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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 may give the lowest purification process cost.

It is possible to develop and validate a cleaning process that meets FDA requirements, so the Flash cartridge can be used for multiple runs. This cleaning process is the user responsibility. SiliCycle does not warranty any Flash cartridge for multiple injections and all process validation is the clients’ responsibility.

Please see www.fda.gov/ohrms/dockets/dailys/04/oct04/101904/03n-0059-c00004-01-vol1.pdf, for the Guidance for Industry ChromPac, Manufacturing Chromatography Systems Post-Approval Changes: Chemistry, Manufacturing and Controls Document, submitted to Docket #03N-0059 Pharmaceutical cGMPs by bhr PDA for detailed discussion

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

Activated carbon cartridges

Activated carbon is typically used to adsorb trace levels of contaminants. The large surface area, complex surface chemistry and strong adsorption characteristics makes cleaning impractical. These cartridges do not have a reliable or validated process to ensure adequate cleaning of activated carbon, whether it is used in traditional batch mode or in a flow through cartridge format.

Therefore, it is recommended that Flash carbon cartridges be used for a single run, or until breakthrough of impurity is seen, then flushed and discarded.

Silica flash cartridges

Porous silica is used in adsorption chromatography processes, where the product and its impurities “bind” to the surface at different strengths. 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 or these impurities may elute in a subsequent run. Clearly, if the user wants to use the cartridge for a second or subsequent run, the process will require a validated cleaning protocol.

Some guidelines are given below:

  • 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.
  • 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. The user must demonstrate each of the multiple injections gives the same elution profile and that the product purity is consistent in each of the sequential runs. Typically, users will set the process control points 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.
  • 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 a user is considering this multiple lot strategy, the cleaning process will require a high level of data to support the decision*.
  • Used for multiple batches of multiple API
    SiliCycle is not aware of any user who has developed a validated process to run multiple different API’s on a single silica cartridge. 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.

C18 flash cartridges

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 full validated cleaning procedure must be implemented. If a user is considering this multiple lot strategy, the cleaning process will require a high level of data to support the decision*.

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 (typically methanol, ethanol or acetonitrile) in the elution mixture, often carried out in reverse flow mode. The cartridge must be re-equilibrated, in normal flow mode, with the initial solvent mix prior to the next injection. The cleaning step and re-equilibration step will each use a minimum of 3-column volumes each of solvent.

SiliCycle recommends that Flash C18 cartridges be dedicated to an individual API and never be used for multiple API compounds.

 

(*) 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 user must set and define the upper and lower control limits 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 may be prohibitive.