As early as 1997, 21 CFR Part 11 stipulated that electronic records related to the approval and release of pharmaceutical products should adopt the same control requirements as paper records1, including proper access control for generating or maintaining electronic records Measures, record changes must be reflected in the record audit trail.
In 2003, FDA issued a guidance document emphasizing that the requirements specified in 21 CFR Part 11 should focus on relevant records required to achieve batch records and related records that can affect product release decisions2.
EU GMP Annex 113 adds risk assessment and system design or technical parameters to the core elements of access and signature control measures, thereby expanding the scope of application of electronic data and electronic signature requirements.
In 2018, the FDA issued a guidance document "Questions and Answers on Data Integrity and Drug cGMP Compliance 6" to the industry. According to the requirements of 21 CFR Part 210, 211 and 212, it clarified that data integrity is in the current Good Manufacturing Practice (cGMP) role in. The guidance document provides a more detailed definition of access controls, prescribed static and dynamic records, and other operational requirements to comply with the relevant rules. FDA requires that all data be accurate and reliable, while cGMP guidance requires risk-based strategies for detecting and preventing data integrity issues.
At the same time, the EU has re-examined the guidelines for electronic records, electronic signatures and the UK MHRA4, all based on ALCOA+ principles.
In December 2020, China's National Medical Products Administration (NMPA) began to implement the drug record and data management requirements (trial) regulations. Its basic requirements pointed out that in order to ensure drug quality and patient safety, it must , In use activities, ensure the authenticity, accuracy, completeness and traceability of the whole process information", which is also consistent with the ALCOA+ principle.
Filter testing principle:
1. Bubble point method test principle:
When the filter membrane and filter element are completely infiltrated with a certain solution, and then pressurized on one side through the air source (there is an air intake control system in our instrument, which can stabilize the pressure and adjust the intake air), as the pressure increases, the gas flows from the filter membrane The side of the membrane is released, indicating that bubbles of different sizes and numbers appear on one side of the membrane, and the corresponding pressure value judged by the instrument is the bubble point;
2. Test principle of diffusion flow method:
Diffusion flow test means that when the gas pressure is 80% of the bubble point value of the filter element, a large amount of gas has not yet penetrated through, but a small amount of gas first dissolves into the liquid phase diaphragm, and then diffuses from the liquid phase To the gas phase on the other side, this part of the gas is called diffusion flow;
3. Why the diffusion flow method is better:
The bubble point value is only a qualitative value. It is a relatively long process from the beginning of foaming to the final group of foaming, which cannot be accurately quantified. The measured diffusion flow value is a quantitative value, which can not only accurately determine the integrity of the filter It can also reflect the porosity, flow rate and effective filtration area of the membrane, which is why foreign manufacturers use the diffusion flow method to test the integrity;
4. Test principle of water intrusion method:
The water intrusion method is dedicated to the test of hydrophobic filter elements. The hydrophobic membrane resists water, and the smaller the pore size, the greater the pressure required to squeeze water into the hydrophobic membrane. Therefore, under a certain pressure, the water flow rate squeezed into the filter membrane is measured. To determine the pore size of the filter element.
When the solid particles in the suspension are large and uniform in size, the pores of the filtered filter residue layer are relatively smooth, and the speed of the filtrate passing through the filter residue layer is relatively high. Coagulants are used to assemble the fine particles into larger agglomerates, which is beneficial to increase the filtration speed. For suspensions with fast settling speed of solid particles, a filter that is fed on the upper part of the filter medium is used to make the filtering direction consistent with the direction of gravity, and the coarse particles settle first, which can reduce the clogging of the filter medium and filter residue layer; in difficult-to-filter suspensions ( Such as colloid) mixed with coarser solid particles such as diatomaceous earth, expanded perlite, etc., can make the filter residue layer loose; when the filtrate viscosity is high, the suspension can be heated to reduce the viscosity. These measures can speed up the filtering speed.
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