As an important part of the modern biomedical field, the safety and effectiveness of biological products are directly related to the health and life of patients. In this process, the tightness of the container is undoubtedly one of the key factors to ensure the quality of biological products. In this article, we will examine the importance of CCI (container closure integrity) for biologics reference products from three aspects: regulatory basis, low-temperature tightness risk, and implementation method.
1. Basis of laws and regulations.
In the field of drug supervision, countries have strict regulations that require the packaging and containers of drugs to be regulated. For biologics, the tightness of the containers is particularly stringent due to their special production processes and storage needs. For example, authorities such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have made it clear that the containment integrity of containers must be continuously monitored and controlled throughout the life cycle of a drug. This is not only reflected in the research and development stage of new drugs, but also throughout the whole process of drug production, storage, transportation and use.
China's drug regulatory authorities also attach great importance to the issue of container tightness of biological products. In the "Good Manufacturing Practice" (GMP) and other relevant regulations, the test methods and standards for the tightness of drug packaging and containers are clearly stipulated, and enterprises are required to ensure the tightness of drugs during storage and transportation, so as to prevent the invasion of external microorganisms and harmful substances and ensure the quality and safety of drugs.
2. Low temperature tightness risk.
Biologics often need to be stored and transported at low temperatures to maintain their activity and stability. However, low temperatures can also pose a challenge to the tightness of containers. For example, some plastic products can become fragile at low temperatures, increasing the risk of container breakage or leakage. In addition, temperature changes can also cause changes in the pressure inside the container, which in turn can affect the tightness of the container.
Material shrinkage and embrittlement:
At low temperatures, many plastic materials experience shrinkage, resulting in a smaller size, which can affect the tight fit between the container and the lid, reducing the sealing effect. At the same time, embrittlement of the material is also a problem, making the container more susceptible to physical damage, such as cracking or cracking, increasing the risk of leakage.
Difference in coefficient of thermal expansion:
Different materials have different coefficients of thermal expansion. When the temperature changes, these differences can lead to stress concentrations between parts of the container, especially when the container is composed of multiple materials (e.g., plastic bottles vs. metal caps). This stress can lead to seal failure or deformation of the container.
Material Selection Restrictions:
Due to the special requirements of the low temperature environment for materials, not all materials are suitable for cryogenic storage of biological products. Some materials that perform well at room temperatures may lose their elasticity and sealing properties at low temperatures. Therefore, when choosing a container material, it is important to consider its performance at low temperatures, which limits the range of available materials.
Stress change response:
Low temperatures are often accompanied by changes in pressure, especially when containers are transferred or transported to different altitudes. This pressure change can pose a challenge to the tightness of the container, especially for those that are not fully rigid. To address this risk, the vessel needs to be designed with a pressure relief mechanism in mind or a material that can withstand pressure changes.
Third, the way to achieve.
Ensuring container tightness for biologics reference CCI requires a multi-faceted approach. First of all, in the selection and design phase of the container, its sealing performance needs to be fully considered. For example, materials and structural designs with good sealing properties can be selected to reduce the risk of leakage in the container.
Secondly, in the production and packaging process, the production process and packaging operation need to be strictly controlled to ensure that the tightness of the container is not compromised. In addition, it is also necessary to establish a sound testing system to monitor and spot the tightness of containers in the production process in real time.
Finally, during storage and transportation, the tightness of the container also needs to be continuously checked and controlled. For example, a sample of a reference material in storage can be sampled at regular intervals to assess changes in its sealing performance. At the same time, it is also necessary to establish a sound emergency plan to deal with possible emergencies such as container leakage.
Tightness study services
Mingjie Pharmaceutical has a complete set of equipment, including microbial challenge method, color water method, helium mass spectrometry, vacuum attenuation method, pressure attenuation method, laser gas headspace analysis method, and high voltage discharge method.
Part 1 is fully equipped
1.A variety of methods are available.
Since there is no universal method for tightness research, it is necessary to make a reasonable choice according to the characteristics of the packaging and the characteristics of the preparation, so it is necessary to equip a variety of equipment to deal with different situations.
2.Leak detection of cryogenic frozen samples.
The glass transition temperature of rubber: tg=-60, it will become hard and brittle at -40-45, and the shrinkage rate is significantly greater than that of glass, resulting in the risk of leakage. The common cryopreservation temperature of biological agents is -20 and -80, and even liquid nitrogen cryopreservation (-196) will be used for RNA vaccines and cell lines.
However, vacuum attenuation is not suitable for the detection of cryogenic samples, as the moisture contained on the surface of the cryogenic sample is removed and vaporizes in the vacuum chamber, resulting in a false positive signal. Minjie is equipped with cryogenic helium mass spectrometry, which can detect the risk of leakage in the storage of cryogenic frozen samples with high sensitivity.
3.Avoid biologics that cannot be detected after plugging the hole.
At present, the vacuum attenuation method is the most widely used method in the industry, but this method cannot avoid the problem of hole plugging detection due to the biological agent contacting the punching position. At present, it seems that 50% of the items will be undetectable by the vacuum decay method due to hole blocking.
Mingjie is equipped with pressure decay and high voltage discharge to deal with such problems, and all projects can be detected 100% with reasonable equipment.
4.Laser drilling equipment and metering equipment are complete.
Mingjie's laser drilling can complete the drilling and metering of as low as 1 m. Mingjie participated in the drafting of local standards in Shanghai and can issue CNAS measurement reports.
Part 2 Method development, transfer and on-site support
1.The support method is transferred back to the customer.
Each method is equipped with a variety of equipment, including a variety of domestic and imported equipment, which is convenient for customers to choose and support the transfer of methods after verification - helping customers to implement their methods.
2.In-depth research.
In order to verify the feasibility of a method, we need to do a full set of methodological validations for each method.
3.On-site support.
Mingjie provides on-site verification and technical support, and can provide on-site support for a variety of situations, including 100% full inspection of high-voltage discharge method, color water intrusion method. Provide services such as method development, method validation, and equipment PQ.