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Flash Cartridges Cleaning and Use

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Pre-packed flash cartridges are designed and typically used for a single purification run (1-injection). Single-use gives the highest purification performance and the lowest solvent consumption. It is typically the easiest process to validate and it may give the lowest purification process cost. However, it is possible to develop and validate a cleaning process that meets FDA requirements, so that the flash cartridge can be used for multiple runs. This cleaning process is the client’s responsibility. SiliCycle does not warranty any flash cartridge for multiple injections and all process validation is under the client’s (sole) responsibility.

The following are guidelines for flash cartridge use in cGMP environments:

1. Cleaning silica cartridges for normal phase separations

Porous silica is used in adsorption chromatography processes, where the product and its impurities “bind” to the surface with varying degrees of affinity. The solvent polarity is increased to desorb the product and its impurities at different elution volumes. While it is possible to elute nearly all the product from silica, some impurities typically remain at the end of each separation. If the cartridge is not fully cleaned, this remaining material may reduce the purification effectiveness and these impurities may elute in a subsequent run. Clearly, if the cartridge is planned to be used for a second or subsequent run, the process will require a validated cleaning protocol.

Some guidelines are given below:

  • 1a. Single injection of a single batch of one API
    In this case, the cartridge is eluted and the purified product is collected. The cartridge is flushed and then discarded. This single-use process has the minimum solvent consumption and no-risk of cross-contamination
  • 1b. Multiple injections of a single batch of one API
    In this process, the full batch is too large to purify in a single run, and therefore multiple runs are required. Each injection is from a single batch or lot, and therefore the product and its impurities are identical in each injection or sample load. The cartridge must be cleaned between runs, but no cross-contamination is possible between batches.

    Re-using silica cartridges for multiple injections within a single batch is a well accepted process decision. It must be demonstrated that each of the multiple injections gives the same elution profile and that the product purity is consistent in each of the sequential runs. Typically, the process control points are set to ensure that the impurity profile does not change more than 0.1 %.

    This process can be modeled at the lab or pilot scale and then demonstrated at full production volume. In this process, the cleaning solvent is often 100 % of the most polar solvent in the elution mixture and is often carried out in reverse flow mode. The cartridge must be re-equilibrated, in normal flow mode, with the initial solvent conditions prior to the next injection. The cleaning step and re-equilibration step will each use a minimum of 3 column volumes of each solvent.

  • 1c. Multiple batches of one API with single or multiple injections
    Silica is rarely used for multiple batches of a single API, due the high cost and technical risk of batch-to-batch contamination. If multiple lot strategy is nonetheless considered, the cleaning process will require a high level of data to support the decision. The data set must include analytical methods, such as HPLC and/or GC, and data to determine residue analysis. The standard assay is Total Organic Carbon (TOC) analysis. The upper and lower control limits must be set and defined for this process. The FDA does not set a number, but many organizations have used 1/1000 of a therapeutic dose of Product A in Product B as a guideline. This is a very challenging requirement, and the cost of cleaning solvents and time invested may be prohibitive.
  • 1d. Multiple batches of multiple APIs
    This multiple product cleaning protocol would require an extremely high level of data and would still have significant risks of cross contamination. The cost of cleaning and validation would also be very high.

    It is recommended that flash cartridges be dedicated to an individual API and never be used for multiple API compounds.

2. Cleaning C18 cartridges for reversed-phase separations

Reversed-phase media is often used for multiple batches of a single API. However, due to the high cost and technical risk of batch-to-batch contamination, a fully validated cleaning procedure must be implemented. If a multiple lot strategy is nonetheless considered, the cleaning process will require a high level of data to support the decision. The data set must include analytical methods, such as HPLC and/or GC, and data to determine residue analysis. The standard assay is Total Organic Carbon (TOC) analysis. The upper and lower control limits must be set and defined for this process. The FDA does not set a number, but many organizations have used 1/1000 of a therapeutic dose of Product A in Product B as a guideline. This is a very challenging requirement, but the cost and type of media require a strict validated clean and re-use protocol. However the cost of cleaning solvents and time invested may still be prohibitive.

The cleaning protocol can be modeled at the lab or pilot scale and then demonstrated at full production volume. In this process, the cleaning solvent is often 100 % of the most polar solvent in the elution mixture (typically methanol, ethanol or acetonitrile), and is often carried out in reverse flow mode. The cartridge must be re-equilibrated, in normal flow mode, with the initial solvent conditions prior to the next injection. The cleaning step and re-equilibration step will each use a minimum of 3 column volumes of each solvent.

It is recommended that C18 flash cartridges be dedicated to an individual API and never be used for multiple API compounds.

 

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