Analysis of composite film for packaging of the ho

Analysis of composite film for drug packaging (II)

2. GMP management of composite film for drug packaging

GMP is the abbreviation of good manufacturing prac tices fordrugs in English. GMP can be literally translated as "good production practice". Of course, what we refer to here is the production of drugs. The full name of GMP in China is "good manufacturing quality management practice". Food and cosmetics can also be produced with reference to GMP, that is, "forfood" and "forcosmetic". European and American countries began to implement GMP certification in the food industry in the early 1980s, and Taiwan began to implement GMP certification system in the food industry in 1989. GMP is the inevitable product of human scientific and technological progress and the development of management science. It is produced to meet the needs of ensuring the quality management of drug production. GMP originated abroad and was born as a catalyst for major drug disasters

the United States enacted the first food and drug administration act in 1906. From 1935 to 1937, the United States used dinitrophenol to lose weight, resulting in 177 deaths from cataracts and bone marrow suppression. In 1937, the United States used diethylene glycol as a solvent for the sulfanilamide elixir event, resulting in 107 deaths. In 1938, the United States amended the original food and Drug Act, changed it into the food, drug and Cosmetics Act, and added some prohibitions, The safety of food and drugs was emphasized

thalidomide, a drug used for pregnancy reaction, was produced by the former Federal German pharmaceutical factory Glen nansu from 1956 to 1962. In fact, it is a 100% teratogenic drug. In the six years after the drug was sold, more than 12000 severely deformed fetuses were found in 28 countries including Germany, Australia and Canada. At present, thousands of people still survive, causing a great burden to the society. The teratogenesis incident caused public anger in the world, forcing some governments to strengthen the management of listed drugs. The United States learned the lesson of the sulfa elixir incident in 1938. At that time, FDA refused to import the drug due to the lack of sufficient clinical trial data found in the review of flame retardant 2.0~3.0, thus avoiding this disaster. However, the serious consequences of the protective net of the concrete pressure testing machine caused anxiety in the United States, and eventually led to major amendments to the food, drug and cosmetics act by Congress. The United States Congress promulgated the world's first GMP in 1963. For the first time in the pharmaceutical industry, the quality control of drugs has been transferred from simple quality inspection to comprehensive control of quality inspection and production process in the form of legal inquiry. In the afternoon of 1971, the United States Centers for Disease Control reported an epidemic of sepsis, which was related to intravenous drugs. As of March 6, 1971, 150 cases of sepsis were found in the United States, which rose to 350 cases a week later, and 405 people more than 20 days later. FDA cancelled the intravenous drug on April 22nd, 1971 and conducted an investigation. FDA found through investigation that most of the indicators and data in the production and control process are incomplete, and the data obtained in the production process cannot be used as a basis to support product quality and disinfection. Therefore, it is necessary to test the production control implemented to see whether the purpose has been achieved, thus producing the verification theory of GMP. The emergence and development of GMP validation marks a new stage of GMP management

gmp management has shifted the focus of control from finished product inspection to comprehensive control of the production process. One prominent example is the "parametric release method" introduced into the EU GMP guidelines. The so-called "parameter release method" refers to that the final sterilized product can decide whether to release the product according to the parameters of process operation, especially the monitoring data of the inspection of contaminated bacteria in the product to be sterilized, the sterility guarantee value of the sterilized product given by the sterilization procedure and relevant records, and there is no need to carry out seedling free inspection on the finished product. The European Pharmacopoeia explains the reason for implementing the "parameter release method": for the final sterilized products, the basis and various evidences that show that the whole batch of products meet the requirements in the sterilization process are much better than the reliability of sterility inspection. Canceling the sterility inspection of final sterilized products does not reduce the requirements, but improves the requirements of process control, moving the control focus forward and implementing it in the production process

throughout the development of GMP, GMP management has shifted the focus of control from quality control based on finished product inspection to comprehensive control of production process, and introduced and strengthened dynamic management. China's 1998 GMP clearly stipulates that the relevant records should be reviewed by the quality management department before the release of drugs. The review contents should include: the review of the batching and weighing process, the inspection records of various production processes, the site clearance records, the quality inspection results of intermediate products, deviation treatment, and the inspection results of finished products, which meet the requirements, and can be released only after being signed by the reviewers. The purpose of implementing GMP is to enable pharmaceutical enterprises to establish an effective operation quality system, so that all behaviors of enterprises are regulated, monitored and recorded, so as to minimize human errors, prevent confusion and cross pollution, and ensure product quality

as one of the excipients of drugs, the composite film for drug packaging has a significant impact on the product quality of drugs, so GMP management should be carried out according to the relevant requirements of drugs

