Production management of pharmaceutical enterprises under GMP system
- Categories:Technical articles
- Time of issue:2022-12-13
Production management of pharmaceutical enterprises under GMP system
- Categories:Technical articles
- Time of issue:2022-12-13
Drug quality is related to the safety of patients and is also the lifeline of pharmaceutical companies. Therefore, high-quality compliance with GMP is the only correct choice for pharmaceutical companies.
In the last article we introduced the quality management module of one of the six systems for GMP inspection. Production management is the key link of drug quality formation and the basis of continuous and stable output of high quality drugs. This paper will focus on process management, batch record management, pollution prevention and cross-contamination, clearance management, material balance management to introduce the production management module.
Process rules and post operation method are the basis of enterprise production technology management and the main basis for organizing and guiding production, so we must carefully prepare and strictly implement the rules and post operation method.
The contents of the production process procedures usually include: product name, dosage form, prescription, operation requirements of the production process, quality standards and technical parameters of materials, intermediate products and finished products as well as matters needing attention in storage, calculation method of material balance, requirements of finished product containers and packaging materials, etc.
The contents of post operation method usually include: production operation methods and key points, review and review of key operations, quality standards and control of intermediate products, safety and labor protection, equipment maintenance and cleaning, abnormal situation handling and reporting, process and environmental hygiene, etc.
(1) The whole process of production must strictly follow the process rules and post SOP, and shall not be changed arbitrarily.
(2) weighing and feeding to be reviewed, the operator, review should be signed.
(3) The intermediate in the production process shall meet the quality standards as the basis for the handover and acceptance of the upper and lower processes. Non-conforming products shall not flow into the next process.
(4) Process verification and monitoring shall be carried out in accordance with process verification requirements and quality control points in the production process, timely prevention, discovery and elimination of accident errors and good records.
(5) The process hygiene management in the production process shall be managed according to the requirements of the "Process hygiene Management Procedures". If any deviation occurs in the production process, it shall be handled according to the "Production Deviation Management Procedures".
Batch record management
1. Definition: All documents and records used to describe the production, quality inspection and release review of each batch of drug product, and to trace all history and information related to the quality of finished product.
Batch records usually include product name, production batch number, production date, operator's, rechecker's signature, related operation and equipment, product quantity in related production stage, material balance calculation, production process monitoring records and special problem records.
In addition to the above, it should include: Production instructions, clearance copies of last production, weighing records of materials (batch number and quantity of materials), inspection reports and turnover records of intermediate products, storage records of finished products, records of automatic printing of production equipment or facilities (automatic weighing, automatic temperature control), on-site records of temperature, humidity, pressure difference, cleaning and clearance records of production plant environment. Process verification, deviation analysis, finished product inspection report, product release audit, etc.
3. Manage the process
(1) Blank batch production records shall be issued by the quality Department according to the production batches.
(2) Batch production records shall be filled in by post operators, reviewed by the team leader, reviewed and signed by the workshop director.
(3) Batch production record arrangement (Production Management Department).
(4) Batch production record review (Production Management Department).
(5) Keeping batch production records (QA is responsible for archiving).
4. Fill in the requirements
(1) Batch production records shall be approved by the production and quality management department before being used.
(2) The record should be timely, the content should be real, the data should be complete, and the handwriting should be clear.
(3) Batch production records shall be kept clean and tidy, and shall not be torn or arbitrarily altered. When a change is made, the change is signed and the original data is still recognizable.
(4) The name of the product shall not be abbreviated, and the operator and the reviewer shall fill in the full name of the signature.
(5) Batch production records shall be timely and specific, reflecting the whole process of production operation. The records of each process should be handed over together when the material is handed over to the next process. After the production of a batch of products is finished, the records should be handed over to the production management Department together when the products are handed over to the warehouse.
(6) To review the batch production records, it is necessary to check the recorded content with the production process rules and post operation rules; The quantity, quality, batch number and container number in the upper and lower process and finished product records must be consistent and correct. The filling method that does not meet the requirements in production must be corrected and signed by the fillers; If abnormal circumstances are found, the reasons must be identified, reasonable explanations must be made, and detailed records must be made. The operator and the reviewer must sign.
(7) Batch production records shall be filed according to the batch number and kept until one year after the expiry date of the drug. For drugs with no prescribed period of validity, batch production records shall be kept for at least three years.
Prevent contamination and cross contamination
In order to control quality risks in drug production and prevent drug contamination and cross-contamination, the following measures can be taken in the production operation:
(1) No production residue shall be confirmed before production.
(2) The generation and diffusion of dust should be prevented. Positive pressure control should be maintained between clean and unclean areas and between different clean areas. Relative negative pressure should be maintained in the dust-producing room. Dust production operation room (such as drying, product sampling, weighing, mixing and other production operation room) should maintain relative negative pressure, and take special measures to avoid cross contamination and facilitate cleaning.
