I. Material system
In the production of aseptic drugs, the quality attributes of each material (Raw materials, water for injection, packaging materials that directly contact the drug) are related to the key quality attributes of the final product. The procedures for the receipt, pending inspection, sampling, inspection, release, storage, distribution and use of production materials of the enterprise should be checked to confirm their applicability. For the sampling requirements, please refer to the sampling appendix of GMP (Amended in 2010). Material system inspections should focus on sterile and/or purchased materials without pyrogen.
Areas of particular concern for an aseptic product material management system include:
1. Water system
Water for injection is a component of many sterile products. Water for injection is also used for depyrogenation (or endotoxin) and cleaning of equipment and rubber plugs.
(1) Observe and understand the elements of the water production system and distribution system.
(2) Evaluate the as-built drawings of the water system, check for leaks, pipeline slope (by checking axonometric drawings and slope angles), dead ends, non-sanitary fittings in the distribution system, etc.
(3) Evaluate how to establish microbial alert limits and correction limits.
(4) Evaluate sampling points, procedures, frequency, and testing.
(5) Review critical equipment preventive maintenance and calibration procedures, including planning and equipment renewal procedures.
(6) Check the original data to confirm that the above work has been completed according to the procedure.
(7) Check and observe routine monitoring of water system (on-line TOC and conductivity).
(8) Check trend data for chemical, microbiological, and bacterial endotoxin tests.
(9) Check investigations for results at or above the alert and corrective limits.
2. Pure steam
Pure steam is mainly used for moist heat sterilization and other processes, such as sterilization of equipment and pipes, with direct contact with equipment or item surfaces, or contact with other items that may affect product quality. When pure steam is condensed, it must meet the requirements of water for injection, and at the same time, it is necessary to monitor non-condensable gas, superheat value, drying value and other items.
3. Process gas
Control of process gas and related equipment can be checked in conjunction with facility and equipment systems. Particular attention should be paid to the control of process gas terminal filtration steps and filter integrity testing, including inert gases used to protect the product.
4. Materials
The level of microbial contamination of materials should be minimized. When necessary, the quality standards of materials should include microbial limit, bacterial endotoxin or pyrogen inspection items.
(1) Disposable rubber plug
Manufacturers of preparations using disposable rubber plugs should conduct strict audits on rubber plug suppliers and add endotoxin and visible strange things inspection items to the internal control quality standards.
(2) Microbial and bacterial endotoxin detection of materials
Evaluate the company’s material management system to determine whether or not to establish and justify standards for microbial or bacterial endotoxin testing. Review test data to confirm that materials meet standards. If the standard is not met, confirm whether an investigation is carried out to determine the cause and implement corrective action.
(3) Standard confirmation of packaging materials in direct contact with drugs
The physical and chemical properties of packaging materials that come into direct contact with pharmaceutical products are critical to the sterility and stability of the final product. Some packaging materials that come into direct contact with pharmaceutical products appear similar (color and size), but are made of different materials or have different surface treatments, such as siliconized rubber plugs and Type I glass ammonium sulfide treatment. Therefore, the relevant evaluation procedures of the establishment should be checked to ensure that packaging materials that come into direct contact with pharmaceutical products always meet the appropriate standards.
The completeness of packaging materials that directly contact drugs is very important for sterile products, so it is also necessary to check whether the company has verified the correctness of the material and size of packaging materials that directly contact drugs through testing.
(4) Integrity of packaging materials in direct contact with drugs
Inadequate sealing of container-seals can lead to product contamination. Therefore, the integrity of packaging materials that come into direct contact with pharmaceutical products is critical to ensuring that products remain sterile during transportation, storage, and use. Tests and studies to evaluate the integrity of all sterile product packaging materials that come into direct contact with medicinal products should include at a minimum:
①Check that all incoming container-seal assemblies meet the standards, including specifications and dimensions.
② Confirm that the corresponding research work fully simulates the sterilization process conditions, including the worst conditions in processing and storage.
③Confirm that an appropriate sample is used for the verification test. For example, for terminally sterilized products, the selected test samples should have undergone the specified maximum number of sterilizations.
④The sensitivity of the test is described in detail.
⑤The container-seal integrity should be demonstrated by verification as part of the stability study program (which can be replaced by sterility testing) and should cover the expiration date of the product.
(5) Material transfer
Packaging materials that come into direct contact with the product should follow the simplest route during the delivery process of cleaning, sterilization, and use. Packaging materials that directly contact the product during the delivery process should be sealed and stored in a manner that avoids secondary pollution. The material transfer process must pay attention to the transfer method to prevent secondary pollution, such as: transfer according to the specified operation process, packaging method and corresponding measures, storage time, etc.