Focuses of Validation of Pharmaceutical Liquid Mixing Process System

Category: 

Quality by Design, Risk by Perception

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

When observing the liquid mixing process system, one should focus on its purpose. Different purposes of the liquid mixing process systems influence different aspects of the product quality, e.g. in terms of criticality the semi-finished product preparation system for non-terminally sterilised products slightly differs from the liquid mixing process system for upstream buffer preparation in the biological product raw liquid production.

During the development of most liquid preparations, the focus lies on endotoxin, bioburden and product content (including homogeneity). However, temperature and content (including homogeneity) are usually checked during preparation of upstream buffers. The endotoxin and bioburden are also inspected for upstream buffers of many biological products. Similarly, the control indexes for oral liquid are completely different, especially for the viscous liquid and suspensions. Here, the main focus lies on mixing homogeneity. The following table lists the product types of the liquid mixing process system, and the corresponding product quality information.

 

                                                        Upstream solution                                Concentration, temperature, and microbial limit

Biological products                   Media                                                          Asepsis (or sterilization)

                                                        Downstream buffer or                            Concentration, temperature (if needed), homogeneity,
                                                        chromatography elution, etc                 microbial limit, and endotoxin                                                         .                 

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Blood products                           Protein separation                                   Concentration, temperature, homogeneity, and endotoxin

                                                        Purification                                                Concentration, temperature (if needed), homogeneity,
                                                                                                                             microbial limit, and endotoxin

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Terminally sterilized                Concentrated solution                             Concentration, and homogeneity
products​                                       preparation  

                                                       Diluted solution preparation                   Concentration, homogeneity, and microbial limit

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Non-terminally sterilized       Preparation                                                Concentration, homogeneity, microbial limit                                                                                                           
products                                                                                                           (filtration sterilization), and temperature (if needed)

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Oral liquid                                   Preparation                                               Concentration, homogeneity, and microbial limit

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Aseptic suspensions and        Preparation                                               Concentration, homogeneity, asepsis, and endotoxin   
emulsions (non-terminally
sterilized)

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Gels and creams                        Preparation                                               Concentration, homogeneity, viscosity, and temperature
non-aseptic) 

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Gels and creams                        Preparation                                                Concentration, homogeneity, viscosity, temperature,
(aseptic)                                                                                                             asepsis, and endotoxin

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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 should be calibrated at initial use, and the recalibration should 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.