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An audit should focus on the quality-critical processing steps that are necessary to produce an excipient that meets the established physical and chemical criteria. These steps should be identified and controlled by the excipient manufacturer. Quality-critical processing steps can involve a number of unit operations or unit processes.

Quality-critical steps can include, but are not limited to, the following:

  • phase changes involving the desired molecule, solvent, inert carrier or vehicle (for example dissolution, crystallisation, evaporation, drying, sublimation, distillation or absorption),

  • phase separation (for example filtration or centrifugation),

  • chemical changes involving the desired molecule (for example removal or addition of water of hydration, acetylation or formation of a salt),

  • adjustments of the solution containing the molecule (for example pH adjustment),

  • precise measurement of added excipient components, in-process solutions, recycled materials (for example weighing or volumetric measurements),

  • mixing of multiple components,

  • changes that occur in surface area, particle size or batch uniformity (for example milling, agglomeration or blending).

A5. Audit Check Points


good approach for an excipient plant audit is a review of the following areas: nonconformances, such as the rejection of a batch that did not meet specifications, customer complaints, return of a product by a customer or retrieval of a product. The manufacturer should have determined the cause of the non-conformance, a report of the investigation prepared and subsequent corrective action initiated and documented. Records and documents should be reviewed to ensure that nonconformances are not the result of a poorly developed or inconsistent process, customer complaint files, such as reports that some aspect of the product is not entirely suitable for use, since these may be caused by impurities or inconsistencies in the excipient manufacturing process, change control logs to ascertain whether the company evaluates their significant changes to decide if the customer and/or regulatory authority should be notified, nonconforming products meeting or Material Review Board documents and/or equivalent records that demonstrate that the disposition of nonconforming product is handled in an appropriate manner by responsible individuals, master formula and production records for frequent revisions that may reveal problems in the excipient production process, evidence for the presence of unreacted intermediates and solvent residues in the finished excipient, materials management systems to ensure adequate control over nonconforming materials so they cannot be sold to customers or used in manufacturing without authorisation, review of a process flow diagram to aid understanding of the various processing stages. The critical stages and sampling points should be identified as part of the review of the processing records, review of contamination control measures.

In evaluating the adequacy of measures taken to prevent contamination and cross-contamination of materials in the process, it is appropriate to consider the following risk factors:

Copyright © 2006 The International Pharmaceutical Excipients Council and Copyright © 2006 Pharmaceutical Quality Group

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