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Determining Acceptable Residue Limits in Cleaning Validation

An acceptable residue limit (ARL) is the upper level of residues allowed to remain on a product wherein consumer safety and subsequent product contamination remain controlled. It is part of the standards of cleaning validation undertaken in the pharmaceutical and biopharmaceutical industries.

Setting acceptable residue limits ensures that consumers remain unaffected by residues and that all products manufactured on a single manufacturing line are unaffected in efficacy and accuracy by leftover materials and chemicals.

Elements of Determining ARL

To define the level at which residues will not affect a product and subsequent products, chemical analysts must consider:

  • Dosage levels – Dosage levels are usually pre-determined during the research and development phase. Knowing the standard dosage helps develop a safe and accurate ratio of active pharmaceutical ingredients (APIs), excipients, and residues.
  • Batch sizes – Batch sizes are also usually pre-determined during the research and development phase. Knowing the batch size helps fine-tune the ratio of ingredients to residues to scale.
  • Equipment product contact surface areas – Vendors typically do not offer information on product contact surface areas or dimensions of surface areas. Knowing about these surface areas helps make clear what exposure products will have to surfaces during the manufacturing process.

To build a complete ARL for a pharmaceutical or biopharmaceutical product, a measurement of each product contact surface on the manufacturing equipment is necessary. Once the measurements are completed, they need only be measured again in the event of a fully documented change to manufacturing equipment or practices.

How ARLs Fit into Cleaning Validation

An established acceptable residue limit forms the foundation of a complete and uncompromising cleaning validation that meets required guidelines. It helps establish baselines for cleanliness and works in tandem with:

  • Visible residue limits (VRLs) – VRLs determine at what level a residue is no longer visible after cleaning. Viewing conditions are defined as well, which allow VRLs to be used to perform routine checks on cleaning validation procedures.
  • Worst-case residues – Through the creation of a worst-case matrix, it is possible to determine which residues will be the most difficult to clean and cause the greatest problems if not properly cleaned.
  • Recovery factors – It’s still imperative that manufacturers can prove that the equipment that has been cleaned underwent tests with swabs and rinses that accurately represent the cleanliness of equipment.

Studies that incorporate each level of cleaning validation help to build a more complete picture of the cleaning process back-to-front so that separate points of data do not have to be reconciled.

Getting the Most Accurate Acceptable Residue Limits

Accuracy is largely determined by the combination of data and careful analysis. Performing all studies together helps bolster accuracy and leaves less room for error. Prioritize the determination of acceptable residue limits to increase the efficacy and longevity of cleaning validation.

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