Production management of pharmaceutical enterprises under GMP system

Medical quality is related to patient safety and is also the lifeline of pharmaceutical companies. Therefore, following GMP with high quality is the only correct choice for pharmaceutical companies.

Production management is a key link in the formation of drug quality and the basis for the sustained and stable output of high-quality drugs. This article will focus on introducing the production management module from the aspects of process management, batch record management, prevention of contamination and cross-contamination, site clearance management, and material balance management.

Management of pharmaceutical: Process management

Process regulations and job operation methods are the basis of enterprise production technology management and the main basis for organizing and guiding production. Therefore, the procedures and job operation methods must be carefully prepared and strictly implemented.

1. Content

The contents of the production process regulations usually include: product name, dosage form, prescription, operating requirements of the production process, quality standards and technical parameters of materials, intermediate products, finished products and storage precautions, calculation method of material balance, requirements for finished product containers and packaging materials wait.

The content of the post operation method usually includes: production operation methods and key points, review and review of key operations, intermediate product quality standards and control, safety and labor protection, equipment maintenance and cleaning, abnormal situation handling and reporting, process hygiene and environmental sanitation, etc. .

2. Precautions

(1) The process procedures and post SOP must be strictly implemented during the entire production process, and no arbitrary changes are allowed.

(2) Weighing and feeding must be reviewed by someone, and both the operator and reviewer should sign.

(3) Intermediates in the production process should meet quality standards as the basis for handover and acceptance of the upper and lower processes. Unqualified products shall not flow into the next process.

(4) The production process should be verified and monitored according to the process verification requirements and quality control points, and accidents and errors should be prevented, discovered and eliminated in a timely manner and recorded.

(5) Process hygiene management during the production process should be managed in accordance with the requirements of the “Process Hygiene Management Regulations”. If deviations occur during the production process, they should be handled in accordance with the “Production Deviation Handling Management Regulations”.

Batch record management

1.Definition:

All documents and records used to record the production, quality inspection and release review of each batch of pharmaceuticals, which can trace all history and information related to the quality of the finished product.

2.Content

Batch records usually include product name, production batch number, production date, signatures of operators and reviewers, relevant operations and equipment, product quantities at relevant production stages, material balance calculations, production process monitoring records and special problem records.

In addition to the above, it should also include: production instructions, clearance copies of the last production, material weighing records (material batch numbers, quantities), intermediate product inspection reports and turnover records, finished product warehousing records, and records automatically printed by production equipment or facilities (Automatic weighing, automatic temperature control), the production plant environment includes on-site records of temperature, humidity, pressure difference, etc., cleaning and clearing records, process verification, deviation analysis, finished product inspection report, product release review form, etc.

3.Management process

(1) Blank batch production records are issued by the quality department according to product production batches.

(2) Batch production records are filled in by the post operator, reviewed by the team leader, and reviewed and signed by the workshop director.

(3) Compilation of batch production records (Production Management Department).

(4) Review of batch production records (Production Management Department).

(5) Preservation of batch production records (QA is responsible for archiving).

4.Fill in the requirements

(1) Batch production records must be approved by the production and quality management departments before they can be used.

(2) Records must be timely, the content must be true, the data must be complete, and the handwriting must be clear.

(3) Batch production records should be kept clean and tidy and must not be torn or arbitrarily altered. When making changes, sign the changes so that the original data remains legible.

(4) The product name cannot be abbreviated, and the signatures of the operator and reviewer must be filled in with their full names.

(5) Batch production records must be timely and specific, reflecting the entire production process. Each process should hand over the records when handing over the materials to the next process. After the production of a batch of products is completed, the records should be handed over to the production management department when the products are delivered to the warehouse.

(6) When reviewing batch production records, the record content must be compared with the production process procedures and job operating procedures; the quantity, quality, batch number, and container number in the upper and lower process and finished product records must be consistent and correct. Fill-in methods that do not meet the requirements during production must be corrected and signed by the person who filled in the form; if an abnormality is found, the cause must be identified, a reasonable explanation must be made, and detailed records must be made, and the operator and reviewer must sign.

(7) Batch production records should be filed according to batch number and kept until one year after the expiration date of the drug. For drugs that do not have a specified expiration date, their batch production records must be kept for at least three years.

Prevent contamination and cross-contamination

In order to control quality risks in the pharmaceutical production process and prevent contamination and cross-contamination of pharmaceuticals, the following measures can be taken during production operations:

(1) Before production, it should be confirmed that there are no leftovers from the previous production.