(3) Production operations of different product varieties and specifications shall not be carried out in the same production operation room at the same time. When several packaging lines are packed at the same time, isolation or other effective facilities should be used to prevent contamination and confusion.
(4) In the process of production, cross-contamination caused by gases, vapors, sprays or organisms produced by materials and products should be prevented; Raw materials or products should be prevented from contamination and cross contamination.
(5) In each stage of production, special chamber or laminar flow protection should be adopted to protect products and materials from microbial and other pollution, and avoid secondary pollution after final cleaning or sterilization of materials, containers and equipment.
1. Definition and purpose
In order to prevent confusion and error, each production process shall be cleared before the end of production and the conversion of variety, specification or batch number.
2. Clearance time
Each time before changing the new batch number or after the end of the production process, timely.
3. Clear the contents of the records
Including: process name, last batch product name, production specifications, batch number, date of clearance, inspection items and results, signature of clearance person and rechecker. The clearance record shall be included in the batch production record and accompanied by the clearance certificate. The clearance certificate shall stipulate the period of validity, after which the inspection shall be carried out again. No clearance certificate copy is approved and the workshop is not allowed to produce the next batch of products.
4. Frequency of clearance: usually after the end of production every day, the equipment surface and operation room should be cleaned; When changing the variety and batch number, it should be cleaned thoroughly. After the specified time of continuous production (generally three days), it should also be completely cleared; After a long production interval, it should also be cleared before production starts again.
5. Clearance requirements
(1) Clean materials: All materials used in the production process (including raw materials, auxiliary materials, semi-finished products, intermediates, packaging materials, finished products, residual materials, etc.) shall be cleaned, returned, stored and destroyed.
(2) Clean the site health: the ground is free of dust and dirt, the doors and Windows, indoor lights, air pipes, walls, switch boxes and other shells are free of dust, and no items unrelated to next production are allowed to be stored indoors.
(3) Clear status mark: excess labels, instructions and other packaging materials shall be disposed of according to regulations.
(4) Clean equipment, pipes, containers and tools: if they are in direct contact with drugs, they should be cleaned or cleaned every day or every batch. When the same equipment continuously produces the same sterile product, the cleaning cycle can be carried out according to the production process and standard operation. There are no drugs left over from production inside and outside the equipment, no oil scale.
(5) Non-special equipment, pipes, containers, tools: shall be disassembled, washed and sterilized according to the regulations.
Material balance management
Step 1 Define
The comparison of the sum of the actual production or consumption of a product or material and the collected losses to the theoretical production or consumption, with due regard to allowable normal deviations.
2. Function: Calculating yield and material balance in each key process is not only calculating production efficiency, but also one of the most effective ways to avoid or timely detect errors and confusion.
3. Material balance includes two aspects: one is that the yield must be within the specified limit; Second, it refers to the balance of the amount of printing and packaging materials (indicators, aluminum foil bags, etc.).
4. Evaluation criteria for qualified yield
(1) The yield calculated by the material balance of each process is ≥99%; The total yield of this batch of products >98% is qualified.
(2) Abnormal material balance ratio of labels, instructions and other packaging materials should be found in time.
(3) If there are special provisions in the production process regulation, the special requirements of the process regulation shall be followed.
5. How to deal with material balance exceeding/below the limit
(1) When the material balance exceeds the limit, tracing and investigation must be carried out from the starting material according to the process. Only when the clear investigation results can prove that there is no error, the investigation results shall be recorded before the next step of production or the product can be judged as qualified. At the same time, the causes are evaluated and analyzed, and the balance limit is revised if necessary.
(2) When the material balance is lower than the limit, it can be treated as normal products after investigation and analysis of the reasons and confirmation of no potential quality accidents. The reason for the aberration shall be clear, the explanation shall be reasonable, the product shall be confirmed by QA, and the product shall be fully inspected and meet the internal control standards before it can be released.
6. When the material balance yield is within the range, submit to the next process. When the rate of finished products reaches the specified requirements, the batch of products can leave the factory only after they pass the inspection.
7. Related issues affecting material balance
(1) The process is not mature, feeding, output is not stable, large deviation.
(2) The verification work is rough, the material balance is not strictly investigated and analyzed, and the limit standard is too large or too small.
(3) The actual output of individual materials is difficult to weigh or calculate.
Drug production is a complex system engineering, involving many links. Any negligence in any link may affect the quality of the drug. Therefore, pharmaceutical enterprises should strictly comply with the requirements of GMP. They should not only formulate and implement relevant rules and regulations in the above aspects to ensure the quality of drugs, but also systematically identify all key aspects of production and follow the same principles of management with the concept of quality comes from design, so as to achieve stable and continuous manufacturing of high-quality drugs.
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