptic production, in order to avoid contamination, it is necessary to design and establish an isolation area around the preparation equipment of the aseptic production process, to isolate the operator from the filling area, and to adopt a thorough isolation technology and automatic control system. The environmental impact of the operator can also greatly reduce the risk of microbial contamination of the product in a sterile production environment.

4.1.3 in-place cleaning and sterilization function

4.1.3.1 In-place cleaning (CIP)

In the production of pharmaceuticals, the cleaning and sterilization of equipment is the main means of repelling microbial contamination. CIP is a complete technical system that includes equipment, piping, operating procedures, cleaning agent formulations, automatic control and monitoring requirements. It can clean the dirt by using the circulating flow of the controlled cleaning liquid without disassembling or moving the equipment and piping as much as possible. GMP clearly stipulates that pharmaceutical equipment should be easy to clean. Especially when replacing products, all equipment, pipes and containers must be thoroughly cleaned and sterilized according to regulations to eliminate active ingredients and their derivatives, auxiliary materials, detergents, lubricants and environment. Cross-contamination of pollutants, elimination of foreign matter in the washing water and foreign matter and insoluble particles released during the operation of the equipment, reducing or eliminating the contamination of drugs by microorganisms and pyrogens.

4.1.3.2 In-situ sterilization (SIP)

SIP is another important aspect of GMP compliance for pharmaceutical equipment. The system that can adopt SIP is mainly a pipeline conveying line for a sterile production process, a preparation tank, a filtration system, a filling system, a water treatment system, and the like. SIP requires few disassembly operations and is easy to automate, thereby reducing pollution and other adverse effects caused by personnel.

Other sterilization methods are also worthy of attention. Such as: (1) using the ozone generator configured by the air conditioning system to sterilize the air in the clean area, can kill a variety of pathogenic microorganisms, has a wide spread, no dead angle, no toxic residues, no secondary pollution It has good environmental protection; (2) The sterilizing device should be installed at the outlet of purified water to ensure the quality of the purified water; (3) The UV lamp installed in the buffer chamber sterilizes the tools, materials and packaging materials entering the clean area.

4.1.4 Online monitoring and control functions

The online monitoring and control function mainly refers to the equipment having the analysis and processing system, which can automatically complete several steps or processes, which is also the premise of connection, linkage operation and control. GMP requires that the production of drugs should be continuous, and the time of process delivery is short, which can reduce the contact time between humans and drugs, and shorten the exposure time of drugs. This should be an important guiding ideology in equipment design and equipment transformation. The production practice proves that the joint engine group or the production line can organically connect the front and rear process equipment into a pipeline, effectively overcoming the cross-contamination caused by multiple reordering.

4.1.5 Security protection function

In order to ensure the quality of medicines and protect personal safety, the following points can be considered:

(1) Equipment used in flammable and explosive environments shall be equipped with explosion-proof electrical appliances, and shall be provided with safety alarm devices and safety devices. Such as a flammable gas alarm;

(2) Some have to consider protection under extreme conditions, such as "emergency braking" of high-speed equipment, high-pressure equipment "safety valve", etc.;

(3) Protection functions in the preparation equipment, such as no bottle stop irrigation, automatic waste, jam stop, foreign object rejection, etc., using instruments, instruments, computer technology to realize early warning, display, processing, etc. in equipment operation instead of manual and relying on Experienced operation can reduce waste and improve the automatic operation and automatic protection of the equipment.

4.2 Appearance structure

The use of pharmaceutical equipment involves varieties, batches, and frequent. In order to avoid the cross-contamination of materials and the reaction of components, it is essential to remove the dust and cleaning the inside and outside of the equipment, and the requirements are extremely strict. GMP requires that the shape of the equipment be clean and tidy for easy thorough cleaning.

(1) Emphasis on the simplification of the overall structure and shape, which is in terms of the whole device and the parts that must be exposed (including some visually visible parts). The simplification of the shape under the GMP point of view can make the irregularities, grooves, and stages in the conventional design of the equipment flat and simple, and can greatly reduce dust and dirt, and is easy to clean;

(2) For institutions that are not directly related to production operations, built-in and built-in styles should be designed as much as possible. Parts such as transmissions are designed to be built-in;

(3) The members in contact with the drug shall have a surface with a low roughness value of no adhering material. Polishing is an effective process. The polished objects are mainly stainless steel plates, castings, weldments, etc., and the polished outer contours should be simple and polished in place;

(4) The coated structure is common in pharmaceutical equipment and is also a simple means. The complex body, body, pipeline, and device are wrapped and sealed with a plate for a simple purpose;

(5) Lubrication is necessary for mechanical movement, and a considerable part of the pharmaceutical equipment is a tabletop movement. The moving shafts are concentrated and complex in structure, and are related to the production of pharmaceuticals, and the equipment also has specific requirements for cleaning. Under no circumstances should the lubricant or cleaning agent be in contact with the drug, including the possibility of falling in, infiltrating, etc. There are two main solutions: one is to use the barrier to the drug; the other is to block the lubrication part to ensure that the oil and cleaning water in the lubrication and cleaning are not in contact with the drug raw materials, intermediates and pharmaceutical ingredients.