① it must meet the requirements of GMP to control human errors to a minimum

in order to reduce human errors to a low level, GMP requires the formulation of detailed management documents, so that everything can be done in accordance with the rules, and there is a record. For example, cleaning, China's GMP (revised in 1998) stipulates that the contents of cleaning procedures should include: cleaning methods, procedures, intervals, cleaners or disinfectants used, cleaning methods and storage locations of cleaning tools, cleaning inspection and evaluation, etc. After the formulation of a procedure, whether it has achieved the expected purpose must be verified. Verification is not only the touchstone to check whether the manufacturer really implements GMP, but also a mirror. The implementation of unverified GMP is blind and lacks basis, which is not reliable before the use of the puncture device. The so-called "verification" refers to a series of activities that can prove that any procedure, production process, equipment, materials or system can indeed achieve the expected results in the process of implementing GMP. In other words, verification is a prescribed procedure that requires it to establish a documented and reliable scheme, which can improve high reliability, To ensure that a specific process can consistently produce products that meet the predetermined specifications and quality standards. The key point of verification is to determine the number of influencing factors, which variables are important variables, and the qualified range of these variables, and then the continuous control of these variables (as shown in the figure). Only in this way can the drug quality be formed in the "verified" production process

② the production quality management of composite film for drug packaging must meet the requirements of CMP to prevent pollution and mixing

the types of pollution generally include microorganisms, particles (dust, etc.) and foreign substances (such as pollen). In order to prevent pollution, there must be sanitation, including environmental sanitation, process sanitation and personnel sanitation

clean workshop is the most important measure to prevent pollution and mixing. Many studies have proved that air is the carrier and disseminator of pollutants. The role of air purification system is to maintain environmental quality, which is designed for the special needs of drugs and related products. Air cleanliness refers to suspended particles in the air that may cause damage (≥ 0.5 μ m) The degree of quantity. The air cleanliness level is based on the maximum allowable suspended particles per cubic meter of air. If there are many suspended particles, the cleanliness is low. The air cleanliness of the clean room (area) for the production of pharmaceutical packaging materials is divided into four levels

it can be seen from the table that as a clean room in the pharmaceutical industry, it is not only limited to suspended particles of non living particles, but also includes living suspended particles (bacteria), and it is not limited to suspended particles. "Clean" is a complex with requirements for air exchange rate, static pressure difference, temperature, humidity, illumination, etc. Suspended particles and microorganisms mainly affect the purity, cross contamination and sterility of products; Temperature and relative humidity mainly affect the product process conditions and bacterial reproduction conditions, as well as the impact of operating comfort on product quality; The number of air changes affects cleanliness and personnel comfort; Static pressure difference affects cleanliness. According to the provisions of the appendix of the good manufacturing practice for drugs (1998), the cleanliness level of the exposure process of the final treatment of packaging materials in direct contact with drugs should be the same as that of the drug production environment. For the exposure process of non terminally sterilized oral liquid drugs, external use of deep tissue trauma, exposure process of ophthalmic drugs, and exposure process of intraluminal drugs except rectal drugs, the minimum production environment requirements are 100000 levels. For the exposure process of terminally sterilized oral liquid drugs, exposure process of oral solid drugs, exposure process of epidermal drugs, and exposure process of rectal drugs, the minimum production environment requirements are 300000 levels. Since most of the drugs packaged by the composite film for drug packaging are produced in the environment of 300000 level, the requirements for the clean room (area) for the production of packaging materials and containers in direct contact with drugs organized and formulated by the state drug administration stipulates that the production environment requirements for the printing, compounding, curing, cutting, bag making, inner packaging and material buffer of the composite film for drug packaging are 300000 level cleanliness. However, due to the production environment of individual composite films for drug packaging requires 100000 levels, and the design and manufacturing cost of 100000 level plants is almost the same as that of 300000 level plants. At the same time, foreign GMP has no cleanliness of 300000 levels, only 100000 levels. In order to be in line with international standards, in the long run, many clean plants with composite membranes for pharmaceutical packaging are designed according to 100000 levels

for the management of the clean plant, the 1998 GMP appendix has made some provisions, such as the number of personnel in the clean area should be strictly controlled, its staff should be regularly trained and assessed in the basic knowledge of hygiene and microbiology, clean operations, etc., and the temporary outsiders entering the clean area should be guided and supervised. Buffer facilities must be set between the clean area and the non clean area, and the direction of people flow and logistics should be reasonable, Clean work clothes in areas above 100000 should be washed, dried and sorted in the clean area. If necessary, they should be sterilized as required. The air purification system should be cleaned, repaired and maintained as required, and records should be kept

③ the production quality management of composite film for drug packaging must meet the requirements of GMP quality management system

quality management has experienced the development process of operator quality management, inspection quality management, statistical quality management and prevention oriented total quality management. As an after the fact quality management, there are problems of poor prevention, misjudgment and missed inspection. At the same time, some products are quite complex and cannot be inspected. Some products will gradually expose various quality problems only after being used for a period of time, so they are not suitable for the production quality management of life-threatening drugs with high safety requirements. As the standard of drug production quality management, GMP is a comprehensive quality management, which shifts the focus of control from finished product inspection to process control, and introduces the concept of strengthening dynamic management. GMP management is based on process control, combines prevention and control, takes various methods to identify actual or potential quality problems, and takes preventive and remedial measures to eliminate quality problems in the formation process, so as to