Prevention and control measures for pollution of pharmaceutical equipment in production process

1 factors affecting the quality of drugs

The quality of the drug is related to the safety of the patient's drug use. To produce a quality and qualified drug, there must be 3 elements: (1) qualified personnel; (2) the software conforming to GMP, such as reasonable dosage forms, prescriptions and processes, qualified raw and auxiliary materials, various specifications and management systems, and (3) conforming to the hardware of the GMP, including a qualified production ring. Environment and production conditions, the required factory buildings, equipment and so on.

2 meaning of pharmaceutical equipment to prevent and control pollution in production

From the above we can know that production environment and production conditions and equipment are one aspect affecting the quality of pharmaceutical products. In the production of medicines, the pollution of production environment and production conditions usually includes microorganisms, dust, particles, corrosion, errors and cross contamination. The prevention and control of the pollution in the production of the pharmaceutical equipment contains two layers of meaning. The first equipment itself does not pollute the drug itself, nor does it pollute the environment; and second should have effective means of controlling pollution. To this end, GMP has made a number of guidelines for pharmaceutical equipment directly involved in the production of drugs. The basic points are to guarantee the quality of the drug, to prevent the possible pollution of the drug in the production process, and to affect the environment and the harm to the health of the human body. Therefore, the design of pharmaceutical equipment should meet the requirements of GMP, reduce pollution factors, and have a good prevention and control of pollution.

3 the design of pharmaceutical equipment meets the requirements of GMP

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

(1) the design of the equipment should be in accordance with the requirements of the production and process of drugs. It is safe, stable, reliable, easy to clean, disinfect or sterilize, so as to facilitate the operation and maintenance, and to prevent errors and cross pollution.

(2) the material selection of the equipment should be strictly controlled. Parts that are directly exposed to drugs should be non-toxic, non corrosive, chemically reacted with drugs, and do not release particles or adsorb drugs.

(3) as far as possible, the surface of the equipment directly contacting with the drug and the surface of the working parts shall not be designed as bolts, trenches and exposed bolts. The surface should be smooth, smooth, without dead angle, easy to clean and disinfect.

(4) the equipment should not pollute the environment outside the device. In view of the different pollution caused by each kind of equipment, relevant measures should be taken to prevent the dust, leakage, heat insulation, and noise prevention.

(5) equipment used in flammable and explosive atmospheres shall be equipped with explosion-proof electrical appliances and equipped with electrostatic and safety protection devices.

(6) the equipment for filling or packing sterile preparations should be run in the corresponding clean rooms, and the 100 level laminar clean air and positive pressure protection should be adopted locally.

(7) the design of liquid medicine, water for injection and purification of compressed air pipe should avoid dead corners and blind pipes. The material should be nontoxic and corrosion-resistant. The inner surface should be electrified and polished and easy to clean.

(8) when the trace of the foreign body produced by friction or the use of lubricants can not be avoided, the components should be closed and isolated from the workroom. The lubricants used should not cause pollution to drugs, packaging containers and so on.

(9) sterilization of sterile equipment, especially the sterilization of parts and components directly exposed to drugs, should indicate the date of sterilization, and sterility test is necessary if necessary. Equipment cleaning is best equipped with CIP and SIP systems.

(10) equipment design should meet the requirements of standardization, generalization, serialization and mechatronics.

It is a guarantee for the full implementation of equipment GMP to realize continuous closed and automatic detection of production process.

4 measures for prevention and control of pollution in production by pharmaceutical equipment

The complexity of the pharmaceutical process determines the diversity of the equipment function, and the advantages and disadvantages of the pharmaceutical equipment are reflected in the ability to meet the requirements, to meet the GMP and to prevent and control environmental pollution. In the drug production, the pharmaceutical equipment is the key means to ensure the quality of the drug. The requirements of the GMP equipment are mainly aimed at reducing the drug pollution in the production process and to ensure the requirements of the drug quality. The pharmaceutical equipment can prevent and control the pollution in the aspects of function, 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 must be in the process of drug processing. The purify function should be designed on the principle that the cleanliness of the room area of the drug exposure can not reach the requirement or the human machine pollution is possible. This function form of different equipment requirements is also different. Roughly as follows:

(1) in the process of using gas equipment, especially the gas and drug or the equipment that contact with the material directly, the gas needs to be filtered by terminal filter, such as the compressed air of the blister packing machine.

(2) the cleaning equipment for washing bottles or other pharmaceutical packaging materials should take into account the cleanliness of the process water, the general use of water or purified water, such as the water washing machine, rubber plug cleaning and other equipment.

(3) equipment for dust generation in production should be equipped with dust remover or dust collecting mechanism, such as grinder, granulator, tablet press, etc.