4.3 Material aspects

GMP stipulates that the materials of the manufacturing equipment cannot affect the nature, purity and quality of the medicines, and the materials used must be safe, discernible and intensive. Therefore, when selecting materials, it should be considered that the equipment is in contact with the medium such as drugs, or does not react under corrosive and odorous environment, does not release particles, is not easy to suck or absorb moisture, etc., and reduces the phenomenon of running, running, leaking, dripping, etc. in production. To reduce the occurrence of safety accidents such as fires and explosions and to reduce pollution to the environment and drugs. Both metallic and non-metallic materials should have these properties.

4.3.1 Metal materials

Any equipment that is in contact with drugs or corrosive media and works in a humid environment should be made of austenitic stainless steel with low carbon content, titanium and titanium composite materials, and coated with iron, corrosion-resistant, heat-resistant and wear-resistant. Materials such as coatings should be handled with care. Other metal materials may be used in the above parts. In principle, parts made of these materials shall be surface treated. Second, it is necessary to pay attention to the consistency of the materials used in the same part (component). Stainless steel parts should not be used with ordinary bolts.

4.3.2 Non-metallic materials

Non-metallic materials are commonly used in pharmaceutical equipment. The principle of selecting such materials is non-toxic and non-polluting, that is, it should not be loose or easy to slag or lint. Special-purpose materials should also be considered in combination with the heat-resistance, oil-resistance, non-adsorption, and non-hygroscopic properties of the materials used. Sealing fillers and filter materials should be required to pay attention to hygienic performance.

4.3.3 Harm of material corrosion

Give an example of the danger of corrosion. A plant uses a multi-effect distilled water machine to produce water for injection. The pre-use test found that the pyrogen was unqualified, and the operator mistakenly believed that the shutdown time was long. According to the previous verification results, the pipeline and the storage tank were reprocessed, and the continuous operation for 3 days was qualified. However, after 1 week of continuous operation, it was not qualified. The operator then found the reason and used the segmentation test method to take the water from the outlet of the purified water to the outlet of the injection water. The inlet water of the multi-effect distilled water machine was qualified, and the outlet water was obtained. If it is unqualified, the problem is on a multi-effect distilled water machine. A sectional inspection was also taken. The result was that the silicone sealing ring of the multi-effect distilled water machine condenser was corroded and polluted by distilled water. After the sealing ring was replaced with PTFE material, the problem was solved and no later This type of problem has occurred. It can be seen that corrosion affects product quality.

4.4 Equipment verification

GMP always regards the verification of pharmaceutical production as an important content. Regardless of the verification, the equipment is the main inspection hardware of the verification process without exception. As far as production equipment is concerned, verification refers to a series of activities such as the reliability of the operation of the process equipment, the stability of the main operating parameters and the reproducibility of the operation results through the method of linkage test, so the actual meaning is the simulation production. GMP implements comprehensive control over various factors affecting the quality of drug production. The core is to ensure that the whole process of drug production is under quality control, and the probability of drug production quality accidents is reduced to a low point.

5 Conclusion

As the engineering and technical personnel and production management personnel of pharmaceutical companies, they must understand the manufacturing process of pharmaceutical preparations and the production management methods that meet the requirements of GMP, and the production of qualified medicines cannot be separated from the pharmaceutical equipment that meets GMP requirements. Only by fully understanding and mastering the basic requirements and management of GMP for pharmaceutical equipment, can we select the equipment for selection, operation, maintenance and maintenance, and only be good at discovering the key factors in the production process. Quality factors can improve equipment management and prevent pollution.

It can be seen that the significance of the prevention and control of pharmaceutical equipment in production pollution includes: (1) the basis for ensuring product quality; (2) the sign that the equipment function is perfect; (3) the requirement of GMP for pharmaceutical equipment; (4) (3) is the basis for equipment selection and management; (6) is the guarantee for smooth production; (7) is the development direction of equipment transformation and renewal.