(2) The generation and spread of dust should be prevented. Positive pressure control should be maintained between clean areas and non-clean areas, and between different clean areas, and a relative negative pressure should be maintained in dust-producing rooms. Dust-generating operation rooms (such as drying, product sampling, weighing, mixing and other production operation rooms) should maintain a relatively 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 simultaneously in the same production operation room. When there are several packaging lines packaging at the same time, isolation or other facilities that can effectively prevent contamination and confusion should be adopted.

(4) During the production process, cross-contamination caused by gases, steam, sprays or organisms generated by materials and products should be prevented; raw materials and auxiliary materials or products should be prevented from being contaminated and cross-contaminated.

(5) At each stage of production, special rooms or laminar flow protection should be used to protect products and materials from microorganisms and other contamination, and to avoid secondary contamination of materials, containers and equipment after final cleaning or sterilization.

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Clearance management

1.Definition and purpose

In order to prevent confusion and errors, each production process should be cleared at the end of production and before changing varieties, specifications or batch numbers.

2.Clearing time

This must be done in a timely manner before each replacement of a new batch number or after the end of the production process.

3.Clearance record content

Including: process name, last batch of product name, production specifications, batch number, clearance date, inspection items and results, signatures of the person in charge of clearance and reviewer. Clearance records should be included in batch production records and accompanied by clearance certificates. The clearance certificate should specify a validity period, and should be re-inspected after the validity period. Without a copy of the previous batch clearance certificate, the workshop is not allowed to produce the next batch of products.

4.Frequency of cleaning: usually after the end of production every day, the surface of the equipment and the operation room should be cleaned; the cleaning should be carried out thoroughly when changing varieties and batch numbers; after the prescribed time of continuous production (usually three days), a thorough cleaning should also be carried out Clearing the site; after a long production interval, the site should also be cleared before starting production again.

5.Clearance requirements

(1) Cleaning materials: Clean, return, store, destroy, etc. all materials used in the production process (including raw materials, auxiliary materials, semi-finished products, intermediates, packaging materials, finished products, remaining materials, etc.).

(2) Keep the site clean and hygienic: there should be no dust or dirt on the ground, no dust on doors, windows, indoor lights, air ducts, walls, switch boxes and other casings. No items unrelated to the next production should be stored indoors.

(3) Clear status marks: Dispose of excess labels, instructions for use and other packaging materials in accordance with 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 in each batch. When the same equipment continuously produces the same sterile product, the cleaning cycle can be performed according to the production process regulations and standard operations. There are no chemicals left over from production inside and outside the equipment, and there is no grease.

(5) Non-special equipment, pipes, containers and tools: should be disassembled, washed and sterilized in accordance with regulations.

Material balance management

1.Definition

Comparison between the sum of the actual output or actual usage of a product or material and the collected losses and the theoretical output or theoretical usage, with due consideration of allowable normal deviations.

2.Function:

Calculating yield and conducting material balance in each key process is not only calculating production efficiency, but also one of the most effective ways to avoid or promptly detect errors and confusion.

3.Material balance includes two aspects:

first, the yield must be within the specified limit; second, it refers to the amount balance of printing packaging materials (labels, aluminum foil bags, etc.).

4.Yield qualification criteria

(1) Generally, the yield calculated by the material balance of each process is ≥99%; the total yield of this batch of products is >98%.

(2) Abnormalities in the material balance rate of packaging materials such as labels and instructions should be detected promptly.

(3) If there are special provisions in the production process regulations, the special requirements of the process regulations shall be followed.

5.How to deal with material balance exceeding/lowering the limit?

(1) When the material balance exceeds the limit, a tracking investigation must be carried out from the starting material according to the process. Only when the investigation results can prove that no errors have occurred, the investigation results will be recorded before the next step of production or judgment can be carried out. The product is qualified. At the same time, the causes will be evaluated and analyzed, and the balance limits will be revised if necessary.

(2) When the material balance is lower than the limit, investigate and analyze the cause, and only after confirming that there are no potential quality accidents can the product be processed as a normal product. The reason for the deviation should be clear and the explanation should be reasonable. Only after QA confirms that the product has been fully inspected and meets internal control standards can it be released.

6.When the material balance yield is within the range, submit it to the next process. When the yield reaches the specified requirements, the batch of products can only leave the factory after passing the inspection.

7.Issues affecting material balance

(1) The process is immature, the feed and output are unstable, and the deviation is large.

(2) The verification work is rough, the material balance is not strictly examined and analyzed, and the limit standards are too large or too small.

(3) The actual output of individual materials is difficult to weigh or calculate.

Medicine production is a complex system engineering involving many links. Negligence in any aspect may affect the quality of medicines. Therefore, pharmaceutical companies must strictly follow 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 use the concept of quality by design to systematically identify all key aspects of production and follow the same principles to achieve stable and continuous manufacturing of high-quality pharmaceuticals.

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