(4) in the clean room (area), through purifying the air conditioning system to purify and maintain relative pressure between the various functions, it can prevent dust dispersion and prevent cross contamination.

4.1.2 isolation function

In accordance with the requirements of GMP, the preparation process should avoid microbial or particulate pyrogen pollution as far as possible. Isolation is a good method. As the production of aseptic products should be batching, filling or packing and sealing under high quality environment, there are many variable influencing factors in the process, and special requirements for the production of aseptic drugs are put forward. This is an important embodiment in the design of preparation equipment, which is to realize the closed production process and implement isolation technology.

The isolation technology in the pharmaceutical industry involves various aspects, such as water needle, powder injection, infusion and other sterile products, as well as the production of medical syringes. In aseptic production, in order to avoid pollution, it is necessary to design and establish a isolation area around the preparation equipment of the sterile production process, separate the operator from the filling area, take a thorough isolation and automatic control system, minimize the influence of the operator on the environment, and also greatly reduce the aseptic production ring. The risk of microbial contamination in the product.

The cleaning and sterilizing function of 4.1.3 in the position

4.1.3.1 incumbent cleaning (CIP)

In pharmaceutical production, cleaning and sterilization of equipment is the main way to eliminate microbial contamination. CIP is a set of technology systems including equipment, piping, operation procedures, cleaning agent formulation, automatic control and monitoring requirements. The utility model can clean the dirt by using the circulating flow of controlled cleaning liquid as far as possible without dismantling or moving equipment and pipelines. GMP clearly stipulates that pharmaceutical equipment should be easily cleaned, especially when the products are replaced, all equipment, pipes and containers must be thoroughly cleaned and sterilized to eliminate the cross contamination of active ingredients and their derivatives, accessories, cleaners, lubricants, environmental pollutants, and the removal of residual foreign objects and equipment for washing water. The release of foreign matter and insoluble particles in the process can reduce or eliminate the pollution of microorganisms and pyrogen to drugs.

4.1.3.2 in sterilizing (SIP)

SIP is another important aspect of GMP for pharmaceutical equipment. The system that can adopt SIP is mainly pipeline transportation line, preparation kettle, filtration system, filling system, water treatment system and so on. SIP requires minimal disassembly and operation, and is easy to automate, thereby reducing the pollution and other adverse effects caused by personnel.

Other sterilization methods are also worth paying attention to. Such as: (1) using the ozone generator configured by air conditioning system to sterilize the air in the clean area, it can kill a variety of pathogenic microorganisms, there is a wide spread, no dead angle, no toxic residue, no two pollution, good environmental protection; (2) the export of purified water should be set up sterilization device to ensure the export quality of purified water. (3) the ultraviolet lamp installed in the buffer room sterilize the tools, materials and packaging materials that enter the clean area.

4.1.4 on-line monitoring and control function

On-line monitoring and control function mainly refers to the equipment with analysis and processing system, which can automatically complete the functions of several steps or processes. This 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 transmission is the shortest. This can reduce the contact time between people and drugs and shorten the time of drug exposure. This should be an important guiding ideology in equipment design and equipment reform. The production practice has proved that the linkage unit or production line can organically connect the front and back process and equipment into the pipeline, effectively overcoming the cross pollution caused by the repeated sequence of sequence.

4.1.5 security protection function

In fact, in order to ensure the quality of drugs and protect personal safety, we should consider the following points:

(1) equipment used in flammable and explosive atmospheres should be protected by explosion-proof electrical appliances and equipped with safety alarm devices and safety devices. Such as flammable gas alarm;

(2) some should also consider the protection under unusual circumstances, such as "emergency brake" of high speed running equipment, "safety valve" of high voltage equipment, etc.

(3) the protection function in the preparation equipment, such as no bottle stop irrigation, automatic discarding, blocking and stopping, foreign object elimination, and so on, using instrument, instrument, computer technology to realize the operation of early warning, display and processing in equipment operation instead of manual and experience operation, can reduce the waste products, complete the automatic operation and automatic protection of the equipment.

4.2 aspect structure aspect

In order to avoid cross contamination of materials and react to ingredients, it is essential to remove the dust from the internal and external parts of the equipment and to clean the adhesive and so on. GMP requires that the neat shape of the equipment be specified for achieving thorough cleaning.

(1) emphasize the simplification of the overall structure and form, which is a part of the whole equipment and must be exposed (including some visible parts). In the view of GMP, the simplification of the shape can make the concave, convex, grooves and tables in the routine design of the equipment smooth and concise, and can minimize the dust and pollution, and be easy to clean.

