Focuses of Validation of Pharmaceutical Liquid Mixing Process System

Quality by Design,Risk by Perception

[Abstract] The pharmaceutical liquid mixing process system is a production process system that directly affects the final product quality, therefore, it shall be validated. It is very crucial regarding how to confirm the focuses of validation.

 [Keywords] Liquid mixing process; validation; direct influence on system; biological products; blood products; aseptic preparations; oral liquid

With the improvement of the industrial technology and computer technology, the automatic liquid mixing process system with CIP/SIP function is increasingly used in the Chinese pharmaceutical industry to replace the simple independent liquid mixing tank to complete the preparation of various materials in the pharmaceutical process. The pharmaceutical liquid mixing process system is considered as a production process system that directly affects the final product quality, therefore, it shall be validated.

When considering the validation of the liquid mixing process system, the main consideration is its purpose. Liquid mixing process systems of different purposes will have different influences on the product quality, for example, the semi-finished product preparation system for non-terminally sterilized products will be slightly different from the liquid mixing process system for upstream buffer preparation in the biological product raw liquid production in terms of criticality. Endotoxin, bioburden, and product content (including homogeneity) are focused on during preparation of most liquid preparations, while temperature, and content (including homogeneity) are usually controlled during preparation of upstream buffers, and the endotoxin, and bioburden shall also be inspected for the upstream buffers of many biological products; similarly, the control indexes for oral liquid will be much different, especially for the viscous liquid and suspensions, the mixing homogeneity is the main focus. The following table lists the product types of liquid mixing process system and the corresponding product quality information for attention.

The following aspects need to be considered during validation of almost all liquid mixing process systems:

• Materials of all components in contact with feed liquid;
• Calibration of instrument and apparatus (all instruments and apparatuses shall be calibrated at initial use, and the recalibration shall be determined according to the results of risk analysis);
• Slope and emptying (including pipeline and value);
• Control (PLC or computer system) and permissions;
• Maintenance space (depending on the usage);
• Training (supplier’s training on the equipment use and notice for the owner, and training on relevant internal documents of the owner, such as training on deviation, change, record, and other SOPs);
• Validation of relevant documents (URS, FS, DS, and use and maintenance instructions);
• At the time of OQ: the first-draft operation, cleaning, and maintenance SOPs written by the user;
• At the time of PQ: the approved operation, cleaning, and maintenance SOPs written by the user;

 [Author profile] Zhang Gongchen, expert in the pharmaceutical industry, mainly engaged in research and practice of pharmaceutical fluid and biological process system, expert of committee for national pharmaceutical engineering design competition of China, ISPE training expert, expert for training inspectors of China Food and Drug Administration, and editorial board member of the Chinese national standard GB50913-2013 Code for design of pharmaceutical water system.

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