(2) as far as possible, there is no direct relationship between production and operation. Such as transmission and other parts of the design into a built-in type;

(3) the components with the drug contacting part should have the surface with low roughness value. Polishing treatment is an effective process. The polishing objects are mainly stainless steel plates, castings, weldments and so on, and the exterior contours should be concise and polished.

(4) coated structure is the most common and convenient means in pharmaceutical equipment.

The complex body, body, pipeline, and equipment are coated and sealed to achieve the goal of conciseness.

(5) lubrication is necessary for mechanical movement, and a considerable part of the pharmaceutical equipment belongs to the mesa movement. The dynamic axis of the moving rod is centralized and the structure is complex. It is also related to the production of drugs, and the equipment has specific requirements for cleaning. No matter what circumstances, lubricants and detergents should not be contacted with drugs, including the possibility of falling and infiltration. There are two kinds of solutions: one is the use of drug barrier; the two is the barrier to the lubricating part, so as to ensure that the oil and cleaning water in the lubrication and cleaning do not contact with the pharmaceutical ingredients, intermediates and pharmaceutical ingredients.

4.3 material aspects

GMP stipulates that the material of the manufacturing equipment can not affect the nature, purity and quality of the drug, and the material used should be safe, discriminability and use. Therefore, when selecting materials, we should consider the contact between the medium of equipment and drugs, or not to react in the corrosive and odorable environment, do not release particles, not easily absorb or absorb moisture, so as to reduce the phenomenon of running, risking, leakage and drop in production, reducing the occurrence of safety accidents such as fire and explosion, and reducing pollution to the environment and medicine. Dyed. Both metal and non-metallic materials should have these properties.

4.3.1 metal material

Any equipment that is in contact with a drug or corrosive medium and works in a wet environment should be made of low carbon austenitic stainless steel, titanium and titanium composite. It should be handled carefully for the manufacture of the materials coated with corrosion resistant, heat-resistant and wear-resistant iron. Other metal materials can be selected from other parts. All parts made of these materials in principle should be treated on the surface. Secondly, the consistency of materials used in the same part (part) should be noticed. Stainless steel parts should not be equipped with ordinary bolts.

4.3.2 nonmetallic materials

In the general use of non metal materials in pharmaceutical equipment, the principle of choosing this kind of material is nontoxic and non polluting, that is, it should not be loose or easy to drop and hair. Special uses should also be considered in combination with the properties of heat resistant, oil resistant, non absorbent, and non hygroscopic properties of the materials used, and the requirements for hygienic performance should be paid attention to sealed packing and filter materials.

The damage of 4.3.3 material corrosion

One example shows the harm of corrosion. A factory uses multi effect distilled water machine to produce water for injection. Before use, it finds that the pyrogenic substance is not qualified, and the operator misunderstands the reason for the long outage. According to the previous verification results, the pipes and tanks can be reprocessed for 3 consecutive days. However, the continuous operation for 1 weeks did not qualify, the operator then found the reason, the use of sectional detection method, from the export of purified water to the export of water injection test, found that the inlet water of the multi effect distiller is qualified, the water of the water is not qualified, the problem is on the multi effect distiller. The result is that the silicone sealing ring of the condenser of the multi effect distiller is corroded, the distilled water is polluted, and the seal ring is changed into polytetrafluoroethylene, and the problem is solved, and no such problem has occurred in the future. It can be seen that corrosion affects the quality of the product.

4.4 equipment verification

GMP always regards the validation of drug production as an important part. No matter what verification, the equipment has become 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 by the method of linkage test, so the practical significance is the simulation of production. GMP has carried out comprehensive control of various factors affecting the quality of drug production. The core is to ensure the whole process of drug production under quality control, and to reduce the probability of the quality of the drug production to the lowest point.

5 Conclusion

As the engineering and technical personnel of the pharmaceutical enterprises and the production managers, the manufacturing process of drug preparation and the production management methods that meet the requirements of GMP must be understood, and the production of qualified drugs can not be separated from the pharmaceutical equipment that meets the requirements of the GMP.

Only by fully understanding, and mastering the basic requirements and management of GMP for pharmaceutical equipment, can we do well in the selection, operation, maintenance and maintenance of the equipment, and only be good at finding out the factors that affect the quality of the product in the process of production, so as to improve the management of equipment and prevent the occurrence of pollution.

It can be seen that the prevention and control significance of pharmaceutical equipment to production include: (1) is the basis to guarantee the quality of the product; (2) is the symbol of the perfect function of the equipment; (3) is the requirement of GMP for the pharmaceutical equipment; (4) to provide a guarantee for GMP verification and acceptance of the national GMP certification; (5) is the basis for the selection and management of the equipment; (6) the production is carried out smoothly. Protection; (7) is the development direction of equipment transformation and renewal.